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The LA Experience and Ataxia Medical Update

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The LA Experience and Ataxia Medical Update Powered By Docstoc
					          The LA Experience
     and an Ataxia Medical Update




Susan L. Perlman M.D.
Clinical Professor of Neurology
Director, UCLA Ataxia Center
Medical Director, NAF

March 18, 2011       NAF AMM LA CA Bringing the
                        Ataxia World Together
                 Los Angeles is much more than
                 Hollywood and the Beach Boys
• It started with a seafaring
  culture in Southern
  California in 8,000 B.C.;
• Incorporated Native
  Americans of the Hokan
  and Uto-Aztecan cultures,
  the Spanish, and
  ultimately all the rest of
  us;

• And will end when
  THE BIG ONE
  drops us back into the
  sea.
March 18, 2011           NAF AMM LA CA Bringing the
                            Ataxia World Together
  And I believe it is home to the first Ataxia Center
               West of the Mississippi




March 18, 2011     NAF AMM LA CA Bringing the
                      Ataxia World Together
        And home to some pretty nice weather
                  most of the time




March 18, 2011     NAF AMM LA CA Bringing the
                      Ataxia World Together
     UCLA ATAXIA/NEUROGENETICS CENTER

•   Founded--mid-1970’s as a research clinic for Friedreich’s Ataxia.

•   Has a database of over 3000 neurogenetics patients, most with ataxic
    disorders, as well as a DNA bank. Works with two tissue banks.

•   Evaluates about 75 new ataxia patients each year.
•   Evaluates asymptomatic individuals at-risk for ataxia.
•   Provides continuity care for many of these individuals.

•   Multidisciplinary model (multi-specialty Physician, Nursing, Social Work,
    Psychology, PT, OT, Orthotics, Speech, Nutrition, Genetics).

•   Is a member of the Cooperative Ataxia Group (www.cooperative-ataxia-
    group.org) and the Collaborative Clinical Research Network for FA, and
    collaborates with other ―ataxologists‖ across the USA and around the world.

•   Provides educational programs and inservice training, as well as community
    outreach through the National Ataxia Foundation (www.ataxia.org) and
    Friedreich’s Ataxia Research Alliance (www.curefa.org).

March 18, 2011                NAF AMM LA CA Bringing the
                                 Ataxia World Together
     UCLA ATAXIA CENTER DEMOGRAPHICS

• Catchment area—                                      Ethnic Distribution
                                                        African- Middle East /
  southwestern US, remaining                            American Mediterr Hispanic
                                                          14%       3%         17%
                                                      Asian
  US, Mexico, Canada, Pacific                         14%


  Rim, providing great ethnic                                         Caucasian /
                                                                      NW Europ
                                                                        52%
  and cultural diversity (but
  few large pedigrees).                           Distribution of Ataxia Syndromes
                                                    Friedreich’s           Known

• 40% of cases have either                             Ataxia               SCA
                                                        21%                 18%


  Friedreich’s ataxia or a
                                                                   Other
  known SCA                                                        61%



• 60% of cases have unknown                         Distribution of Dominant Cases
  genotype or sporadic                                 SCA3           SCA6SCA7
                                                                                     SCA6

  presentation, spurring the                       SCA214%
                                                    10%
                                                                       11% 5%        SCA7
                                                                                     Other
                                                  SCA1
  search for new genes and                          5%                               SCA1
                                                                       Other         SCA2
  epidemiologic factors                                                55%
                                                                                     SCA3


March 18, 2011       NAF AMM LA CA Bringing the
                        Ataxia World Together
                                   UCLA ATAXIA CENTER
                       1562 PATIENTS SEEN BETWEEN 1995 AND 2005
                              (CURRENTLY BEING UPDATED)
•     GENETIC (Total 656)                                      •     UNKNOWN GENE/SPORADIC (Total 904)
•     Dominant (329)                                           Adult Arnold-Chiari, CP, other congenital 30
SCA1 15               Cadasil 7                                Combined cortical atrophy 14
SCA2 32               DRPLA 2                                  HSA/HSP 76
SCA3 68               GSS 8                                    Immune-mediated 12
SCA6 34               SPG4 2                                   MSA 72
SCA7 14               FXTAS 2                                  NPH 7
SCA8 6                                                         Paraneoplastic 11
SCA10 2                                                        Post-infectious 17
SCA13 2                                                        PSP 20
SCA14 2                                                        Pure cerebellar (ILOCA) 219
SCA17 3                                                        SOPCA 97
Known mutation 196         Unknown mutation 129                Retroviral 7
No one yet with SCA 12                                         Vascular, post-anoxic, post-trauma 52
•     Recessive (250)                                          With known nutritional/toxic cause 16
A-T 26                                                         With dementia 11
EOCARR 6 (AOA1 1, AOA2 5)                                      With diabetes insipidus 1
Friedreich’s Ataxia 75 (looks like FA but isn’t 112)           With dizziness, vertigo, episodic 71
LOFA 14                                                        With dystonia 17
Confirmed inborn errors 6                                      With myoclonus 32
Late-onset Tay Sachs 11                                        With neuropathy 51
•     X-linked or Mitochondrial (80)                           With spasticity 53
AMN 10                                                         With tremor 14
Rett 2                                                         With white matter changes (not MS or Cadasil) 4
Pedigree suggests X-linked 8
Confirmed mitochondrial point mutation 6
Looks like mitochondrial but isn’t 54




March 18, 2011                                   NAF AMM LA CA Bringing the
                                                    Ataxia World Together
                        OUR GOALS HAVE BEEN
         TO ANSWER THE QUESTIONS ASKED BY OUR ATAXIA PATIENTS
                   TO MAXIMIZE THEIR QUALITY OF LIFE
                AND TO GET THEM INVOLVED IN RESEARCH

•   WHAT DO I HAVE?

•   WHAT IS THE CAUSE?

•   ARE MY CHILDREN AT RISK?

•   WILL IT GET WORSE?

•   HOW BAD WILL IT GET? HOW SOON?

•   CAN IT BE TREATED?

•   CAN IT BE CURED?

•   IS THERE ANY RESEARCH BEING DONE? CAN I GET INVOLVED?


March 18, 2011           NAF AMM LA CA Bringing the
                            Ataxia World Together
                 HOW FAR HAVE WE COME?


     QUESTION           1977                    2011
     What do I have?    10% known               >50% known
     Can it be cured?   No                      No
     Can it be treated? No drugs tested         18 drugs tested
                        Rehab helps             (more on the way)
                                                Rehab helps
     Is there research? 223 articles            1342 articles
     Are my children    No gene tests           21 gene tests
     at risk?           available               available($17K),
                                                more on the way


March 18, 2011            NAF AMM LA CA Bringing the
                             Ataxia World Together
          1. Diagnosis—Is this Ataxia?
• What are we actually seeing?
• It is important to nail down a phenotype that can be
  retrieved (with the patient) as advances are made in
  diagnosis and treatment of progressive ataxia.


• The launch of the National Ataxia Registry and
  Database will make this easier.
• Patient self-registration at:
     https://www.nationalataxiaregistry.org/
• Dr. Subramony is here helping people sign up in the
  National Ataxia Registry.


March 18, 2011     NAF AMM LA CA Bringing the
                      Ataxia World Together
             2. Proper Evaluation—
         Everyone Deserves a Screen For

  • Neural localization (MRI, ENG, EPs, EMG/NCV)
  • Acquired factors--prior illnesses, toxic exposures
                       or medication (Dilantin, amiodorone)
  • Other medical problems—
                 thyroid dysfunction
                 low B12 or E
                 syphilis, EBV, Lyme, HTLV1, HIV
                         rheumatologic factors
  • Immune/paraneoplastic—
                 anti-GAD, anti-gliadin, anti-thyroid
                 anti-Yo, Hu, Ri, others; imaging for hidden Ca
  • Possible genetic factors—why? Are they treatable? Not yet.
    But can aid in prognosis and family counseling if found.

March 18, 2011         NAF AMM LA CA Bringing the
                          Ataxia World Together
      Our Approach to the Adult-onset,
    Predominantly Cerebellar Syndromes
•   Assign a phenotype by H & P, imaging, electrodx, LP
•   Obtain a detailed family and environmental history
•   Rule out known acquired causes.
•   Consider genetic testing—
    Screening for FXTAS, SCA6, FRDA, as well as
    SCA1,2, and 3 will identify over 50% of possible
    inherited causes and cost less than $3000.
    2-5% of sporadic cases turn out to be genetic.

• Establish a treatment plan that includes
  symptomatic medication and rehabilitation.
• Help patients find resources and get involved in
  research.
March 18, 2011      NAF AMM LA CA Bringing the
                       Ataxia World Together
    Growth of Clinical Research at UCLA (1)
                   the 1980’s
•   1980-82—4 unfortunate publications looking for the cause of Friedreich’s ataxia before we had molecular
    genetic technologies to help us

•   The rest of the 1980’s not so bad, as we focused on the clinical aspects of FA and related ataxias:
•   Evoked potential abnormalities in the various inherited ataxias.
•   Nuwer MR, Perlman SL, Packwood JW, Kark RA.
•   Ann Neurol. 1983 Jan;13(1):20-7.
•   Eye movements in Friedreich's ataxia.
•   Furman JM, Perlman S, Baloh RW.
•   Arch Neurol. 1983 Jun;40(6):343-6.
•   Cardiac involvement in Friedreich's ataxia: a clinical study of 75 patients.
•   Child JS, Perloff JK, Bach PM, Wolfe AD, Perlman S, Kark RA.
•   J Am Coll Cardiol. 1986 Jun;7(6):1370-8.
•   The mental status of patients with Friedreich's ataxia.
•   Flood MK, Perlman SL.
•   J Neurosci Nurs. 1987 Oct;19(5):251-5
•   Idiopathic central diabetes insipidus followed by progressive spastic cerebral ataxia. Report of four cases.
•   Birnbaum DC, Shields D, Lippe B, Perlman S, Phillipart M.
•   Arch Neurol. 1989 Sep;46(9):1001-3.

•   And were able to run early pilot studies of physostigmine as a symptomatic treatment for ataxia:
•   Double-blind, triple-crossover trial of low doses of oral physostigmine in inherited ataxias.
•   Kark RA, Budelli MM, Wachsner R.
•   Neurology. 1981 Mar;31(3):288-92.


March 18, 2011                            NAF AMM LA CA Bringing the
                                             Ataxia World Together
    Growth of Clinical Research at UCLA (2)
                   the 1990’s
•   The 1990’s:
•   Saw the beginning of our ongoing collaboration with the Ataxia Telangiectasia
    Research Laboratory at UCLA (Dr. Richard Gatti).

•   We continued work with neuro-otology and neuro-opthalmology:
•   Comparison of oculomotor findings in the progressive ataxia syndromes.
•   Moschner C, Perlman S, Baloh RW.
•   Brain. 1994 Feb;117 ( Pt 1):15-25.
•   Ophthalmologic findings in patients with ataxia.
•   Rabiah PK, Bateman JB, Demer JL, Perlman S.
•   Am J Ophthalmol. 1997 Jan;123(1):108-17.
•   Oculomotor phenotypes in autosomal dominant ataxias.
•   Buttner N, Geschwind D, Jen JC, Perlman S, Pulst SM, Baloh RW.
•   Arch Neurol. 1998 Oct;55(10):1353-7.




March 18, 2011                NAF AMM LA CA Bringing the
                                 Ataxia World Together
•   And finally the scientific revolution, brought about by molecular genetic
    technology, opened up the first multi-center collaborations, with Dr. Gomez at
    U Minn (after his stint at UCLA), as well as our own UCLA-based
    phenotype/genotype studies.

•   The prevalence and wide clinical spectrum of the spinocerebellar ataxia type 2
    trinucleotide repeat in patients with autosomal dominant cerebellar ataxia.
•   Geschwind DH, Perlman S, Figueroa CP, Treiman LJ, Pulst SM.
•   Am J Hum Genet. 1997 Apr;60(4):842-50.
•   Friedreich's ataxia GAA repeat expansion in patients with recessive or sporadic
    ataxia.
•   Geschwind DH, Perlman S, Grody WW, Telatar M, Montermini L, Pandolfo M, Gatti
    RA.
•   Neurology. 1997 Oct;49(4):1004-9.
•   Spinocerebellar ataxia type 6. Frequency of the mutation and genotype-phenotype
    correlations.
•   Geschwind DH, Perlman S, Figueroa KP, Karrim J, Baloh RW, Pulst SM.
•   Neurology. 1997 Nov;49(5):1247-51.



March 18, 2011                NAF AMM LA CA Bringing the
                                 Ataxia World Together
    Growth of Clinical Research at UCLA (3)
                   2000-2010
•   In the new millennium:

•   We published our first review of symptomatic treatment for ataxia, based on
    our experiences as well as the published experiences of other ―ataxologists‖.
•   Cerebellar Ataxia.
•   Perlman SL.
•   Curr Treat Options Neurol. 2000 May;2(3):215-224.

•   Joined Dr. Dave Lynch’s Collaborative Clinical Research Network for FA.
•   As well as the Cooperative Ataxia Group under Drs. Ashizawa and Subramony.

•   And were finally able to get back into drug trials:
•   A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia.
•   Lynch DR, Perlman SL, Meier T.
•   Arch Neurol. 2010 Aug;67(8):941-7.

•   And the pilot study of Varenicline in SCA3 under Dr. Theresa Zesiewicz



March 18, 2011                  NAF AMM LA CA Bringing the
                                   Ataxia World Together
•   Began our collaboration with the neuroimaging groups at UCLA:
•   Analysis of the brain-stem white-matter tracts with diffusion tensor imaging.
•   Salamon N, Sicotte N, Alger J, Shattuck D, Perlman S, Sinha U, Schultze-Haakh H,
    Salamon G.
•   Neuroradiology. 2005 Dec;47(12):895-902. Epub 2005 Sep 13.
•   Late-onset Friedreich ataxia: phenotypic analysis, magnetic resonance imaging
    findings, and review of the literature.
•   Bhidayasiri R, Perlman SL, Pulst SM, Geschwind DH.
•   Arch Neurol. 2005 Dec;62(12):1865-9.
•   Pontine and cerebellar atrophy correlate with clinical disability in SCA2.
•   Ying SH, Choi SI, Perlman SL, Baloh RW, Zee DS, Toga AW.
•   Neurology. 2006 Feb 14;66(3):424-6.
•   White matter fiber tractography and color mapping of the normal human cerebellum
    with diffusion tensor imaging.
•   Salamon N, Sicotte N, Drain A, Frew A, Alger JR, Jen J, Perlman S, Salamon G.
•   J Neuroradiol. 2007 May;34(2):115-28.
•   Patterns of fractional anisotropy changes in white matter of cerebellar peduncles
    distinguish spinocerebellar ataxia-1 from multiple system atrophy and other ataxia
    syndromes.
•   Prakash N, Hageman N, Hua X, Toga AW, Perlman SL, Salamon N.
•   Neuroimage. 2009 Aug;47 Suppl 2:T72-81. Epub 2009 May 14

March 18, 2011                 NAF AMM LA CA Bringing the
                                  Ataxia World Together
•   Continued our work with genotype/phenotype:
•   SCA8 repeat expansions in ataxia: a controversial association.
•   Sobrido MJ, Cholfin JA, Perlman S, Pulst SM, Geschwind DH.
•   Neurology. 2001 Oct 9;57(7):1310-2.
•   Association of moderate polyglutamine tract expansions in the slow calcium-activated potassium channel type 3 with ataxia.
•   Figueroa KP, Chan P, Schöls L, Tanner C, Riess O, Perlman SL, Geschwind DH, Pulst SM.
•   Arch Neurol. 2001 Oct;58(10):1649-53.
•   The SCA12 mutation as a rare cause of spinocerebellar ataxia.
•   Cholfin JA, Sobrido MJ, Perlman S, Pulst SM, Geschwind DH.
•   Arch Neurol. 2001 Nov;58(11):1833-5.
•   Late-onset pure cerebellar ataxia: differentiating those with and without identifiable mutations.
•   Kerber KA, Jen JC, Perlman S, Baloh RW.
•   J Neurol Sci. 2005 Nov 15;238(1-2):41-5. Epub 2005 Aug 16. Review.
•   Depressive and memory symptoms as presenting features of spinocerebellar ataxia.
•   McMurtray AM, Clark DG, Flood MK, Perlman S, Mendez MF.
•   J Neuropsychiatry Clin Neurosci. 2006 Summer;18(3):420-2.
•   Novel mutations in the senataxin DNA/RNA helicase domain in ataxia with oculomotor apraxia 2.
•   Fogel BL, Perlman S.
•   Neurology. 2006 Dec 12;67(11):2083-4.
•   A family with combined mutations of the hemophilia A and X-linked adrenoleukodystrophy genes.
•   Fogel BL, Young P, Thompson AR, Perlman S.
•   Neurogenetics. 2008 Jul;9(3):215-8. Epub 2008 May 15.
•   Aberrant splicing of the senataxin gene in a patient with ataxia with oculomotor apraxia type 2.
•   Fogel BL, Lee JY, Perlman S.
•   Cerebellum. 2009 Dec;8(4):448-53.
•   Candidate Screening of the TRPC3 Gene in Cerebellar Ataxia.
•   Becker EB, Fogel BL, Rajakulendran S, Dulneva A, Hanna MG, Perlman SL, Geschwind DH, Davies KE.
•   Cerebellum. 2011 Feb 16.



March 18, 2011                                  NAF AMM LA CA Bringing the
                                                   Ataxia World Together
  Clinical Studies We are Currently Doing
                  at UCLA
   1. Clinical Research Consortium for Spinocerebellar Ataxias [CRC-SCA] to Study
   Natural History and Genetic Modifiers in Spinocerebellar Ataxias [SCA]--Natural
   History Study for SCA1, 2, 3, and 6 only.
   Not a drug trial. All ages and levels of disability. Visits every 6 months for 2 years. No
   travel reimbursement.
   2. Clinical Outcome Measures in Friedreich Ataxia--Natural History Study for
   Friedreich's Ataxia.
   Not a drug trial. All ages and levels of disability. Visits once a year. Some travel
   reimbursement.


   3. Molecular Genetic Studies in Diseases of the Brain Affecting Movement and
   Balance--one visit for anyone with any type of ataxia, all ages and levels of disability.
   Not a drug trial. A neurological history and exam plus blood draw will be done. No
   travel reimbursement.
   4. Benefits of Hydrotherapy Versus Conventional Physical Therapy in the
   Treatment of Friedreich Ataxia--open to Friedreich's ataxia patients 18 years of age
   and older who are still ambulatory (with or without assistive devices) and can come in
   for physical therapy 3 mornings per week for 1 to 3 months. No travel reimbursement.


March 18, 2011                  NAF AMM LA CA Bringing the
                                   Ataxia World Together
    The Geschwind Lab for Basic Research

•    Dr. Daniel Geschwind is the Gordon and Virginia MacDonald Distinguished
    Chair in Human Genetics and is a professor of neurology and psychiatry at
    the UCLA School of Medicine. He is director of the Neurogenetics Program
    and the Center for Autism Research and Treatment (CART) and co-director
    of the Center for Neurobehavioral Genetics at UCLA.
•    The Geschwind laboratory is working to improve our understanding of
    human neuropsychiatric diseases, such as autism and neurodegenerative
    diseases, and their relationship to the range of normal human higher
    cognitive function. We use a combination of genetic, functional genomic and
    neurobiological methods in our work--frequently in collaboration with other
    laboratories or disciplines. Our methodological focus involves the
    application of network analyses and systems biology, which offer the
    promise of integration of multiple levels of data, connecting molecular
    pathways to nervous system function in health and disease.


March 18, 2011              NAF AMM LA CA Bringing the
                               Ataxia World Together
    Partners in Clinical Neurogenetics Research
                       at UCLA
•   Daniel Geschwind, M.D., Ph.D., Neurogenetics Program Director (Molecular Genetics, DNA bank)
•   Susan Perlman, M.D., Ataxia Clinic Director (Ataxia Database, Drug Trials)
•   Robert Baloh, M.D. (Neuro-Otology)
•   George Bartzokis, M.D. (Neuroimaging, Biomarkers)
•   Yvette Bordelon, M.D., Ph.D. (Huntington’s disease, Biomarkers, Drug Trials)
•   Stephen Cederbaum, M.D. (Medical Genetics, Metabolic Disorders)
•   Giovanni Coppola, M.D. (Molecular Genetics)
•   Brent Fogel, M.D., Ph.D. (Molecular Genetics, DNA bank)
•   Ming Guo, M.D., Ph.D. (Drosophila)
•   Michelle Hamilton, M.D., Juan Alejos, M.D. (Cardiology)
•   Joanna Jen, M.D., Ph.D. (Episodic Ataxias, Drug Trials)
•   Arik Johnson, Psy.D. (Psychology)
•   Catherine Mamah, M.D. (Molecular Genetics)
•   William Oppenheim, M.D. (Orthopedics)
•   Noriko Salamon, M.D. (Neuroradiology)
•   Eric Wexler, M.D., Ph.D. (Psychiatry)
•   Ernest Wright D.Sc., Ph.D, Vladimir Kepe Ph.D,, Jorge Barrio Ph.D. (Neuroimaging, Biomarkers)

•   GlennyJane Gabriel — Clinic Coordinator (310) 825-3370
•   Tarshiah Nulliah— Ataxia Research Coordinator (310) 206-8153
•   Barbara Fallick, MSW — Social Work Coordinator (310) 794-1225
•   Michelle Fox, M.S. — Genetic Counselor (310) 206-6581

•   New Patient Appointments — (310) 794-1195 and follow the menu


March 18, 2011                       NAF AMM LA CA Bringing the
                                        Ataxia World Together
    Goals for Future Clinical Trials at UCLA

•   A longitudinal natural history study for people with non-genetic ataxia
    or less common genetic ataxias.

•   An epidemiologic study of environmental and lifestyle factors that can
    influence the cerebellum and progression of ataxia.

•   More Drug trials—pilot or Phase I, II, or III
               for the SCAs
               for Friedreich’s ataxia
               for Ataxia Telangiectasia
               for other recessive ataxias
               for non-genetic ataxia
               for Multiple System Atrophy

•   Our clinical neurogenetic research team is eager to push forward with
    these important projects, together with all our colleagues here and
    around the world. We need each other and WE NEED YOU.

March 18, 2011               NAF AMM LA CA Bringing the
                                Ataxia World Together
March 18, 2011   NAF AMM LA CA Bringing the
                    Ataxia World Together
            Upcoming Ataxia Medical Update
    Diagnosis, Symptomatic Treatment, Disease-Modifying Therapy, Resources
•   You will be hearing a lot more about advances in all areas of ataxia over the rest of the convention and in
    the Birds of a Feather sessions:
•   The rest of Friday morning:
    9:45 a.m. ............ Melinda Guttry, PT & Jacquelyn Glenn, OTR ......OT/PT for Ataxia
•   10:40 a.m. .......... Anne Lefton, CCC-SLP ......................................... Speech & Swallowing
•   11:20 a.m. ........... Al LaSpada, MD, PhD, FACMG ............................ Poly Q SCAs/SCA7

•   Saturday
•   8:30 a.m. ............ Jamie Hoffman, CTRS ............................ Adaptive Recreation, What You CAN DO!
•   8:55 a.m. ............ Richard Ivry, PhD ....................                     How Cerebellar Dysfn Affects Motor Control
•   9:20 a.m. ............ Joel Gottesfeld, PhD ............................... HDAC Inhibitors in FRDA
•   9:45 a.m. ............ Vikram Shakkottai, MD, PhD .................. Clinical Trials and Natural History Study
•   10:10 a.m. .......... Theresa Zesiewicz, MD, FAAN ............... Analysis of Chantix Clinical Trial
•   10:35 a.m. .......... Clive Svendsen, PhD .............................. Stem Cell Research for Ataxia
•   11:00 a.m. .......... Henry Paulson, MD, PhD ........................ Research Update
•   2:00 p.m. ............ Christopher Gomez, MD, PhD ................ Medication for Ataxia Symptoms
•   2:25 p.m. ............ S.H. Subramony, MD .............................. National Ataxia Registry
•   2:50 p.m. ............ Ralph Miller .............................................. Wheelchair Yoga
•   3:15 p.m. ............ Arnie Gruetzmacher, CFP ....................... Financial Planning

•   Sunday
•   9:00 a.m. ............ Sid Gilman, MD .......................................Sporadic Ataxia and MSA Research
•   9:25 a.m. ............ Una Lee, MD ........................................... Management of Neurogenic Bladder
•   9:50 a.m. ............ Joanna Jen, MD, PhD ............................. Management of Dizziness in Ataxia
•   10:15 a.m. .......... Jon Rodis, MBA .......................................Applying for Social Security Disability
•   10:40 a.m. .......... Brent Fogel, MD, PhD ............................. Recessive & Paraneoplastic Ataxia


March 18, 2011                                NAF AMM LA CA Bringing the
                                                 Ataxia World Together
            And with the Internet,
         you can become the teachers
•   http://www.ncbi.nlm.nih.gov for PubMed and OMIM
•   http://www.neuro.wustl.edu/neuromuscular
•   http://www.geneclinics.org
•   http://www.curefa.org
•   http://www.ataxia.org
•   http://cooperative-ataxia-group.org/
•   http://www.eurosca.org/


March 18, 2011     NAF AMM LA CA Bringing the
                      Ataxia World Together
                         A Brief Literature Search
    for the past 10 years in humans (double the numbers if you include animal studies)
                               http://www.ncbi.nlm.nih.gov for PubMed
                              and www.clinicaltrials.gov for Clinical Trials


•    Spinocerebellar ataxia—--2486 articles
•    Multiple system atrophy--1903 articles
•    Friedreich’s ataxia-------- 619 articles
•    Sporadic ataxia------------ 375 articles
        ____________________________________________________
•    Spinocerebellar ataxia—----44 clinical studies
•    Multiple system atrophy—-35 clinical studies
        (fluoxetine, lithium, IVIG, stem cells, riluzole, rasagiline, minocycline)
        (14 dealing with low blood pressure)
•    Friedreich’s ataxia------------19 clinical studies
•    Sporadic ataxia------------------4 clinical studies
                                           (coQ10, Riluzole, IVIG-all completed)

       ______________________________________________________________________
       ______________________________________________________________________
•    Parkinson’s disease--------30,022 articles
                                   746 clinical studies

March 18, 2011                       NAF AMM LA CA Bringing the
                                        Ataxia World Together
                 First Thing To Remember

• Everything we are doing with the genetic and
  non-genetic ataxias can be applied to the
  other genetic and non-genetic brain diseases
  and vice versa.

• This includes research about normal nerve
  cell functioning, nerve cell sensitivities,
  nerve cell death, ―normal aging‖, and
  environmental and lifestyle factors that
  influence the brain.

March 18, 2011         NAF AMM LA CA Bringing the
                          Ataxia World Together
              COOPERATIVE ATAXIA GROUP
         founded in 2002 for the development of natural history studies and therapeutic trials in ataxia

      * T Ashizawa,            University of Florida,          Sue Perlman                       UCLA
                                   Gainesville           _______________________       _______________________
     S H Subramony
                                                              Kathleen Poston              Stanford University
Laura Ranum, Mike Waters
         SCA10                                             *Louis Ptacek SCA7             University of San
       Thomas Bird            University of Washington          Gail Kang                    Francisco
________________________    ________________________
     Thomas Crawford          Johns Hopkins University           Stefan Pulst              University of Utah
           AT                                                       SCA2

 John Day, Khalif Bushara     University of Minnesota       (Bernard Ravina)           University of Rochester
 SCA5, 8; Gluten Ataxia
                                                           * Andrew McGarry                      NY
     Kurt Fischbeck                  NINCDS
                                                         * Jeremy Schmahmann                Mass General
    Sid Gilman MSA            University of Michigan               MSA
   Hank Paulson SCA3
                                                                Lew Sudarsky              Brigham and Womens
      Chris Gomez              University of Chicago
         SCA6
       Mark Hallett                  NINCDS                    George Wilmot                     Emory


     Robert Herndon             Univ of Mississippi                                        Johns Hopkins
                                                         * Joseph Savitt
                                                            Sarah Ying
    Al La Spada SCA7                 UCSD
________________________    ________________________         Theresa Zesiewicz         University of South Florida
       Ja-Shin Lou             University of Oregon
 Dave Lynch, Rob Wilson     University of Pennsylvania
                                                                Huda Zoghbi                     Baylor
   Friedreich’s ataxia
                                                                  SCA1                             East Coast 13
                             Columbia University                                               Middle America 4
   * Pietro Mazzoni                                                                                West Coast 6
March 18, 2011   NAF AMM LA CA Bringing the
                    Ataxia World Together
March 18, 2011   NAF AMM LA CA Bringing the
                    Ataxia World Together
       We need enough sites to run all the
        clinical trials barreling toward us
• Clinical Trials




March 18, 2011      NAF AMM LA CA Bringing the
                       Ataxia World Together
   NECESSARY COMPONENTS FOR A
 SUCCESSFUL CLINICAL TRIAL (besides $)
•   Disease mechanism understood
•   Candidate drugs
•   Natural history baseline
•   Rating scales, QOL measures
•   Biomarkers to speed up the trials
•   Research centers to do the trials
•   Patient Registries to find the subjects
•   Database to keep it all in
March 18, 2011   NAF AMM LA CA Bringing the
                    Ataxia World Together
                 WHAT WE ALREADY HAVE

• Disease mechanism understood--somewhat
• Candidate drugs— some ideas, need more
• Natural history baseline— being collected
X Rating scales, QOL measures
• Biomarkers — being developed
X Research centers – telemedicine would help
X Patient Registries
X Database to keep it all in
March 18, 2011        NAF AMM LA CA Bringing the
                         Ataxia World Together
                          ―18 Drugs Tested‖
                 (But Almost None in Controlled Trials)
            Some Commonly Used Off-Label Ataxia Treatments

•   1. ImmunoRx—Corticosteroids                      •   4. Action tremor
                Mycophenolate mofetil (CellCept),           Carbamazepine
                Rituximab (Rituxan)                         Clonazepam
                IVIG, plasmapheresis                        Gabapentin
                                                            Isoniazid
•   2. Anti-Oxidants                                        Levetiracetam
       Alpha lipoic acid                                    Ondansetron
       Coenzyme Q10                                         Primidone
       Creatine                                             Propranolol
       L-carnitine                                          Topiramate
       N-acetylcysteine                                     Valproate
       Omega 3 fish oil/EPA (eicosapentanoic acid)          Zonisamide
       Selenium
       Vitamin E (d-alpha tocopherol succinate)      •   5. Nystagmus Dizziness
                                                            Acetazolamide
•   3. Ataxia                                               Baclofen
       Acetazolamide                                        3,4-diaminopyridine
       Amantadine                                           Carbamazepine
       Buspirone                                            Clonazepam
      Gabapentin                                            Gabapentin
       L-5-OH tryptophan                                     Meclizine
      Thyrotropin releasing hormone                          Ondansetron
      Varenicline                                            Promethazine
      Several others in very small trials based on           Valproate
    animal or in vitro studies

March 18, 2011                         NAF AMM LA CA Bringing the
                                          Ataxia World Together
          Brain Stimulation Rather than Drugs
           again, very few and small studies

• Deep brain stimulation with implanted
  electrodes—used mainly for tremor.

• rTMS—repetitive transcranial magnetic
  stimulation over motor cortex and over
  cerebellum.



March 18, 2011      NAF AMM LA CA Bringing the
                       Ataxia World Together
             Exercise Always Helps Ataxia
                          Brain Aerobics




March 18, 2011       NAF AMM LA CA Bringing the
                        Ataxia World Together
         Treatment Trial Retrospective
•   Mov Disord. 2009 Jun 15;24(8):1111-24.
•   Effectiveness and safety of treatments for degenerative ataxias: a systematic
    review.
•   Trujillo-Martín MM, Serrano-Aguilar P, Monton-Alvarez F, Carrillo-Fumero R.
•   Canary Islands Research and Health Foundation (Fundación Canaria de
    Investigación y Salud-FUNCIS), Santa Cruz de Tenerife, Canary Islands, Spain.
    matrumar@gobiernodecanarias.org

•   The aim of this study was to determine the effectiveness and safety of available
    treatment alternatives for degenerative ataxias (DA). We systematically reviewed
    studies that assess pharmacological, rehabilitative, or psychological treatments in
    patients with DA. Twenty-five studies were included

•   Most studies were of small sample sizes, wide age variations, and low scientific
    validity.

•   Availability of quality studies to evaluate the safety and efficacy of treatments for most
    DA is scarce. Further investigations with improved trial designs are necessary.

•   BUT THE PROCESS CAN SEEM OVERWHELMING.

March 18, 2011                   NAF AMM LA CA Bringing the
                                    Ataxia World Together
                 TYPES OF CLINICAL TRIALS
       TYPE         # SUBJECTS LENGTH                     AIM OF STUDY

                    1                         Ongoing     Do I get better or stop getting
       N of 1                                             worse on this drug?
                    Up to 20                  Weeks to    Is a larger study worth doing,
       Pilot        All get drug              months      will there be problems?
                    20-80 normal or patient   2 years     Escalating doses to learn side
       Phase 1      in groups of 3                        effects, safety, best dose
                    20-300                    2 years     To assess potential for good
       Phase 2      Placebo and                           effects, as well as side effects.
                    drug groups                           Also designed as ―futility‖
                                                          study—to show a drug doesn’t
                                                          not work(fewer subjects, less$)
                    300-3000                  3-5 years   To prove efficacy
       Phase 3      Placebo and                           May include crossover design,
                    drug groups                           open extension trial
                    100’s-1000’s              Ongoing     To find out more about the
       Phase 4      Open drug use                         effects of an approved drug.

March 18, 2011                    NAF AMM LA CA Bringing the
                                     Ataxia World Together
   OFFICIAL PIPELINE FOR NEW DRUGS

Up to 15 years and $500-700million      •   Discovery—clinicians and
                                            scientists working out the cause of
                   to get to market         the disease, the ―dominos‖ that fall
                                            over, and targeted candidate drugs.
                                        •   Preclinical testing—test tube and
                                            animal studies.
                                        •   Phase I—dosing, safety

                                        •   Phase II—safety, possible efficacy

                                        •   Phase III—efficacy
                                        •   FDA Approval
                                        •   Phase IV--Post-marketing studies
                                            for long-term side-effects and good
                                            effects.

                                        •   To help with promising drugs for serious
                                            diseases with unmet needs:
                                        •   NIH—Rapid Access to Intervention
                                            Development (RAID)
                                        •   FDA—Orphan Drug Status

March 18, 2011            NAF AMM LA CA Bringing the
                             Ataxia World Together
                 FUNDING
      A PUBLIC-PRIVATE PARTNERSHIP
•   Discovery—clinicians and                 •   Government
    scientists working out the cause of          Private research foundations
    the disease, the ―dominos‖ that fall
    over, and targeted candidate drugs.
    $25-80,000 per yr over many years

•   Preclinical testing—test tube and        •   Government
    animal studies.                              Private research foundations
    $100,000 per year for at least 2 yr          Pharmaceutical companies

•   Phase I and Phase II--                   •   Government
    $500-700,000 per year for 4 yr               Private research foundations
$2-4 million to get to this point                Pharmaceutical companies

•   Phase III—$4-5 million ($10K/subject)    •   Pharmaceutical companies
•   FDA Approval
•   Post-marketing studies for long-
    term side-effects and good effects
    and possible other uses of the drug.

March 18, 2011                 NAF AMM LA CA Bringing the
                                  Ataxia World Together
                 The Bottom Line

• Every ataxia patient must participate in
  clinical trials.
• Every researcher designing a clinical trial
  must make it accessible to all ataxia
  patients.
• There will be exceptions to both of these
  fiats, but they must be justified.


March 18, 2011    NAF AMM LA CA Bringing the
                     Ataxia World Together
  Every Ataxia Patient Must Participate in
              Clinical Trials
1. Registries will enable you to be found.
   These are rare diseases with very small
   numbers of patients who can participate.
   Every person counts.
2. Be knowledgeable about what makes a good
   clinical trial—don’t make bad investments.
3. Speak up about the roadblocks to participation.
   Become involved in planning the trials.
4. Be prepared to make sacrifices.

March 18, 2011   NAF AMM LA CA Bringing the
                    Ataxia World Together
                   Sacrifices

• Time
• Money
• Confidentiality
• Giving up one drug trial to participate in
  another.
• Risking receiving a placebo.


March 18, 2011   NAF AMM LA CA Bringing the
                    Ataxia World Together
      DO WE REALLY NEED PLACEBOS?
•   Gold Standard for Phase III clinical trials is the double–blind, placebo-
    controlled, randomized study.

•   The ―placebo effect‖ is very real and ideally accounts for all the other effects
    not related to the drug directly.

•   Dramatic differences between the placebo and drug groups will usually result
    in all subjects being placed on drug before the end of the trial.

•   If it would be dangerous for a potential subject to end up on placebo, that
    subject would not be enrolled in the study. This includes the subject having to
    stop other medications to enter the study.

•   Active placebos may be used.

•   Use of historical controls or subject acting as own control may require a longer
    study to prove benefit of drug.

March 18, 2011                 NAF AMM LA CA Bringing the
                                  Ataxia World Together
   Every Researcher Designing A Clinical
    Trial Must Make It Accessible To All
              Ataxia Patients.
• Design trials that can use the fewest patients over the
  shortest period of time (this usually means testing better
  drugs and using biomarkers).
• What is the rationale for excluding certain patients? Can
  those excluded be used in other ways? Parallel or
  compassionate studies?
  But remember that a patient can participate in only one
  trial at a time and that participation in some trials may
  permanently disqualify participation in others.
• Reimbursing travel costs is essential for recruitment and
  compliance. Telemedicine?
• Don’t expect the patients to make unreasonable
  sacrifices.

March 18, 2011       NAF AMM LA CA Bringing the
                        Ataxia World Together
     Roadblocks for Clinical Researchers

• Picking the right drugs.
• Designing the trial properly—number of patients,
  measures/biomarkers, length of study, placebo,
  how many sites.
• Getting the FDA to agree.
• Getting funding.
• Finding sites and getting them approved.
• Finding subjects.
• Doing the work in a timely fashion.
March 18, 2011   NAF AMM LA CA Bringing the
                    Ataxia World Together
 WHAT WE HAVE DONE IN SPITE OF ALL THIS
                 October 2007----------------------------------------------------Today




March 18, 2011                    NAF AMM LA CA Bringing the
                                     Ataxia World Together
•
                             THANK YOU
       National Ataxia Foundation—
        sponsor of grants for our internal database, our DNA bank, our web-based
       database project, and the SCA3 Chantix study.

•      The Cooperative Ataxia Group—
         sponsor of the grant for the SCA Natural History Study.
         NINDS RC1 NS68897 and NIH Office of Rare Diseases Research

•      Muscular Dystrophy Association and
•      Friedreich’s Ataxia Research Alliance—
         sponsors of the grant for the collaborative project on ―Clinical Outcome
       Measures in Friedreich’s Ataxia‖.
         http://www.curefa.org/registry.html EVERYONE REGISTER!

•      The Smith Family Foundation
•      The Bettencourt Family Foundation
•      The Norman Lapin Fund
•      The Mariette Monnier Fund

•      And to our patients and their families for their willingness to work with us and
       to share with us their ideas and hopes.

    March 18, 2011                NAF AMM LA CA Bringing the
                                     Ataxia World Together

				
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