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					        PROCEEDINGS OF THE
  8TH EUROPEAN WORKING GROUP ON
    GAUCHER DISEASE (EWGGD)
                   4th to 7th June 2008

                  BUDAPEST, HUNGARY




  Published by the European Gaucher Alliance on behalf of the EWGGD.
EWGGD Supplement                      1                         JULY 2008
                                                                                                           June 2008

Dear Friends,

At the opening of the EWGGD in Budapest this year we thought it right to consider the rationale behind the
formation of the organization and also to examine its future. Our initial aim was to bring together clinicians and
scientists, industry and patients and to provide a forum for open discussion. The EWGGD was born as a daughter
of the older, highly successful organization, the European Working Group for Lysosomal diseases (ESGLD). The
EWGGD was to be the forum for presenting unpublished scientific data and free discussion with colleagues who
have different perspectives as to how we should address unanswered questions - as well as to develop the best
clinical practices.

In some ways the EWGGD has become a victim of its own success. Much has been learned about Gaucher Disease,
clinical practice has developed rapidly since our first meeting in Trieste in 1992. Moreover, the interest of
pharmaceutical companies in Gaucher and other Lysosomal Disorders has burgeoned. Many of these companies
hold their own meetings (of varying scientific quality and openness) and there is clearly a danger that the
independence of our already fragile community will become fractured.

These rapid changes in the whole field have created the need for a more formalized structure – an aspect that,
perhaps naively, we did not have in place when the EWGGD was founded. However, in response to widely canvassed
and positive opinions from all stakeholders in Budapest, we are determined to continue the EWGGD and maintain
its original precepts within the emerging world. This, we feel, will require the involvement of the EGA – once a
small acorn but now a mighty tree!

In Budapest, as always, we had a truly international meeting: we focussed on what we need to investigate and on
aspects of the disease where treatment does not yet meet all the needs of patients. Several very innovative findings
of substantial clinical significance were presented - freely and in advance of publication. We highlighted areas that
demand much more work and turned the spotlight on fresh challenges to address before we meet at the next
EWGGD.

One emerging theme is the responsibility felt by those of us who have long been in the field to encourage younger
clinicians and scientists to take an interest in this fascinating and multi-faceted condition which, in many ways has
led the way for advances in other challenging lysosomal disorders. We want to bring about better career and
attractive training opportunities for them.

Our early decision to involve patients in the proceedings of the EWGGD was not only the correct - it has proved to
be extremely fruitful. Gaucher patients are, after all, at the centre of everything that we do, whether we are
scientists, health care professionals or work in industry: their active participation in the activity of the EWGGD has
helped us and inspired all our work.

We were especially pleased therefore that the EGA took the initiative and has offered to publish the proceedings
of the EWGGD and to make them available to all who are interested. We thank all the officers of the EGA for their
faith in our organization and their generosity in seeing though our work together.

Professor Hans Aerts                   Professor Timothy Cox
Chairman                               Vice-Chairman
EWGGD                                  EWGGD


EWGGD Supplement                                                2                                          JULY 2008
                                                                               C/o Gaucher Association UK
                                                                                 Tel: 00 44 1453 549231
                                                                               E-mail: ga@gaucher.org.uk




                                                                                                            June 2008

                        Dear Friends,

                        I am delighted on behalf of the European Gaucher Alliance (EGA) to bring to you this
                        Publication of the proceedings of the eighth European Working Group on Gauchers Disease
                        (EWGGD) held in Budapest on 4th to 7th June 2008.

The EWGGD was the catalyst for the founding of the original EGA. It was the initiative of Professor Hans Aerts and
Professor Timothy Cox to involve patient groups at the very first EWGGD in Trieste and it was at that meeting that
the groups came together to form the first EGA. The group was initially small and although successful was largely
reactive. A group of leading members met earlier this year and decided that the time had come to formalise our
structure. As many of you will know the 24 countries present at the meeting of the EGA prior to the EWGGD
unanimously agreed to incorporate the EGA into a formal body, to speak for Gaucher patients on a Pan European
level. Membership of the EGA is open to official patient associations that represent the interest of Gaucher
patients. Full membership (which entitles a member to vote at annual meetings) is open to patient organisations
from all European countries. Associate membership (which is welcomed but carries no voting rights) is available
to official patient associations from countries from other parts of the world.

Patients have always welcomed the opportunity to attend at and participate in the meetings of the EWGGD. By
sponsoring the dissemination of the proceedings at the EWGGD the EGA is seeking to meet one of its prime
objectives which is to ensure the latest information on Gaucher Disease is disseminated as widely as possible. All
papers have been approved and are published with the authority of the presenters. I especially thank Dr Nicholas
Smith and Dr Robert Ayto for all their hard work in writing up the presentations. We hope recipients will find this
publication useful and informative.

The EGA will be seeking to work with clinicians, scientists and industry in any way it can to address unmet medical
need, to enhance the impact of clinical treatment and to encourage scientific research so as to achieve its goal of
addressing the needs of Gaucher patients whatever and wherever they may be.

I feel honoured to have been elected the first Chairman of the “new” EGA and on behalf of my Executive Board
offer our services to all who are working in the field of Gaucher Disease. If we are able to help you in your vital
work, we will be fulfilling our mission.

Yours sincerely

JEREMY MANUEL OBE
CHAIRMAN
EUROPEAN GAUCHER ALLIANCE




EWGGD Supplement                                               3                                            JULY 2008
Index of Presentations in order of delivery
• LIMP-2 is a receptor for lysosomal mannose-6-phosphate independent targeting of â-
  Glucocerebrosidase.
  Paul Saftig, Christian-Albrechts University, Kiel, Germany.                                                p7

• Pathophysiology: liver and lung manifestations
  Pramod Mistry, Yale University School of Medicine, New Haven, CT, USA                                      p7

• A new type 1 Gaucher Disease severity score index for the phenotypic classification and
  evaluation of responses to treatment.
  Maja Di Rocco, University of Genoa, Italy.                                                                 p8

• Development of a disease severity scoring system for type 1 Gaucher Disease
  Stephan Vom Dahl, St Franziskus-Hospital, Academic Teaching Hospital, University of Cologne, Germany p8

• Saposin C deficiency
  Anna Tylki-Szmanska, Children’s Memorial Health Institute, Warsaw, Poland                                  p9

• Insulin resistance in Gaucher Disease
  Mirjam Langeveld, Academic Medical Centre Amsterdam, The Netherlands.                                      p9

• Gaucher Disease and Cancer
  Derralynn Hughes, Royal Free and University College Medical School, London, UK                            p10

• Dose Response Relationships in Gaucher Disease
  Stephan Vom Dahl, St Franziskus-Hospital, Academic Teaching Hospital, University of Cologne, Germany p10

• Monitoring skeletal response in Type 1 Gaucher Disease
  Jack Goldblatt, School of Paediatrics and Child Health, University of Western Australia, Australia        p11

• A multicentre, randomised, dose frequency study of the safety and efficacy of Cerezyme
  infusions every 4 weeks versus every 2 weeks in the maintenance therapy of patients with
  type I Gaucher Disease
  Atul Mehta, Royal Free Hospital and University College London, London, UK                                 p11

• Recent advances in type 3 Gaucher Disease
  Ashok Vellodi, Metabolic Unit, Great Ormond Street Children’s Hospital, London, UK                        p12

• Existing and Novel ERT approaches
  Ari Zimran, Shaare Zedek Medical Centre, Jerusalem, Israel                                                p12

• Non-Enzyme Replacement Therapy treatment options for Gaucher Disease
  Deborah Elstein, Shaare Zedek Medical Centre, Jerusalem, Israel                                           p13

• Experience with SRT
  Pilar Giraldo, University of Zaragoza, Zaragoza, Spain                                                    p13

• Bone mineral density and Substrate Reduction Therapy
  Gregory Pastores, New York University School of Medicine, New York, USA                                   p14

• A phase 2 clinical trial of the pharmacological chaperone AT2101 for the treatment of
  Gaucher Disease.
  Neil J. Weinreb, University Gaucher Treatment Center, Tamarac, Florida, USA.                              p14

• Development of novel orally administered non-viral gene therapy for Gaucher disease using
  DNA nanoplexes encapsulated in yeast cell wall particles.
  Edward Ginns, University of Massachusetts Medical School, Worcester, MA, USA                              p15

• Neurological complications in type 1 Gaucher Disease
  Carla Hollak Academic Medical Centre, University of Amsterdam, The Netherlands.                           p15

•   The neurological manifestations of type I Gaucher Disease: The French Observatoire on
    Gaucher Disease (FROG)
    Patrick Cherin, University Pierre et Marie Curie Paris VI, Paris, France                                p16

                                                                                            (continued opposite)

EWGGD Supplement                                             4                                         JULY 2008
• Parkinsonism in relatives of Gaucher patients heterozygous for GBA1 mutations
  Ralf Hartung, University Children’s Hospital, Mainz, Germany.                                           p16

• Rare Diseases: a European perspective
  Gyorgy Kosztolanyi, University of Pecs, Pecs, Hungary                                                   p17

• Shire Human Genetic Therapies: Differential in vitro responses in inflammatory and immune
  cytokine production elicited by enzyme replacement therapies for Gaucher Disease
  Andrew Onderdonk, Harvard Medical School, Boston, Massachusetts, USA
  Paolo Martini, Shire HGT, Boston, Massachusetts, USA                                                    p17

• Novel enzyme replacement therapy for Gaucher disease: On-going phase III clinical trial with
  recombinant human glucocerebrosidase expressed in plant cells
  Einat Almon, Protalix Biotherapeutics, Carmiel, Israel                                                  p18

• Amicus therapeutics: Scientific rationale for the use of pharmacological chaperones in
  Gaucher Disease.
  Brandon Wustman, Amicus Therapeutics, Cranbury, New Jersey, USA                                         p18

• Pregnancy and delivery in females with Gaucher Disease
  Eugen Mengel, University Children’s Hospital, Mainz, Germany                                            p19

• Pregnancy in Type 1 Gaucher Disease and the effect of Enzyme Replacement Therapy
  Ari Zimran, Shaare Zedek Medical Centre, Jerusalem, Israel                                              p19

• Recent advances in gene therapy of LSDs with CNS manifestations
  Timothy Cox, Department of Medicine, University of Cambridge, UK                                        p20

• Biomarkers of avascular necrosis in Gaucher disease
  Elena Pavlova, University of Cambridge, Cambridge, UK                                                   p21

• Chitotriosidase-monitoring during pregnancy in women with Gaucher Disease
  Verena Lehmann, University Children’s Hospital, Mainz, Germany                                          p21

• Yet another glucocerebrosidase?
  Hans Aerts, University of Amsterdam, Amsterdam, The Netherlands                                         p21

• ER associated degradation and unfolded protein response in Gaucher disease patients
  Mia Horowitz, Tel Aviv University, Tel Aviv, Israel                                                     p22

• A nonsense mutation in the LIMP-2 gene associated with progressive myoclonic epilepsy and
  nephrotic syndrome.
  Maria Clara Sa Miranda, Institute for Molecular and Cell Biology Porto, University of Portugal, Portugal p22

• Common variants in the glucosylceramide synthase gene are associated with the disease
  severity in Gaucher disease patients
  Pilar Alfonso, University of Zaragoza, Zaragoza, Spain                                                  p23

•   Plamsmalogen Levels in Gaucher Disease
    Helen Michelakakis, Institute of Child Health, Athens, Greece                                         p23

• Bone Marrow Transplantation for Acute Myeloid Leukaemia from donor with Gaucher Disease
  followed by enzyme replacement therapy
  Mirando Mrsic, University Hospital Zagreb, Zagreb, Croatia                                              p23

• Validation of saccadic latency as a biomarker of cerebral injury in lysosomal storage disorders
  Jonathan Roos, University of Cambridge, Cambridge, UK.                                                  p24

• Chaperone effect of several iminosugars and aminocyclitols on mutated glucocerebrosidases
  as a possible approach to Gaucher Disease
  Lluïsa Vilageliu Arqués, University of Barcelona, Barcelona, Spain                                      p24

• Inefficiency of drilling in the early stages of osteonecrosis in Gaucher Disease.
  Ehud Lebel, Shaare Zedek Medical Centre, Jerusalem, Israel.                                             p25

• Gaucher disease: a model to study the role of glycosphingolipids in atherosclerosis
  Johanna Groener, Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The
  Netherlands                                                                                             p25

EWGGD Supplement                                              5                                     JULY 2008
Index by Speakers
Aerts Hans                                         p21     Mehta Atul                                         p11
Alfonso Pilar                                      p23     Mengel Eugene                                      p19
Almon Einat                                        p18     Michelakakis Helen                                 p23
Altarescu Gheona                                   p13     Mistry Pramod                                       p7
Cherin Patrick                                     p16     Mrsic Mirando                                      p23
Cox Timothy                                        p20     Onderdonk Andrew                                   p17
Di Rocco Maja                                       p8     Patroes Gregory                                    p14
Elstein Deborah                                    p13     Pavlova Elena                                      p21
Ginns Edward                                       p15     Roos Jonathan                                      p24
Giraldo Pilar                                      p13     Sa Miranda Maria Clara                             p22
Goldblatt Jack                                     p11     Saftig Paul                                         p7
Groener Johanna                                    p25     Tylki-Szymanska Anna                                p9
Hartung Ralf                                       p16     Vellodi Ashok                                      p12
Hollak Carla                                       p15     Vilageliu Arques Lluise                            p24
Horowitz Mia                                       p22     Vom Dahl Stephan                               p8 & 10
Hughes Derralyn                                    p10     Weinreb Neil                                       p14
Kosztolanyi Gyorgy                                 p17     Wustman Brandon                                    p18
Langeveld Mirijam                                   p9     Zimran Ari                                    p12 & 19
Lebel Ehud                                         p25     Susan Lewis Memorial Fund                     p26 & 27
Lehmann Verena                                     p21     European Gaucher Alliance                          p28




   Our Thanks Go To……………….
The Gauchers Association are extremely grateful to
Dr Nicholas Smith and Dr Robert Ayto who attended
the EWGGD in Budapest as guests of the UK
Gauchers Association to write the summaries in this
supplement, so that our members, families, friends
and those interested in Gaucher disease not able to
attend this workshop could be kept up to date on
what is happening in the field.

    Dr Nicholas Smith is an Australian physician
specialising in paediatric neurology. His particular
interest at both a clinical and research level is the
diagnosis and management of neurometabolic disease.
Robert has recently joined the University of Cambridge
Lysosomal Storage Disease Research Group lead by Prof.
Timothy Cox where he plans to study the
neuropathology of a variety of lysosomal storage                   Dr Nicholas Smith left, Dr Robert Ayto right
disorders including Gaucher Disease. Dr Smith hopes
that a greater understanding of the neurological pathogenesis in these conditions will contribute to the development
of improved therapeutic interventions for patients with neurological disease.

  Dr Robert Ayto is a clinical research fellow who has joined the Lysosomal Storage Diseases unit in order to
undertake research into the linkage between Gaucher disease and Multiple Myeloma at the Royal Free Hospital.

    Robert studied at Saint Batholomews Hospital and graduated in 1998 with both a medical degree and a BSc(Hons)
in Anatomy and Basic Medical science. He went on to undertake a period of general medical training and gained
his membership to the Royal College of Physicians in 2001. Robert entered specialist training in haematology
within the North Thames region in 2003 and gained Diplomate status to the Royal College of Pathologists in 2005.
He re-joined the Royal Free Hospital in May 2007 in order to undertake research and obtain a higher degree to help
fulfil long term career goals towards malignant and academic haematology.

EWGGD Supplement                                               6                                         JULY 2008
   LIMP-2 is a receptor for lysosomal mannose-6-phosphate
   independent targeting of ß-Glucocerebrosidase.
Paul Saftig, Christian-Albrechts University, Kiel, Germany.

Professor Saftig opened the EWGGD presentation programme with a fascinating
lecture on his discovery and characterisation of the mannose-6-phosphate
independent trafficking of glucocerebrosidase via the LIMP-2 pathway. Since
Christian de Duve first described the lysosome in 1955 (leading him to receive the
Nobel prize in 1974) the metabolic importance of the lysosome has been increasingly
recognised and many diseases associated with its dysfunction, including Gaucher
disease identified. Lysosomes are responsible for the metabolic catabolism of
carbohydrates, proteins, lipids and nucleic acids. However, lysosomal enzymes must
first be transported to their site of action within the lysosome and an array of
molecules responsible for this process have been characterised. Chief amongst
which is the mannose-6-phosphate pathway. The importance of this pathway is
demonstrated by a number of lysosomal storage diseases in which it is defective
including the severe I-cell disease. However, it has long been recognised that the
enzyme deficient in Gaucher disease, glucocerebrosidase, does not rely on mannose-
6-phosphate and targets the lysosome by an independent pathway which, until
now, had not been identified. This finding is clearly demonstrated by a mouse model where a complete deficiency
of mannose-6-phosphate receptors was engineered. Despite a significant disruption of enzyme trafficking to the
lysosome in these mice, transport of glucocerebrosidase was not impaired.

    The characterisation of glucocerebrosidase transport to the lysosome by Professor Saftig and his research
group has therefore accomplished a major breakthrough in our understanding of glucocerebrosidase metabolism
and lead to new insights into the pathophysiology of Gaucher disease. As part of their research they have succeeded
in engineering a LIMP-2 deficient mouse model to assist in studying this disorder. These mice display strongly
decreased levels of beta-glucocerebrosidase within lysosomes despite it being manufactured by the cell, a reflection
of impaired transport to the lysosome. However, this can be overcome by reintroducing functional LIMP-2 to these
mice. Further characterisation of the LIMP-2 protein suggests that it binds to glucocerebrosidase within the
endoplasmic reticulum and subsequently facilitates its transport through the golgi apparatus and into the lysosome.
This introduces the possibility that Gaucher disease may not only arise from an abnormality of glucocerebrosidase
(as results from mutations in the GBA1 gene) but that a variant form could be due to a LIMP-2 deficiency with
impaired targeting of glucocerebrosidase to its site of action. In fact a number of clinical cases of LIMP-2 deficiency
have been recently reported presenting with a form of progressive myoclonic epilepsy associated with renal disease
(Glomerulosclerosis) and evidence of central nervous system storage. Further research into this exciting discovery
and the implications it holds for the pathogenesis of Gaucher disease and its treatment are ongoing, led by
Professor Saftig and collaborators worldwide.



   Pathophysiology: liver and lung manifestations
Pramod Mistry, Yale University School of Medicine, New Haven, CT, USA

This presentation concentrated on the liver complications of the disease together with
a short summary of lung manifestations encountered. One of the pathological hallmarks
of Gaucher disease is liver dysfunction and enlargement. Gaucher disease leads to a
decrease in glucocerebrosidase activity which results in glucosylceramide accumulation.
Deposition of glucosylceramide accounts for only a minority of the expanded liver
volume seen. Inflammation, Gaucher cell infiltration and recruited immune cells
contribute more significantly to the increase in liver size. The spectrum of liver disease
encountered includes liver enlargement (hepatomegaly), gallstone formation, cirrhosis,
fibrosis, an increased incidence of liver carcinoma, hepato-pulmonary syndrome and
liver failure. Enzyme replacement therapy (ERT) has been shown to be effective in
cases of both early and advanced liver disease including some cases of fibrosis.

   A prior splenectomy (asplenic), together with either a more severe Gaucher
genotype or phenotype has been linked to an increased incidence of hepatomegaly.
                                                                                                 (continued overleaf)

EWGGD Supplement                                                    7                                      JULY 2008
(continued from previous page)
Asplenic patients have an increased risk of abnormal liver function tests and liver cirrhosis. Gallstone disease is
prominent and is found in about 25% of patients with increased incidence in females. Disturbances in lipid fractions
that can be corrected with ERT may contribute to the elevated incidence of gallstone formation. Glucosylceramide
has have been shown to be increased within the bile of Gaucher patients. Gallstone formation is not well correlated
to disease severity. Pulmonary complications of Gaucher disease include lung tissue damage, pulmonary hypertension
and hepato-pulmonary syndrome. Pulmonary hypertension like hepatomegaly is associated with prior splenectomy.



   A new type 1 Gaucher Disease severity score index for the
   phenotypic classification and evaluation of responses to
   treatment.
Maja Di Rocco, University of Genoa, Italy.

Dr. Di Rocco from the University of Genoa provided a highly informative account of
her and her colleague’s development of a new severity score index for type 1 Gaucher
disease, the Gaucher Disease Severity Score Index - type 1 (GauSSI-1). Severity
scoring systems are important tools for clinicians and researchers working in the
field of Gaucher disease. Given the clinical variability amongst patients it is
important to develop methods for objectively rating disease severity and quantifying
responses to treatment both in the patient population as a whole and over the
course of an individual patient’s treatment regimen. The Gaucher Disease Severity
Score Index has been constructed from the collective clinical experience of the
author’s and an extensive review of the world literature. It takes into account six
specific domains in which different items are scored according to their impact on
disease morbidity. These domains include bone marrow infiltration, skeletal
involvement, haematological disease, visceral involvement, pulmonary involvement,
neurological disease and biomarker levels (Biomarkers are measurable indicators
of disease activity). Dr Di Rocco and her colleagues have validated their rating
system in a cohort of 53 type 1 Italian Gaucher patients treated with imiglucerase and further compared it to the
first scoring system developed, the Zimran score. Although further work is required to confirm the validity of the
GauSSI-1, Dr. Di Rocco and her colleagues have demonstrated it to be a reliable method for staging the severity of
type 1 Gaucher disease in adults and a more sensitive rating scale than the Zimran score when monitoring response
to treatment. The GauSSI-1 provides a useful tool for objectively monitoring patients throughout the course of
their disease and its treatment.



   Development of a disease severity scoring system for type
   1 Gaucher Disease
Stephan Vom Dahl, St Franziskus-Hospital, Academic Teaching Hospital,
University of Cologne, Germany

The development of robust Severity Scoring Systems (SSS) to classify Gaucher disease
activity and the response to therapy is essential in order to objectively monitor
patients. Introduction of new SSSs aim to be more sensitive than the currently
used Zimran score and be more effective in assessing patients over time. Here is
described a new scoring system known as DS3 (disease severity scoring system)
for adults with type I Gaucher disease. The DS3 scoring system is composed of
three different categories that score haematological, bone and visceral (spleen,
liver and lung) complications. Each of these three categories is scored based on
severity and integrated to give an overall severity score. Bone parameters assessed
include the presence of erosive lesions, avascular necrosis, bone pain, episodes of
bony crises and bone mineral density and bone marrow infiltration. Haemoglobin
level, platelet number and bleeding tendency are included in the haematological
component. An enlarged liver or spleen and Gaucher-related lung disease are assessed in the visceral category.
                                                                                         (continued overleaf)

EWGGD Supplement                                               8                                         JULY 2008
(continued from opposite page)
Evaluation of this scoring system has shown good inter-physician reproducibility. Furthermore individual physicians
have been shown to be consistent with their scoring. The DS3 scoring system needs to be evaluated further to
assess its sensitivity in assessing patients serially at follow-up, as a dynamic measure of therapy success and
requires comparison to the currently used Zimran score. There is no recognition of age in this scoring system.



   Saposin C deficiency
Anna Tylki-Szmanska, Children’s Memorial Health Institute, Warsaw, Poland

Dr. Tylki-Szmanska provided an excellent review of Saposin C deficiency in Gaucher
disease. In the majority of patients disease results from a deficiency of the lysosomal
enzyme glucocerebrosidase which is caused by a mutation in the glucocerebrosidase
(GBA1) gene. However, a smaller number of patients have an abnormality in the
function of the sphingolipid activator protein type C (Sap C). This is a small
glycoprotein which acts to assist glucocerebrosidase in the degradation of
glycosphingolipids. It belongs to a family of four saposins which are derived from
a single precursor protein called prosaposin.

   Dr Tylki-Szmanska described three patients with mutations involving the Saposin
C domain of the prosaposin gene. Classically these patients present with a
neuronopathic form of Gaucher Disease. However, of great interest she proceeded
to describe the first report of a non-neuronopathic clinical phenotype resulting
from a Sap C mutation presenting in two siblings. These patients were found to
carry two mutations in the heterozygous state, a missense mutation located in the
sap C domain and a second mutation located at a regulatory region of the prosaposin gene. Dr Tylki-Szmanska
and her colleagues conclude that this finding represents a newly described genotype of saposin C dysfunction
without neurological involvement. They hypothesise that this is due to sufficient residual glucocerebrosidase activity
to allow glucocerebroside degradation within the central nervous system.



   Insulin resistance in Gaucher Disease
Mirjam Langeveld, Academic Medical Centre Amsterdam, The Netherlands.

Dr Langeveld provided us with a fascinating overview of her groups work
investigating the potential association between type 2 diabetes mellitus and Gaucher
disease. She detailed surprising similarities in the pathophysiology of these disorders,
both displaying abnormalities in glycosphingolipid metabolism.

   In type 2 diabetes mellitus the major predisposing risk factor is obesity. This
leads to increased palmitate levels with a subsequent increase in glycosphingolipid
synthesis. Glycosphingolipids located within the plasma membrane have been
shown to interfere with insulin receptor action. This may result in insulin resistance,
a state known to precede type 2 diabetes.

    Gaucher disease also results in elevated glycosphingolipid levels, albeit by the
unrelated mechanism of glucocerebrosidase deficiency. Dr. Langeveld and her
colleagues have shown that this also results in an insulin resistant state. The insulin
resistance in untreated Gaucher disease and the weight gain associated with enzyme
replacement therapy (ERT) led to the hypothesis that the risk for developing type 2 diabetes could be increased in
Gaucher patients.

    Their subsequent studies showed a prevalence of obesity and type 2 diabetes mellitus in patients treated with
ERT for several years comparable to that of the general population. They conclude that although enzyme replacement
therapy results in a partial correction of pathological glycosphingolipid elevation, which may enhance insulin
sensitivity, treatment also results in weight gain, which may counteract this positive effect. The net effect on the
risk for development of type 2 diabetes in Gaucher patients is therefore difficult to predict and it is therefore
recommended to monitor weight and, if obesity develops, plasma glucose levels during treatment with ERT.



EWGGD Supplement                                                  9                                       JULY 2008
   Gaucher Disease and Cancer
Derralynn Hughes, Royal Free and University College Medical School, London

Studies in both Europe and Israel have shown an increased risk of cancer in Gaucher
patients including multiple myeloma and liver carcinoma. Multiple myeloma is a
rare cancer of the bone marrow associated with the presence of a specific blood
protein known as a paraprotein and shares similar bony pathology to that seen in
Gaucher disease. Interrogation of 2,742 patients from the Gaucher registry by
Rosenbloom et al.(2005) showed up to 6 times increase in risk of multiple myeloma.
Many other studies have reported an even higher incidence of myeloma with other
studies showing no increase in risk at all.

    The malignant cell in multiple myeloma is the plasma cell. Non-cancerous
conditions affecting the plasma cell include monoclonal gammopathy of
undermined significance (MGUS) and polyclonal gammopathy; these are also found
with an elevated incidence in Gaucher disease. MGUS is associated with the same
type of protein found in Myeloma patients but without any of the associated sinister
clinical features. Polyclonal gammopathy, MGUS and Myeloma may represent a
spectrum of pathologies driven by a common process in Gaucher disease. The incidence of MGUS in some cohorts
has been described has high as 25% with the incidence in the general population being around 1%. Case reports
within the literature describe Gaucher patients with other haematological malignancies including chronic lymphocytic
leukaemia, non-Hodgkins lymphoma and acute leukaemia; although whether there is an increased risk of these
disorders is not known. The Royal Free Hospital, London data demonstrates that many patients have small clonal
lymphoid populations within their blood. The clinical significance of this finding in isolation is not fully known.

    The diagnosis of Myeloma from bone marrow examination is based on plasma cell percentage and this is
difficult to assess in the face of large Gaucher cell infiltrates. Chronic immune stimulation, a reduction in certain
white blood cells subsets, alterations in the bone marrow microenvironment, abnormal cell secretion profiles
(cytokines), aberrant glycolipid presentation by immune cells and glucosylceramide accumulation has all been
postulated to be involved in the increased incidence of Multiple Myeloma.



   Dose Response Relationships in Gaucher Disease
Stephan Vom Dahl, St Franziskus-Hospital, Academic Teaching Hospital,
University of Cologne, Germany

The optimal dosage of enzyme replacement therapy (ERT) in Gaucher disease is
unknown and this may be different in the various disease stages. Studies including
the DD-AMC study (German/Dutch cohorts) and analysis from the International
Collaborative Gaucher Group (ICGG) have examined this relationship between dose
and clinical effectiveness. Dose response relationships have been demonstrated
for platelet count, haemoglobin level, spleen size, liver volume, bone marrow
infiltration, bone mineral density and chitotriosidase activity. Although during initial
treatment haematological and visceral (liver and spleen volume) parameters were
shown to be improved with higher doses at equivalent time points, differences
may not lead to increased clinical benefit and were not large. However bone marrow
burden and bone mineral density responses were reported to be much improved
earlier in those on higher doses.

   The optimal dose at initiation and post-stabilisation remains a topic of much
debate.




EWGGD Supplement                                                  10                                      JULY 2008
   Monitoring skeletal response in Type 1 Gaucher Disease
Jack Goldblatt, School of Paediatrics and Child Health, University of Western
Australia

Dr Goldblatt provided a comprehensive review of the skeletal manifestations of
type 1 Gaucher Disease. He emphasised the primary treatment goals of normalising
quality of life and the prevention of irreversible skeletal pathology such as avascular
necrosis. In order to achieve these goals it is important for clinicians to have an
effective means of determining disease severity and monitoring response to
treatment.

   Dr Goldblatt presented data from the Australian National Gaucher Treatment
Program which monitors skeletal disease by a centralised assessment process. This
includes annual MRI scans where a standardised imaging protocol is used to derive
a semiquantitative Bone Marrow Burden (BMB) score in addition to providing
detailed anatomical information of local bony disease. Adjunctive evidence is also
gained from the measurement of chitotriosidase levels and bone mineral density
measurements. It is the experience of Dr Goldblatt and his colleagues that MRI
provides the best method of assessing bony disease and its response to therapy in Gaucher patients. By comparison
bone mineral density is subject to confounder bias from local pathology at the site of measurement.

    The annual MRI monitoring protocol incorporated into the Australian National Gaucher Treatment Program has
enabled Dr Goldblatt and his colleagues to titrate enzyme replacement therapy with pleasing results including
improved bone marrow burden scores, a reduction in patient reported symptoms and most importantly an absence
of irreversible bony complications in the Australian patient cohort since its inception.



   A multicentre, randomised, dose frequency study of the
   safety and efficacy of Cerezyme infusions every 4 weeks
   versus every 2 weeks in the maintenance therapy of
   patients with type I Gaucher disease
Atul Mehta, Royal Free Hospital and University College London, London, UK

Cerezyme is currently the benchmark standard of treatment for type 1 Gaucher
disease and is normally administered intravenously every two weeks. This schedule
can be inconvenient, especially when it is delivered in a hospital based setting. This
multi-centre randomised study carried out over 24 months reported on the feasibility
and efficacy of delivering the same total dose every four weeks. Patients who had
been stable on Cerezyme for greater than two years with the same dose over the
last six months were eligible for inclusion. In total 95 patients were recruited.
Infusion of the total dose four weekly was generally well tolerated. Measures such
as the haemoglobin level, platelet count, liver/spleen volume, frequency of bone
crisis and burden of bone disease were maintained almost as well in those that
received four weekly administration compared to those on two weekly regimes.. It
was concluded that four weekly administration is safe, well tolerated and may be
an acceptable treatment option for selected Gaucher type I patients who are stable
and have achieved their therapeutic goals but who find two weekly administration
inconvenient.




EWGGD Supplement                                                 11                                   JULY 2008
   Recent advances in type 3 Gaucher disease
Ashok Vellodi, Metabolic Unit, Great Ormond Street Children’s Hospital,
London, UK.

Dr. Vellodi presented a very interesting overview of some recent thoughts and
insights into the possible pathophysiology of type 3 Gaucher disease and the
implications they may have for therapeutic intervention. He began by highlighting
the possibility of altered neural plasticity in type 3 Gaucher disease, and how this
might be improved. Neural plasticity refers to the ability of the brain to undergo
changes in function and organisation both during development and, in some cases,
as an adaptive response to cerebral insult. This is a well studied aspect of cerebral
development, and a number of genes involved in this phenomenon have been
identified. One of these, the BDNF gene, has been found to have reduced expression
in Gaucher disease brains. This may be related to intracellular calcium gradients, as
regulated by specialised calcium channel receptors. One such receptor, the ryanodine
receptor, has been shown by Dr Futerman and his team to be impaired in some
Gaucher patients. Interestingly, a mouse model in which this receptor has been
knocked out shows reduced neural plasticity. Therefore, it is possible that patients
with NGD have reduced neural plasticity, although further study is required to investigate this. The potential for
stimulating neural plasticity by way of specific training programs is an intense area of study for clinicians, and may
hold future promise for a variety of neurological disorders, including Neuronopathic Gaucher disease. Dr. Vellodi
also focused on the potential pathological role of exocytic machinery dysfunction in Neuronopathic Gaucher
disease. This machinery effects delivery of perforins and granzymes, the means by which Cytotoxic T lymphocytes
and Natural Killer cells attack and kill their targets. Researchers at the Institute of Child Health in London have
found that this process was impaired in a patient with Neuronopathic Gaucher disease. It is important to look into
this further, but it may explain some of the inflammatory processes affecting various organs, including the brain.



   Existing and Novel ERT approaches
Ari Zimran, Shaare Zedek Medical Centre, Jerusalem, Israel

Enzyme replacement therapy (ERT) has revolutionised the treatment of Gaucher
disease. Early introduction of ERT prior to the development of significant bony
disease leads to a better clinical outcome. ERT is suitable for home administration
and thus reduces disruption to the patient and the need for hospital visits. ERT has
reduced the rate of splenectomy and has been shown to have beneficial effects on
haematological parameters, liver/spleen volume and the level of bony pain. It is
however less effective in the treatment of lung manifestations such as pulmonary
hypertension. High dose ERT compared to lower doses shows a statistical advantage
in many outcome measures at equivalent time points (e.g. platelet count/
Haemoglobin level) but this may not convey any real clinical advantage. Super
high doses of ERT or Miglustat (substrate reduction therapy) are not effective in
the treatment of neuronopathic Gaucher disease. The development of chaperone
therapy (transports mis-folded glucocerebrosidase to the lysosomal compartment
in order to restore a degree of enzyme activity) has yet to be fully evaluated in its
ability to cross the blood brain barrier and treat type III Gaucher disease. Two new
recombinant Glucocerebrosidases are currently undergoing clinical trial. Velaglucerase Alfa (Shire Human Genetics)
is produced in a human cell line and its amino acid sequence is identical to the natural human enzyme. prGCD
(Protalix Biotherapeutics) is a plant cell expressed recombinant glucocerebrosidase. The development of new ERT
promotes competition, choice and cost reduction with the potential of increased clinical effectiveness.

     A single centre Israeli study at Shaare Zedek Medical Center in Jerusalem in Velaglucerase alfa (phase I/II) involving
12 patients over 9 months has been shown to be well tolerated and clinically effective in adult patients (age > 18 years)
with type I Gaucher disease. Phase III studies will also recruit pediatric patients from the age of two. The Protalix product
prGCD is plant derived and due to its manufacturing process is anticipated to be cheaper than the existing ERT product.
It is structural identical to Cerezyme and is currently undergoing phase III trial at two different doses.

   The continuing success and introduction of new therapies requires continuing pharmaceutical development,
willingness of investigators and patient participation.

EWGGD Supplement                                                   12                                            JULY 2008
   Non-Enzyme Replacement Therapy treatment options for
   Gaucher Disease
Deborah Elstein, Shaare Zedek Medical Centre, Jerusalem, Israel

This talk was presented by Dr. Gheona Altarescu for Dr. Deborah Elstein who was
unable to attend. Dr Altarescu outlined historical and current options for the non-
enzymatic treatment of Gaucher Disease. Although a revolution in the management
of this disorder, enzyme replacement therapy (ERT) is not an absolute solution.

   Historically treatment options for Gaucher disease were limited to splenectomy
(total or partial), orthopaedic surgery for bony disease and supportive treatment
only. However, treatment options have expanded to include ERT, bone marrow
transplantation and the promise of gene therapy. Nevertheless, these too have
their limitations. Bone marrow and organ transplants have the potential for
significant adverse sequalae, gene therapy is yet to achieve clinical utility and ERT
has reduced efficacy in the treatment of bony, pulmonary and particularly central
nervous system disease.

    Oral substrate reduction therapy with the iminosugar miglustat (Zavesca) has
been demonstrated to reduce glucosylceramide accumulation with a reduction in organ size (improvement of
splenomegaly). In addition, it displays beneficial effects in some bony and pulmonary pathology. There is also
evidence that miglustat crosses the blood brain barrier and may have a role in the treatment of neurological
disease including one study which has demonstrated an improvement in visuo-spatial functioning post miglustat
treatment. The side-effect profile of miglustat includes gastrointestinal disturbance, weight loss and an association
with neurological features including tremor and peripheral neuropathy. However, debate exists as to whether this
reflects a proven drug effect or a manifestation of the underlying disease. Extensive work is being undertaken to
address these issues in addition to long-term efficacy monitoring of miglustat as both a monotherapy agent and
as part of a combination therapy regimen.



   Experience with SRT
Pilar Giraldo, University of Zaragoza, Zaragoza, Spain

FEETEG is an independent, non-profit, scientific organisation that has maintained
the Spanish Gaucher Registry since 1993. It plays a role in the screening, diagnosis,
treatment, guideline formation and clinical trials associated with Gaucher disease.

   The Spanish Gaucher Registry was reported to have 319 patients (277 type I
disease, 25 type II disease and 17 type III disease). There were 56 different Gaucher
gene mutations found within the Spanish cohort with 21 being novel. Miglustat
(substrate reduction therapy; SRT)) was approved in the EU in 2004. Reported was
the result of the ZAGAL Study (Zavesca en Gaucher Leve) which looked at the use
of migulstat within the Spanish Gaucher population. This study was performed
between May 2004 and April 2008. The majority of the patients recruited swapped
to substrate reduction therapy from enzyme replacement therapy (ERT) with the
minority being naive to treatment.

    The follow-up period was 36 months. It was reported that based on clinical
outcome parameters that Miglustat faired comparatively to a cohort on ERT (haemoglobin level, platelet count,
chitotriosidase activity and spleen/liver volume). Trends were marginally better in the ERT group but not significantly.
Quality of life scores at 36 months were comparable between SRT and ERT. It was also reported that there was no
difference in outcome between naive patients on SRT for this period compared to ERT. Those that swapped to SRT
from ERT remained stable at 36 months. Mild gastro-interstinal side effects were reported in 8/37 patients on SRT
with weight loss (>10%) being noted in a minority(n=5).




EWGGD Supplement                                                 13                                         JULY 2008
   Bone mineral density and Substrate Reduction Therapy
Gregory Pastores, New York University School of Medicine, New York, USA

Dr. Pastores provided an informative review of bony pathology in Gaucher disease
and an excellent appraisal of bone density measurement in the assessment and
monitoring of skeletal pathology and its response to substrate reduction therapy
(SRT).

   Dr. Pastores and his colleagues have shown miglustat, which is now registered
for use in both the European Union and the United States, to effect a small, though
statistically significant improvement in bone mineral density measurement at both
the femoral neck and lumbar spine. Although encouraging, Dr. Pastores observed
that these findings require confirmation by larger cohort studies and emphasized
the need to characterise the outcome of long-term SRT upon skeletal pathology in
Gaucher patients.

   As the SRT market expands new agents will also require investigation of their
treatment potential in the management of skeletal disease in addition to elucidation of their long-term safety
profiles. Dr. Pastores concluded by highlighting the need for further research in this area including an evaluation
SRT in combination with bisphosphonate use in the management of skeletal pathology in Gaucher disease.



   A phase 2 clinical trial of the pharmacological chaperone
   AT2101 for the treatment of Gaucher Disease.
Neil J. Weinreb, University Gaucher Treatment Center, Tamarac, Florida, USA.

Dr Weinreb reported on a randomized open label multicentre clinical trial of AT2101
(isofagomine tartrate) in the treatment of adult patients with Type 1 Gaucher
Disease. AT2101 is an oral pharmacological chaperone that selectively binds both
wild type (normally functioning) and mutant glucocerebrosidase.

   In the majority of Gaucher patients the mutant enzyme is misfolded which
inhibits its transport from the endoplasmic reticulum (ER) where it is synthesized
to its site of action within the lysosome. AT2101 acts by binding the misfolded
protein within the ER and increasing its intrinsic stability resulting in enhanced
trafficking of the enzyme-chaperone complex to the lysosome. Release of the
chaperone occurs upon contact with the acidic pH of the lysosome.

   The primary objective of the presented study was to evaluate the safety and
tolerability of AT2101 at variable dosing regimens. All study participants had
achieved prior disease control with imiglucerase. Secondary study objectives
included an evaluation of glucocerebrosidase levels and other biomarkers of type 1 Gaucher disease in patients
taking AT2101. In all patients imiglucerase infusions were held and for two weeks before commencing a four
week trial of AT2101. AT2101 proved to be well tolerated at all doses with no serious adverse events reported.
Glucocerebrosidase activity was increased in the majority of patients whilst haematological and other laboratory
measures including biomarkers of Gaucher Disease remained stable.

   Longer term trials are planned to further evaluate the clinical efficacy and safety of this agent in patients with
type 1 Gaucher Disease.




EWGGD Supplement                                               14                                         JULY 2008
   Development of novel orally administered non-viral gene
   therapy for Gaucher disease using DNA nanoplexes
   encapsulated in yeast cell wall particles.
Edward Ginns, University of Massachusetts Medical School, MA, USA

An ingestable formulation of hollow, porous yeast cell wall particles encapsulating
DNA nanoplexes encoding therapeutic proteins is being developed as a non-viral
gene therapy for Gaucher disease. Reported at the EWGGD meeting were
encouraging results in Gaucher mice using DNA that contains the genetic code for
human glucocerebrosidase, the enzyme deficient in Gaucher disease. Following
oral administration, the glucan particles (a neutraceutical of Baker’s yeast derived
â-1,3-Glucan) and their payload of DNA encoding human glucocerebrosidase are
rapidly taken up within the gastrointestinal tract by macrophages, a subset of
white blood cells. As the macrophages migrate to disease affected tissues, including
the bone marrow, spleen, liver and lung, the glucocerebrosidase DNA is released
from the glucan particle, and the macrophages use the DNA to synthesize normal
functional glucocerebrosidase and deliver it to the lysosome. Administration of
the glucan particle-glucocerebrosidase DNA formulations to Gaucher mice resulted
in extensive particle uptake in many tissues. Compared to untreated Gaucher mice,
treated mice had significantly increased liver glucocerebrosidase activity and
decreased amounts of tissue Gaucher cells. Results of a small pilot study also suggest that this therapy sufficiently
corrects tissue glucocerebrosidase activity to decrease symptoms and improve survival in treated, compared to
untreated, severely affected Gaucher mice. Additional preclinical studies with larger numbers of mice are in progress.
The ability of this ingestible macrophage targeted gene therapy to improve delivery and restore human
glucocerebrosidase activity to tissues suggests that this approach could achieve significant reversal of tissue
pathology, including bone. In addition to enabling a safer, more efficient and cost effective treatment for Gaucher
disease, this macrophage targeted therapeutic strategy could be used to treat a wide range of other medical
conditions, including low bone density and inflammatory diseases, and may provide an attractive alternative to
other non-viral or viral gene therapy approaches.



   Neurological complications in type 1 Gaucher Disease
Carla Hollak Academic Medical Centre, University of Amsterdam, The Netherlands.

Type 1 Gaucher disease is defined by an absence of neurological involvement.
However there are increasing reports of neurological manifestations in patients
with classic type 1 disease. Dr. Hollak provided a valuable insight into these
neurological manifestations following an extensive literature review and
retrospective analysis of a large Dutch cohort of type 1 Gaucher disease patients.
As our knowledge increases, the spectrum of central nervous system involvement
in type 1 disease falls into several broad categories. The first consists of patients
who are misclassified as type 1 disease when they are better categorised as type 3.
Of those patients with true ‘type 1’ disease, extrapyramidal features broadly
described as ‘Parkinsonian’ are increasingly being reported. Dementia of the Lewy
body type is also described, but no data are available that support a higher
prevalence in the Gaucher population. Additionally peripheral nervous system
disease is recognised including mono and polyneuropathies which in most cases
are mild or indeed clinically silent. Cranial nerve disease has also been noted.
Secondary neurological involvement is also well characterised with spinal cord,
nerve root and peripheral nerve compression as a result of primary skeletal pathology. In the Dutch cohort Dr.
Hollak and her colleagues recorded 34 of 75 patients having neurological disease at a median follow-up of 11
years. This included more general disorders such as migraine. One patient was found to have Parkinsonian features
whilst three displayed dementia (the aetiology of which was not defined). Two patients had spinal cord compression
secondary to bony disease. Interestingly, within a larger multicenter study, the prevalence of peripheral neuropathy
was noted to be significantly higher than in the general population (11% versus 3.5%). In general those patients

                                                                                                (continued overleaf)

EWGGD Supplement                                                15                                        JULY 2008
(continued from previous page)
found to have a peripheral neuropathy were older and had higher plasma titres of chitotriosidase. Dr. Hollak
concluded by highlighting the debate over the traditional classification of type 1 Gaucher disease as a non-
neuronopathic variant. Whether it should be reclassified as a specific subtype of neurological involvement or, as
many believe, a continuous spectrum of disease remains contentious. It should be emphasized that the majority of
type 1 patients never develop a serious neurological condition.



   The neurological manifestations of type I Gaucher Disease:
   The French Observatoire on Gaucher Disease (FROG)
Patrick Cherin, University Pierre et Marie Curie Paris VI, Paris, France

Type I Gaucher disease historically has been classified as non-neuronopathic but
currently this concept is being challenged. Prospectively collected data regarding
clinical manifestations including neurological complications was reported based
on a cohort of 105 patients with type I Gaucher disease (March 2005 to September
2006). Patients were distributed across many centres in France. The mean age was
45.6 years (standard deviation 13.7years). Thirty-eight of the patients were
genotyped with 71% having at least one N370S mutation with a further 39%
exhibiting having either a L444P or D409H mutation. Neurological enquiry and
examination was performed as part of their clinical follow-up. It was reported that
19% of patients had a family history of Parkinson’s disease with the incidence in
the general population being quoted as less than 3%. Approximately half of patients
had evidence of abnormal neurological findings including peripheral nerve
anomalies, depression, epilepsy, abnormal tendon reflexes, muscle spasms, deafness
and Parkinsonism (do not fulfil all clinical criteria for Parkinson’s disease but share
some features). Parkinson’s disease was seen in 4 patients and 3 of these had
additional neurological anomalies. Some features of Parkinsonism were found in 21% of patients and this cohort
was significantly older than those not displaying these signs. It was stated that Gaucher Patients with Parkinson’s
disease maybe less responsive to treatment with L-Dopa.

    It was concluded that Gaucher disease may represent a continuum of disease and challenges the current sub-
classification into type I, II and III disease. It also raised the importance of thorough neurological enquiry in type I
patients at routine clinical review. It should be bore in mind that neurological symptoms/signs maybe more prevalent
in those without Gaucher disease than expected and some of the neurological anomalies stated above may not be
part of their Gaucher disease.

   Their abstract states only 3 patients with Parkinson’s



   Parkinsonism in relatives of Gaucher patients heterozygous
   for GBA1 mutations.
Ralf Hartung, University Children’s Hospital, Mainz, Germany.

Increasing evidence of the association between Gaucher disease and parkinsonian
features is being presented in the medical and scientific literature. Whilst a number
of studies have demonstrated heterozygosity of GBA1 mutations in patients and
their families diagnosed with Parkinson’s disease fewer have looked at the incidence
of parkinsonian features in the families of patients with Gaucher disease. Dr Hartung
presented data from the Mainz patient cohort which included 47 families from 56
Gaucher disease patients. A questionnaire was sent to patients to ascertain whether
any had relatives with parkinsonian features (confirmed by a neurologist). Follow
up of identified relatives was undertaken and mutation analysis for the GBA1 gene
was performed. Eleven relatives with parkinsonism were detected. Three of these
were parents of affected patients, 4 were grandparents and 1 a great grandparent.
Whilst the remaining 3 were either uncles or aunts of a Gaucher disease patient.
                                                                                                 (continued opposite)

EWGGD Supplement                                                 16                                         JULY 2008
(continued from opposite page)
The detected heterozygous alleles in the identified relatives with parkinsonism included N409S (56%), L483P
(13%), RecNcil (4%) and del55 (3%). All other mutations were rare whilst no mutation was identified in 6%. Dr
Hartung and his colleagues present their study as further confirmation of the higher prevalence of parkinsonism in
heterozygous carriers of Gaucher disease.



   Rare Diseases: a European perspective
Gyorgy Kosztolanyi, University of Pecs, Pecs, Hungary

Unification of Europe and the creation of the European Union (EU) have led to new
challenges in securing recognition and provision for those with rare diseases (RDs)
such as Gaucher disease.

    The EU public health programme between 2008-2013 will continue to provide
for those with RDs as one of their main priorities. The EU definition of a rare disease
is that which affects less than 1 in 2,000 patients; this is estimated to include 6%
of the total population at one point in their life.

   EU health policy is being implemented via several European spanning
organisations. The benefit of a European approach to rare diseases includes the
sharing of expertise, pooling resources including diagnostics, aiding countries with
limited resources, promoting collaborative research, the creation of common clinical
guidelines, facilitating the rapid dissemination of information including patient
safety issues and improving cost-effectiveness. Population screening policies,
preventative measures and development of knowledge databases (e.g. Orphanet) are also encouraged within the
EU.

  Care should be provided within expert centres with a multi-disciplinary approach. European based conferences
and databases are encouraged and there should be three yearly updates regarding the healthcare of those with
RDs within the EU. An overseeing agency for rare diseases will encourage the implementation of the above policies.



   Shire Human Genetic Therapies: Differential in vitro
   responses in inflammatory and immune cytokine
   production elicited by enzyme replacement therapies for
   Gaucher Disease
Andrew Onderdonk, Harvard Medical School, Boston, Massachusetts, USA
Paolo Martini, Shire HGT, Boston, Massachusetts, USA

Shire Human Genetic Therapies presented two sessions.

   Dr. Andrew Onderdonk provided an overview of the human innate immune
response whereby antigen recognition (the identification of molecules such as
surface carbohydrates or lipo-polysaccharide) leads to activation of the immune
system and release of pro-inflammatory chemical mediators called cytokines.
Gaucher disease has been characterized as a pro-inflammatory disease with
similarities to innate immune system activation.

    Dr. Paolo Martini from Shire HGT went on to report his group’s work which
demonstrates that Shire’s enzyme therapy product, velaglucerase alfa, does not
induce a significant cytokine response upon its administration to normal human
blood cells (PBMCs) in the laboratory. Shire HGT will continue to test this hypothesis
and explore the potential significance of these findings for velaglucerase alfa in
cells from Gaucher patients.




EWGGD Supplement                                                 17                                    JULY 2008
   Novel enzyme replacement therapy for Gaucher disease:
   On-going phase III clinical trial with recombinant human
   glucocerebrosidase expressed in plant cells
Einat Almon, Protalix Biotherapeutics, Carmiel, Israel

Here was reported a recombinant glucocerebrosidase produced within a plant
derived protein expression system based on carrot cells (ProCellExTM). This leads to
a comparatively simpler manufacturing system with cost benefits. There are further
modifications within the plant cell of the expressed recombinant glucocerebrosidase
(prGCD) that may lead to a potential therapeutic benefit (i.e. a glycosylation profile
with the exposure of mannose molecules that lead to enhanced uptake). As this is
a plant based expression system there is no risk of transmission of either mammalian
viruses or mammalian pathogens. There is also very little batch to batch variability
in the final product.

   It was commented on by the presenter that this prGCD product has at least
equal efficacy to Cerezyme in vitro and both have similar 3 dimensional structures
(protein crystallisation). This product has undergone successful phase I trial in Israel
which revealed good tolerability including no association with the development of
antibodies or immune reactions. The half-life of prGCD was demonstrated to be
prolonged and it was suggested that this may confer additional therapeutic benefit. There is currently an open
phase III trial with the aim of recruiting 30 naïve patients in a multi-centre setting. Inclusion criteria include being
older than 18 years of age with a spleen volume greater than 8 times of normal size. Patients will be randomised
to 9 months of therapy either at 30u/kg or 60u/kg per infusion during study duration. Following completion of this
study there is an opportunity to continue in an extension trial. In addition, a switch-over study to prGCD is to begin
soon, for stable patients who have been treated with Cerezyme for at least two years and have been on the same
dose for at least 6 months.



   Amicus therapeutics: Scientific rationale for the use of
   pharmacological chaperones in Gaucher Disease.
Brandon Wustman, Amicus Therapeutics, Cranbury, New Jersey, USA.

Dr Brandon Wustman from Amicus Therapeutics provided an overview of pharmacological chaperone therapy in
the management of Gaucher disease. In the majority of Gaucher patients mutations
in the GBA1 gene result in the expression of an abnormal glucocerebrosidase protein
which undergoes misfolding within the endoplasmic reticulum where it is
synthesised. As a result the mutant enzyme displays impaired transfer (trafficking)
to its site of action within the lysosome. Chaperones are molecules which bind to
the abnormal glucocerebrosidase enzyme and stabilise its folding which improves
the efficiency of enzyme trafficking to the lysosome and leads to increased enzyme
activity in the patient.

   Amicus is currently developing its own chaperone AT2101 (isofagomine). Studies
have shown this agent to be effective in increasing glucocerebrosidase activity. In
addition it is evident in rodent studies that this drug crosses the blood brain barrier,
giving hope that it may have some effect upon central nervous system disease. A
phase 2 clinical trial of this agent has recently been completed and although of
short duration there did not appear to be any significant adverse side-effects and
the agent was well tolerated by patients.

   Further studies are ongoing in the development of this agent as a new option in the management of Gaucher
disease.




EWGGD Supplement                                                  18                                        JULY 2008
   Pregnancy and delivery in females with Gaucher Disease
Eugen Mengel, University Children’s Hospital, Mainz, Germany

Here was reported data from Mainz, Germany on the outcome of pregnancy in
type I Gaucher patients between 1961 to 2008 (pre and post enzyme replacement
therapy era). It was noted that their Gaucher disease did not worsen during
pregnancy despite the majority not being on enzyme replacement therapy (ERT).

    The administration of ERT was not associated with a worse pregnancy outcome
and ameliorated the increased risk of post-partum bleeding witnessed in those not
on ERT. An elevated incidence of spontaneous abortion and intra-uterine death
were however documented within this cohort of women. There was no difference
in birth weights compared to a normal population. It was also concluded that ERT
was safe in this group of women during pregnancy and should not be discontinued.
Pregnancy was not discouraged.




   Pregnancy in Type 1 Gaucher Disease and the effect of
   Enzyme Replacement Therapy
Ari Zimran, Shaare Zedek Medical Centre, Jerusalem, Israel

Professor Zimran presented an excellent review of issues pertaining to conception
and pregnancy in patients with type 1 Gaucher disease. He has extensive experience
in the clinical management of Gaucher patients during pregnancy and maintains
a research interest in this area. Professor Zimran presented several illustrative cases
highlighting many of the issues faced by women and families with regards to
conception, prepartum, delivery and postpartum management. Gaucher disease is
associated with a higher rate of spontaneous abortion which, not surprisingly,
tends to be more frequent in moderate to severe disease. Women with Gaucher
disease may be at increased risk of complications during pregnancy and delivery
because of peripartum and postpartum bleeding. Worsening of their bony
involvement may also occur at this time (conversely, many women report
improvement in their symptoms during pregnancy).

    Imiglucerase has been demonstrated to be safe in pregnancy for both the mother
and the foetus (No teratogenic effects have been noted) and is of proven benefit
for women with symptomatic disease or pregnancy complications such as recurrent spontaneous abortion. Professor
Zimran concluded his talk with a number of recommendations for the management of pregnancy in Gaucher
Disease patients.

      1. Wherever possible planned conception and a multidisciplinary approach to pregnancy management is
         desirable.
      2. Regular monitoring of haematological parameters including platelet function testing should be performed.
      3. Imiglucerase is safe for both the mother and foetus in pregnancy and at the time of contraception
      4. Imiglucerase is indicated in patients with a history of pregnancy complications such as recurrent
         spontaneous abortions.
      5. Patients with mild, asymptomatic disease may not require ERT and generally have a risk of complication
         about the same incidence as the general population.
      6. Women treated with imiglucerase prior to pregnancy should be encouraged to continue their enzyme
         replacement therapy throughout pregnancy and breast-feeding.

Professor Zimran concluded his presentation with a reminder of the potential teratogenic effects of miglustat in
pregnant patients.




EWGGD Supplement                                                 19                                   JULY 2008
   Recent advances in gene therapy of LSD’s with CNS
   manifestations
Timothy Cox, Department of Medicine, University of Cambridge, UK

Professor Timothy Cox presented an exciting overview of current advances and
future directions in the application of gene therapy for the treatment of Lysosomal
Storage Disorders (LSDs), particularly those with central nervous system involvement.
At least 50 different LSDs have been identified and many, including Gaucher disease,
manifest neurological features. So often, it is disease of the nervous system that is
responsible for much of the disability faced by patients and their families in these
disorders.

    The development of appropriate means to deliver treatment to the nervous
system remains a priority goal for researchers, clinicians and the many patients
and their families affected by neuronopathic disorders. Scientists and pharmaceutical
companies are investing in the development of small molecules that have the ability
to cross the blood-brain barrier (a physiological barrier between the vascular supply
to the brain and the brain itself). Despite burgeoning research into new therapies
- including enzyme replacement, substrate reduction and chaperone therapy-
effective treatment for diseased brain and spinal cord has remained elusive. The benefit of this approach in
established disease is unknown and delivery of sufficient drug to the brain and spinal cord to effect a beneficial
response continues to be a challenge.

    It seems that the most promising advances in the treatment of central nervous system disease lie in the
development of genetic transfer technology – ‘gene therapy’, which may ultimately be combined with emerging
stem-cell techniques. The value of such an approach includes the potential of a permanent and total correction of
the underlying enzymatic and cellular defect (glucocerebrosidase in Gaucher disease) in those tissues targeted for
therapy. Intensive development of such techniques requires the conquest of numerous obstacles to its effective
application. However, encouraging progress has been made by worldwide efforts on the part of scientists involved
in vector development in the past decade.

   Dr. Begoña Cachón a senior research associate in the University of Cambridge, has pursued gene therapy
research for over 10 years with Professor Cox. Prof. Cox provided a summary of their work in this field, including
the exciting progress recently made and the promise this holds for the treatment of central nervous system disease
across a wide spectrum of lysosomal diseases and related disorders.

    Much of their research has concentrated on the GM2 gangliosidoses (known to many as Tay-Sachs and Sandhoff
disease) as a rigorous model for therapeutic intervention. The group has focused on the introduction and expression
of healthy genetic copies of the genes that are mutated in these disorders (HEXA and HEXB, encoding the pivotal
human hexosaminidase isozymes A and B) using a non-replicating adeno-associated virus system and several
critical ‘tricks’ to enhance expression of the therapeutic transgene products. AAV is a commonly encountered and
non-disease-causing virus that has been modified to provide a delivery system for the introduction of the chosen
corrective gene; the system is devoid of intrinsic pathogenic capacity.

   In the case of the very severe genetically modified and spontaneous animals with neurodegeneration resembling
Tay-Sachs disease, with extensive loss of neural functions, success with this technique has extended beyond
expectations and with promising outcomes in both small and large animal models. Much has been published in
the field but the functional outcomes of corrective gene transfer in the living animal models of acute
neurodegeneration in GM2 gangliosidosis are the best so far reported, despite the intimidating complexity of the
hexosaminidases in ganglioside metabolism. Mice and cats, which have a disease closely resembling the human
disorder, have shown dramatic improvements in neurological function and longevity following gene therapy.

    Prof. Cox and Dr. Cachón are actively pursuing their research into this treatment and are key founding members
of a recently formed international Tay-Sachs and Allied diseases gene therapy consortium, which has the aim of
conducting human trials in the near future. To this end, they have enlisted the collaborative assistance and support
of the Genzyme Corporation in the production of their vectors for experimental testing and ultimately, it is hoped,
convincing translation to the clinic.

   This research, and that of other groups involved in the field of gene therapy, clearly holds great promise for
patients with neuronopathic Gaucher disease and other LSDs, whose clinical needs remain unmet.



EWGGD Supplement                                               20                                        JULY 2008
   Biomarkers of avascular necrosis in Gaucher disease
Elena Pavlova, University of Cambridge, Cambridge, UK

Dr Pavlova provided an interesting overview of her research into the identification
of potential biomarkers for the severe skeletal manifestation of avascular necrosis
in Gaucher disease as part of the UK bone research consortium. Biomarkers are
identifiable indicators of a specific disease state or its progression, an example of
which and one well known to Gaucher patients is the monitoring of plasma
chitotriosidase activity. Dr Pavlova and her colleagues examined 100 adult patients
with type 1 Gaucher disease in order to ascertain their individual chemokine and
cytokine profiles. These are biochemical mediators with particular importance in
the inflammatory response. They are readily measurable through serum analysis
from blood samples and hold promising potential for use as biomarkers. Dr. Pavlova
identified a number of cytokines including CCL18, MIP-1â, and IL-8 to be significantly
elevated in patients with avascular necrosis when compared to patients without
avascular necrosis. These findings are encouraging and support further development
of cytokine profile analysis as biomarkers of avascular necrosis in Gaucher disease.
It is hoped that such tools will allow clinicians to predict the risk of avascular
necrosis in individual patients and allow early intervention in an effort to prevent progression to this severe skeletal
complication. Further studies in this area are planned by Dr. Pavlova and her colleagues.



   Chitotriosidase-monitoring during pregnancy in women
   with Gaucher disease
Verena Lehmann, University Chldren’s Hospital, Mainz, Germany

Chitotriosidase is a serum enzyme marker of Gaucher severity, which is routinely
measured to assess disease burden and decreases in activity are seen with successful
enzyme replacement therapy (ERT). Here was presented the alterations in chitotriosidase
level during five pregnancies. It was commented that in three women on ERT and in
another not on treatment, chitotriosidase activity decreased during pregnancy. It was
noted that there was a rebound exaggerated increase in enzyme activity compared to
pre-pregnant values post-delivery. This correlated with symptomatic disease in the
women not on ERT; this led to the commencement of enzyme therapy post-delivery.
Within the three women on ERT no change in dose was required during gestation. The
fifth women elected to stop ERT during pregnancy but due to symptomatic disease,
which was mirrored by an increase in chitotriosidase, infusions were re-started with
good therapeutic effect prior to delivery. It was concluded that symptoms and disease
correlated with enzyme activity during pregnancy. Hormonal or immunological reasons
were postulated to be behind the changes in chitotriosidase activity during pregnancy.
ERT was well tolerated by all in this study.



   Yet another glucocerebrosidase?
Hans Aerts, University of Amsterdam, Amsterdam, The Netherlands

Prof Aerts provided a fascinating review of glucocerebroside metabolism. He then
focused in detail on alternative pathways to metabolism by the lysosomal
glucocerebrosidase (GBA1), the enzyme deficient in Gaucher disease. Some
researchers have suggested that these alternative pathways may, in part, explain
the clinical differences observed between individual Gaucher patients. The first
alternative enzymatic pathway outlined by Professor Aerts was the GBA2 or non-
lysosomal glucosylceramide pathway. Unlike GBA1 this enzyme is located near the
surface of the cell, not within the lysosome. However, following an extensive study
                                                                                                  (continued overleaf)

EWGGD Supplement                                                 21                                         JULY 2008
(continued from previous page)
of this enzyme by his research group, Professor Aerts has not found any evidence to suggest that GBA2 plays any
role in modifying the clinical outcome in GBA1 deficient patients. Professor Aerts then proceeded to characterise
a second alternative metabolic pathway via by an enzyme which has been given various names by individual
researchers including broadly specific betaglucosidase, Klotho-related protein and most appropriately GBA3. This
enzyme has been well described and has been generally believed to play a role in the metabolism of plant matter
derived (xenobiotic) betaglucosides rather than intrinsic glucocerebroside. Professor Aerts and his research group
have re-examined this enzyme and have not identified any modifier role for genetic variation in GBA3 impacting
upon the clinical manifestation of Gaucher disease. In conclusion Professor Aerts confirmed that, although there is
no current evidence that GBA2 or GBA3 impact upon the clinical phenotype of GBA1 deficient Gaucher patients
further work is continuing into the investigation of these and other alternative pathways for glucocerebroside
metabolism.



   ER associated degradation and unfolded protein response
   in Gaucher disease patients
Mia Horowitz, Tel Aviv University, Tel Aviv, Israel

Mutations within the gene responsible for Gaucher disease lead to abnormal
glucocerebrosidase, reduced enzyme activity and glucosylceramide accumulation.
Glucocerebrosidase is synthesised from a genetic template in a factory designated:
“ribosomes”, from where it is transferred into another compartment of the cell called
the endoplasmic reticulum (ER). The ER has the ability to detect abnormal
glucocerbrosidase structures (mis-folded) and prevent them from being trafficked
to another part of the cell called the lysosome, its intended target. Instead, abnormal
glucocerebrosidase is detected within the ER and sent to part of the cell called the
proteosome, for degradation. This process is called ER Associated Degradation (ERAD).
The aim of treatment in Gaucher disease is to restore enzyme activity. Therefore
blocking ER ‘sensing’ mechanisms for abnormal glucocerebrosidase or the degradation
process within the proteosome is postulated to be therapeutically useful; this may
lead to an increase in both enzyme level and activity, mutation depending. ER function
is affected by changes in cholesterol level. Inhibitors of cholesterol synthesis were
reported here in cells grown in tissue culture to increase glucocerebrosidase levels.
Other experiments were presented in relation to unfolded protein response (UPR) in the ER. Accumulation of
glucosylceramide in normal cells did not affect this process, which was shown to be impaired in Gaucher cells. Work
continues into this important area. Manipulation of this process has potential therapeutic benefits.



   A nonsense mutation in the LIMP-2 gene associated with
   progressive myoclonic epilepsy and nephrotic syndrome.
Maria Clara Sa Miranda, Institute for Molecular and Cell Biology, Porto
University, Portugal

Dr Sa Miranda presented findings from two siblings with mutations of the LIMP-2
gene, a newly described trafficking receptor for betaglucocerebrosidase which
facilitates its mannose-6-phosphate independent transfer from the endoplasmic
reticulum to the lysosome. These patients presented with a form of progressive
myoclonic epilepsy and renal disease in the form of a nephrotic syndrome.
Biochemical analysis revealed a severe deficiency of betaglucocerebrosidase in skin
fibroblasts despite normal enzyme activity upon standard leukocyte screening
assays. Similarly, Chitotriosidase levels were normal. These findings lead Dr Sa
Miranda and her group to hypothesis that a defect in intracellular trafficking of
betaglucocerebrosidase was occurring and this lead to identification of LIMP-2
protein deficiency and screening for the LIMP-2 mutation in these patients. These
findings are of great interest and highlight the need to consider a deficiency of
LIMP-2 in patients with Gaucher disease when no mutation in GBA1 is identified.


EWGGD Supplement                                              22                                        JULY 2008
   Common variants in the glucosylceramide synthase gene
   are associated with the disease severity in Gaucher disease
   patients
Pilar Alfonso, University of Zaragoza, Zaragoza, Spain.

Dr Alfonso provided an overview of her and her colleagues research investigating genetic variation in the
glucosylceramide synthase (GCS) gene and its potential impact upon clinical severity and progression of Gaucher
disease. Glucosylceramide synthase (also known as UDP-glucose ceramide glucosyltransferase) is the first enzyme in
the glycosphingolipid synthetic pathway. It is hypothesised that genetic variability in this gene may influence the
clinical presentation of patients with Gaucher disease. Dr Alfonso analysed variations of the GCS gene in a Spanish
cohort of Gaucher patients and correlated these with disease severity as measured by the Gaucher disease Severity
Score Index (SSI). Her results demonstrate that, in the studied cohort, a number of genetic variations in the GCS gene
did in fact correlate with higher severity scores in patients with specific Gaucher disease genotypes. This has led Dr
Alfonso and her colleagues to conclude that genetic variants in the GCS gene may influence the development and
progression of Gaucher disease severity. They are continuing to their work to investigate this association.



   Plamsmalogen Levels in Gaucher Disease
Helen Michelakakis, Institute of Child Health, Athens, Greece

This oral presentation was focused on red blood cell levels of molecules called
plasmalogens. These play a role in cell membrane modulation, intra-cellular
signalling, cholesterol transport and protection against cell stress (oxidative
damage); all of these are reported to be disturbed in those with lysosomal storage
disorders including Gaucher disease. Here was reported that in patients with
untreated Gaucher disease red blood cell plasmalogen levels were lower than in a
control population. Enzyme replacement therapy was found to significantly increase
the level of these plasmalogens. The level of decrease in red blood cell plasmalogens
was correlated positively to chitotriosidase activity (routinely measured serum
marker of disease burden). It was concluded that further research into these
molecules are required to understand their function and role in Gaucher disease.



   Bone Marrow Transplantation for Acute Myeloid Leukaemia
   from donor with Gaucher disease followed by enzyme
   replacement therapy
Mirando Mrsic, University Hospital Zagreb, Zagreb, Croatia

Here was reported an interesting case where a newly diagnosed type I Gaucher
patient was used successfully as a bone marrow donor for his sister who was in
remission for standard risk acute myeloid leukaemia. Briefly the donor was found
to be have a low haemoglobin level, failed twice to have his stem cells collected
(the type of cell used to re-populate the recipients bone marrow) and subsequent
workup lead to a new diagnosis of Gaucher disease. There was a prior history of
splenectomy. Given the clinical benefit of receiving a fully matched sibling transplant
from her brother (rather than derived from a fully matched unrelated donor,
although results recently have much improved) it was decided to proceed. The
patient engrafted well from her brother’s bone marrow and subsequent
chromosomal analysis revealed her haematological cells to be 100% derived from
her sibling. She was initially treated expectantly with Cerezyme from 3 months
post-transplant in the fear that the development of Gaucher disease from her

                                                                                                (continued overleaf)

EWGGD Supplement                                                 23                                       JULY 2008
(continued from previous page)
brother’s transplanted bone marrow would jeopardise her graft. Due to administration reasons this was stopped
after two years but later was re-introduced due to the development of symptomatic Gaucher disease. Currently
she remains controlled on Cerezyme with no recurrence of her acute leukaemia, several years post-transplantation.
It was concluded that stem cell transplantation of bone marrow with Gaucher disease is feasible and can be
successful when clinically indicated.



   Validation of saccadic latency as a biomarker of cerebral
   injury in lysosomal storage disorders
Jonathan Roos, University of Cambridge, Cambridge, UK.

Jonathan Roos provided an interesting overview of the work he and his colleagues
have undertaken in their efforts to validate the use of saccadic latency as a measure
of cerebral involvement in lysosomal storage diseases. Saccadic eye movements
are the rapid simultaneous adjustments our eyes make when fixing upon a target,
whilst saccadic latency is the period of delay before they do so. Mr. Roos used an
infrared oculometric device with head mounted at laser targets to accurately
measure saccadic latencies in five patients with Sandhoff disease, a severe
neuronopathic storage disease and one patient with type 3 Gaucher disease. He
found that in the five patients with Sandhoff disease, prolonged latencies correlated
with a poorer clinical rating scores whilst, somewhat unexpectedly, other saccadic
parameters (used in clinical trials of miglustat) could not differentiate between the
patients and healthy volunteers. In the single patient with Gaucher disease
neurological involvement was only mild and this was reflected by latencies at the
higher end of the reference range. Mr. Roos’ study suggests that saccadic latency
measurements provide a robust, non-invasive and sensitive means of assessing
neurological involvement and most notably cortical dysfunction in patients with neuronopathic lysosomal storage
disease. This of course has important implications for the monitoring of an individual patient’s disease course and
response to therapy, and casts doubt on the use of non-latency parameters in the lysosomal disease setting.



   Chaperone effect of several iminosugars and aminocyclitols
   on mutated glucocerebrosidases as a possible approach
   to Gaucher Disease
Lluïsa Vilageliu Arqués, University of Barcelona, Barcelona, Spain

Reported in this oral presentation was the use of experimental compounds as
potential chaperone therapies for several different glucocerebrosidase mutations
that lead to reduced enzyme activity and Gaucher disease. Mutations within the
glucocerebrosidase gene lead to abnormal structural folding which in turn leads
to degradation within part of the cell called the endoplasmic reticulum.
Consequently the enzyme is not delivered to the lysosome, its intended intra-cellular
target, with subsequent lipid (glucosylceramide) accumulation. The idea behind
chaperone therapy is to cause stability to the mis-folded glucocerebrosidase. The
complex then moves to the lysosome to restore a degree of enzyme activity and
reverse Gaucher disease pathology. Six different compounds were tested (two
iminosugars and four aminocyclitols) against a panel of cells harbouring various
Gaucher gene mutations. It was concluded that these molecules were more effective
in stabilising mutations that were clinically mild with some residual activity.
Chaperone therapy, as expected, was reported to be less effective for severe
mutations that lead to little residual activity, despite transportation to the correct
intra-cellular compartment.




EWGGD Supplement                                                24                                      JULY 2008
   Inefficiency of drilling in the early stages of osteonecrosis
   in Gaucher disease.
Ehud Lebel, Shaare Zedek Medical Centre, Jerusalem, Israel.

Dr. Lebel provided a review of available therapeutic interventions for osteonecrosis
(avascular necrosis) in Gaucher disease.

   He addressed in detail the orthopaedic surgical technique of drilling or core
decompression that is widely advocated in managing pre-collapse stages of
osteonecrosis. To assess the outcome of this approach Dr. Lebel and his colleagues
undertook a review of their experience using drilling for juxta-articular (in close
proximity to the joint) osteonecrosis in a series of young adults with Gaucher disease.

   Eleven patients in their series underwent drilling at a total of 12 sites of
precollapse osteonecrosis. A further three patients with diseased in the precollapse
stage refused surgical intervention. They found that 9 joints treated by drilling
displayed progressive degeneration as did the 3 patients who refused drilling.

   As a result Dr. Lebel and his colleagues conclude that there is no significant
benefit to performing core decompression procedures in Gaucher patients with
precollapse stage osteonecrosis. They recommend that conservative measures such as preserving range of joint
motion, aspiration of joint effusions and adequate analgesia achieve similar short term efficacy without the risks
of surgery.

   Dr Lebel concluded by highlighting the need for further research to understand bone physiology and the
pathophysiology of skeletal involvement in Gaucher disease in order to develop effective intervention strategies.



   Gaucher disease: a model to study the role of
   glycosphingolipids in atherosclerosis
Johanna Groener, Department of Medical Biochemistry, Academic Medical
Center, Amsterdam, The Netherlands

Dr Groener provided a very interesting review of the plasma lipid profile in patients
with Gaucher disease.

   Patients are known to have low levels of High Density Lipoprotein (HDL)
cholesterol (often referred to as ‘good cholesterol’), high levels of apolipoprotein
E and increased levels of glucosylceramide and the ganglioside GM3.

    Dr Groener and her colleagues undertook a study to further characterise plasma
lipid profiles in Gaucher patients. They determined that, in addition to low HDL
cholesterol levels Gaucher patients have small sized HDL particles and an increased
number of small sized Low Density Lipoprotein (LDL) or ‘bad cholesterol’ particles,
a profile which is associated with a high risk of atherosclerosis in the general
population. However, despite this profile Gaucher patients do not have an increased
risk of atherosclerosis. This phenomenon indicates a role for glycosphingolipids in
lipoprotein metabolism and the development of atherosclerosis.

   As a consequence, Gaucher disease provides an exciting model for further study into the hugely important field
of atherogenesis. Dr. Groener and her colleagues are undertaking further studies to address their findings.




EWGGD Supplement                                                 25                                    JULY 2008
     Gauchers
                  ASSOCIATION
                  ASSOCIATION
       Susan Lewis Memorial Fund


The Susan Lewis Memorial Award was established          One of the first things that Susan did was to gather
by the UK Gauchers Association to provide grants        information from all sources and published a
and bursaries to doctors and other healthcare           newsletter to disseminate everything that the
professionals from developing countries (particularly   Association had learned. She knew that the collective
Eastern Europe) to allow them to                                           knowledge and experience would
travel to the UK Centres of                                                help patients. It quickly became
Excellence to undertake mentoring                                          clear that patients needed access
and educational programmes in the                                          to healthcare professionals
treatment and management of                                                experienced in treating Gaucher
Gaucher Disease.                                                           Disease. In the UK relationships
                                                                           quickly developed with the doctors
Susan Lewis was a founder                                                  and their teams who had both an
member of both the UK Gauchers                                             interest in Gaucher Disease and
Association and the European                                               had exposure to Gaucher patients.
Gaucher Alliance (EGA). The                                                Inevitably as more patients came
constant focus of all of Susan’s                                           to the Association for advice they
Gaucher activities was to help                                             were encouraged towards those
Gaucher patients and their                                                 doctors and other healthcare
families. She approached every                                             professionals who had such
meeting,      conference        or                                         experience thereby enlarging the
presentation with the aim of                                               pool of patients these doctors were
improving the position of patients                                         seeing. Susan passionately
both individually and collectively.                                        believed that the establishment of
                                                        the National Centres for the treatment of Gaucher
In 1991 when the UK Gauchers Association was first      Disease was essential in ensuring patients are
established patients’ prime need was information.       provided with the very best advice and treatment.




  EWGGD Supplement                                        26                                    JULY 2008
Through the establishment of national patient associations, their contacts with other patient groups and the European
Gaucher Alliance and through the internet and newsletters, patients throughout the world now have access to a
considerable amount of information about Gaucher Disease.

However what patients in some parts of the world are not able to enjoy is access to expert doctors experienced in
diagnosing, managing and treating their disease. Through the Susan Lewis Memorial Fund the Association hopes
to address in Susan’s name this lack of expertise where there may be few Gaucher patients and where treatment is,
or (until recently) has not been available. In the name of Susan Lewis we want to help doctors with little experience
in treating Gaucher disease and their teams achieve the excellent levels of expertise available to patients seen in
the long established centres.

What will the Fund cover?
Grants will cover travel costs; accommodation and will provide a small daily subsistence allowance.

What will the award cover and what is expected of the applicant?
The programmes will be individually tailored to take into account the applicants experience and special areas of
Gaucher interest. Successful applicants will be expected to write up the experience gained and on return to their
countries to work with and assist others in gaining experience of Gaucher Disease.

Who can apply?
Healthcare Professionals from Eastern Europe are a priority for this fund, however applications from other
developing countries will be considered. It is essential that all applicants are currently involved in the field of
Gaucher disease or other Lysosomal Storage diseases.

Applicants must be able to read, speak and understand English to a high level and be willing to spend up to 6
weeks in the UK on the programme.

How to apply?
Interested persons should complete an application form which is available in hard or electronic form from the
Gauchers Association Tel; 00 44 1453 549231 or by e-mail: ga@gaucher.org.uk

Completed application forms must be received by 26 September 2008 for consideration in the first round. Electronic
copies must be sent back to: ga@gaucher.org.uk and hard copy to: Gauchers Association, 3 Bull Pitch, Dursley,
Gloucestershire, GL11 4NG.

If you have any queries or would like to discuss this fund further please contact Tanya Collin-Histed, Executive
Director on: 00 44 1453 549231 or e-mail; ga@gaucher.org.uk




       This award has been established from funds generously donated by members and friends of the Gauchers
       Association, friends of Susan and her family from around the world and from grants received from the
       Pharmaceutical and Healthcare Industries.




              Registered Charity No: 1095657 Email: ga@gaucher.org.uk Website: www.gaucher.org.uk
               Patrons: Lord Janner of Braunstone QC, Sir Ivan Lawrence QC, Lord Stone of Blackheath
 The Gauchers Association Limited Registered in England & Wales No. 4468323. Registered Office: Red Court, Beaconsfield Road, Farnham Royal, Slough SL2 3BY
   EWGGD Supplement                                                                 27                                                    JULY 2008
   New look European Gaucher Alliance
At a meeting of European Gaucher Alliance (EGA) on 3rd and 4th
June in Budapest, Hungary representatives from 23 European
countries and South Africa unanimously agreed to incorporate
the EGA as a formal body and to apply for charitable status in
the United Kingdom.

The EGA adopted the following objectives:-

 1.    To collect information on the latest development in
       the understanding management and treatment of
       Gaucher Disease and to disseminate such information
       to all parties who have an interest in Gaucher Disease
       and other similar disorders.                                  Members of the EGA

 2.    To provide information, support, guidance and encouragement to groups of individuals representing Gaucher
       patients throughout Europe and elsewhere in the world.
 3.    To represent the interest of Gaucher patients to European and International organisations and bodies and to
       ensure that the voice of the Gaucher patient is heard at all times.
 4.    To encourage and promote scientific and medial research into Gaucher disease and improve therapeutic
       approaches and quality of life issues and to seek to ensure all research recognises centrality of the Gaucher
       patient.
 5.    To work with the medical and scientific community to help define priorities in the understanding of Gaucher
       Disease, its management and treatment.
 6.    To work with, facilitate, support and encourage the activities of the European Working Group on Gaucher
       Disease (EWGGD) and other organisations or working groups with similar objectives.
 7.    To be a forum to consider ethical issues arising from the study of Gaucher Disease, its management and
       treatment.
 8.    To ensure appropriate treatment is available to all patients with Gaucher Disease who require treatment
       regardless of race, creed, colour, ethnic origin or national religious background.

The EGA agreed to adopt a constitution with a management council composed of 9 directors each to be elected
for a term of 2 years with a specific field of responsibility.

In addition the Chairman, Secretary, Treasurer and Fund Raisers and Executive Members will have responsibilities
for collection and dissemination of information, relations with European bodies, relations with local patient
associations, relations with industry, relations with the EWGGD and relations with the scientific and medical
community. The EGA wishes to facilitate collaboration in any way that it can.

Although the EGA is a European organisation it recognises that it has in the past accepted responsibility to help
Gaucher patients and patient groups from all parts of the world and wants to be able to continue in this role. It
was agreed that Full membership be available to the original founding associations of the EGA (the UK, Italy,
Netherlands, Israel, France and Sweden) and to all other European Gaucher Associations. Patient groups from non
European countries are encouraged to apply to be Associate Members of the EGA although they will not be able
to vote at EGA Meetings.

Jeremy Manuel, Chairman of the UK Gauchers Association and Co Founder of the EGA was elected the first Chairman
of the Council. The other Council Members elected were:-

   •   Joseph Cohen (Israel)
   •   Tanya Collin-Histed (UK)
   •   Gil Faran (Israel)
   •   Anne-Grethe Laurdisen (Denmark)
   •   Lars Magnusson (Sweden)
   •   Pascal Niemeyer (Germany)
   •   Wojtek Oswiecinski (Poland)
   •   Fernanda Torquati (Italy)

For more information or to join the EGA please contact any of the Council Members known to you or Tanya Collin-
Histed at tanya@gaucher.org.uk

EWGGD Supplement                                                28                                       JULY 2008