Phylomers Synthetic peptides derived from genomic fragments by mercy2beans120

VIEWS: 12 PAGES: 55

									Phylomers: Synthetic peptides derived from genomic fragments
      suitable for intracellular and extracellular targets

                 Paul Watt, VP Drug Discovery

                     www.phylogica.com
                          Forward-looking statements
This presentation includes forward-looking statements that are subject to risks and uncertainties.
 Such statements involve known and unknown risks and important factors that may cause the
  actual results, performance or achievements of Phylogica to be materially different from the
                                    statements in this presentation.
                Actual results could differ materially depending on factors such as
 the availability of resources, the results of clinical studies, the timing and effects of regulatory
                      actions, the strength of competition and the effectiveness
                                         of patent protection.
   Contents of presentation
Harvesting structurally diverse peptide sequences from natural proteins

   Why are biological therapies increasingly important?
   What are Phylomers?

   Multiple Phylomer hits to extracellular targets with biological efficacy

   Hit rates from Phylomer library screens against intracellular targets
   In vitro validation of biological activity of Phylomers
   Stability and immunogenicity profiles of Phylomer® peptides
   In vivo validation of Phylomers against intracellular targets
        - Phylomers validated in traumatic brain injury/stroke, acute burns, and
        Acute Respiratory Distress Syndrome (ARDS)
   Using Phylomers as a tool for target validation (protein interference)
   Summary
                       More than half of the targets tractable
                       with small molecules have been drugged!

Biological therapeutics provide a means
of significantly expanding target space
  More diverse structures mean more hits on target




Phylomers libraries contain multiple classes of subdomain
structures from diverse evolutionary protein lineages
         Origin of Phylomer® Peptides
   a diverse class of drug harvested from nature’s biodiversity
Phylomers® are new class of peptide derived from cloned fragments
of biodiverse bacterial and archael genomes

From 25 characterised bacterial genomes we have derived up to 260 million
distinct Phylomer® peptides from thousands of protein structural folds

Highly stable protein structures from microbes living in extreme environments




                                                              Watt PM (2006)
                                                              Nature Biotechnology
                                                              Vol 24 (2):177-83
              Extracellular targets program:
screening Phylomers® to inhibit the function of targets that play a
                   crucial role in inflammation
Screening against extracellular targets
               validated therapeutic targets for inflammation




     GM-CSF ligand (antagonist)

     TNF! ligand (antagonist)

     CD40 ligand (antagonist)
            Hit rates with Phylomer Phage Display Libraries

Multiple Phylomers isolated from library samples of only 108 independent
clones bind specifically to extracellular targets
    Phage M13pIII-displayed (low copy) Phylomer Library
                         GM-CSF         TNF-a             CD40L

    No of pannings          5              6                4

    Total Screened        1017           1179             1244

    Total Positive         11            110              195
    % Positives            1.1           9.3              15.7

    Phage M13pVIII-displayed (high copy) Phylomer Library
                         GM-CSF         TNF-a             CD40L

    No of pannings          2              2                2

    Total Screened         282           470               282

    Total Positive         56             51               48
    % Positives           19.9           10.9             17.0
High-throughput screens for high affinity hits
                                         spot competition ELISA assay
 Phylomer® libraries were screened using Phage Display to identify target
 specific hits. Assessment of relative binding and specificity was carried out
 using Phage ELISA.

 Immobilised target competes for binding to phage-displayed Phylomer®
 peptide in the presence of 0.5 !M and 1 !M free target

 48 Phylomer® hits against CD40L with IC50s of under 500nM
Phylomer® affinities before maturation
                     low nanomolar IC50 values with naïve Phylomers®
Assessment of relative binding affinity using competition ELISA

Immobilised target competes for binding to phage-displayed peptide in the
presence of synthesised free Phylomer® peptide (26 aa) or free target

High affinity hits obtained before application of affinity maturation
  Clone No      Clone ID        IC50 nM
     1       CD40L_M1_6           61.3
     2       CD40L-M1_7           64.8
     3       CD40L-M1_9           81.1
     4       CD40L-M1_10          43.8
     5       CD40L-M1_18          25.0
     6       CD40L-M1_4          100.8
     7       CD40L-M1_8           35.8
     8       CD40L-M1_28          21.9
     9       CD40L-M1_74          45.5
     10      CD40L-M1_83          47.6
     11      CD40L-M1_51          46.0
     12      CD40L-M1_38          81.5
     13      CD40L-M1_50          45.8                        IC50
     14      CD40L-M1_63          79.8                        22±5 nM (free target)
                                                              68±5 nM (free peptide)
        Functional validation of CD40L-specific hits
Antagonism of a neutralizing monoclonal antibody
with naïve Phylomer hits before any affinity maturation
ELISA-based Assay: Phylomer peptide blocks binding of CD40L to
neutralising anti CD40L antibody


             0.70
                                                         Hit No M_1 18
                                                         Control Peptide
             0.65


             0.60


             0.55


             0.50
                 0.01   0.1        1          10   100
                              Phylomer [uM]
   Functional validation of CD40L-specific hits
Functional antagonism of CD40L-dependent biological activity
FACS-based Bioassay: Phylomer peptide inhibits expression of
CD40L-induced CD86 on primary B cells
                  Hit No M_1 18                                            Control peptide
     100
                                                             100

     75                                                      75

                                                             50
     50
                                                             25
     25
                                                              0
      0                                                             1.25         5.00      20.00
           0.15   0.30   0.60  1.25    5.00                  -25
                                                                            Control Phylomer Peptide (uM)
                    Test Phylomer (uM)


                                               Hit No M_1 18
                                   100


                                    75


                                    50


                                    25


                                     0
                                     10-7         10-6             10-5
                                              Phylomer (M)
    Functional validation summary of CD40L-specific Phylomers

                               Competition ELISA                Bioassays
                        anti-CD40L Antibodies
 Peptide ID         MAB617/CD40L CBC24-31/CD40L    CD40/CD40L
    1   M1_1S            -               ND           ND           ND
    2   M1_1             -                -           ND           ND
    3   M1_2S            +                +            +            +
    4   M1_4             -                -           ND           ND
    5   M1_4S            +                -           ND           ND
    6   M1_6S            +                +            +            +
    7   M1_7S            -                -           ND           ND
    8   M1_8S            -                -           ND           ND
    9   M1_9S            -                +           ND            +
   10   M1_10            -                +            -           ND
   11 M1_12              -                +            -            +
   12   M1_17            -                -            -           ND
   13   M1_18            +                +            +            +
   14   M1_26            -                -            -           ND
   15   M1_38S           -                +            -            +
   16   M1_42S           +                +            +            -
   17   M1_50S           -                -            -           ND
   18   M1_51            -                -            +            -
   19   M1_65            -                -            -           ND
   20   M1_70            +                +           ND            +
   21   M2_83S           +                +            +            +
   22   M1-87            -                -           ND           ND
   23   M2_148           -                -           ND           ND
   24   M2_150           -                -           ND           ND
   25   M2_154S          -                -           ND           ND
   26   M2_158           -                -           ND           ND
   27   T1_228S          -                -           ND           ND
   28   T1_223S          -                -           ND           ND
   29   T1_225S          +                +           ND            +


ND - Not done yet
Phylomer can have exquisite target specificity

             Binding of phylomer mimetic of Der P2 allergen competed by Der
             P2 allergen itself
             No inhibition of binding of phylomer mimetic of Der P2 allergen was
             observed by the closely related allergen Der f2 and EurM2
                        - allelic specificity (discrimination of only 2 amino acids)

                             Competitive inhibition of Phylomer™
                         binding to anti-allergen monoclonal antibody

                        10B2pan8
   80000
   60000
                                           Der p 2
   40000
                                           Der f 2
   20000
         0
   TRF




             0    200     400        600   800       1000
                        ng competitor
  Binding of specific phylomer to anti-Der p2
  Competition with cognate allergen (Der p2)
  No competition with related allergen (Der f2) sequence
  (Only two amino acid difference)
                Intracellular targets program:
    Identifying Phylomers® to inhibit the function of targets that play a
crucial role in inflammation: eg. MAPK, NF"B and TLR signaling pathways
               Opsona Collaboration
                   Intracellular blocking of TLR-dependent signalling
• Opsona are experts in the field of TLRs and TLR signalling
  – key inflammatory disease pathways


• Opsona founded by Luke O’Neill (Trinity College Dublin)
   – Discovered major intracellular TLR signalling adaptor mechanisms


• Together, we have generated a series of specific lead
  phylomer compounds which bind an intracellular adaptor
  protein involved in modulating TLR signalling

• The target TLR adaptor is amenable to number of chronic
  and acute inflammatory diseases
Phylomer® screen statistics show high hit-rates
  Yeast two-hybrid screen of a Phylomer library of approximately 106
  Phylomers against an intracellular adaptor protein involved in TLR signaling

  More than 50% of the validated hits show biological activity in mammalian
  reporter gene assays linked to TLR signalling

  Significant enrichment for natural ORFs
      •    <15% of library is in natural frame, yet 41% natural ORFs found in hits

      STATISTICS                  SCREEN #1       SCREEN #2       TOTAL
      number of specific hits          16              21           37

      % natural ORF                   44%             38%          41%

      mean size                      52 aa           35 aa         42 aa

      mean size of ORFs              72 aa           60 aa         66 aa

      mean size of Non-ORF           36 aa           20 aa         26 aa
Blocking TLR-signaling with Phylomers®
Blocking TLR-signaling with synthetic Phylomers®
Synthetic phylomer sequence fused to TAT protein transduction domain




 THP-1 Blue CD14 (1x106 cells/ml) preincubated 1hr with samples (µM) and stimulated overnight with
 20 ng/ml ligand. Readout= Quantiblue.
Brain Damage in Stroke
                                 Ischemia is followed by apoptotic damage
Long-term apoptosis is a significant cause of enduring brain damage

After a stroke the cells surrounding the initial lesion die over hours to days

No effective treatment exists to prevent this neuronal cell death and
associated loss of function following a stroke

                                               Impairment of function (penumbra)

                                                                Structural lesion




                Minutes


                                       Hours




                                                                         Days & weeks
        Adapted from Dirnagl U et al, Trends in Neurosciences (1999)
Phylomer® efficacy in vitro
                                         neuronal injury models




     Glutamate excitotoxicity model


     NMDA excitotoxicity model


     Transient oxygen-glucose deprivation model
Glutamate excitotoxicity model
                         protection against glutamate-induced apoptosis


                             Exposure                       Measure
               Synthesised   to 100!M Culture               neuronal
                 peptide     glutamate at 37°C              survival




 Rat neuronal cells
Rat neuronal cells     15 min      5 min         24 hours
Synthetic Phylomers® protect neuronal cells
      multiple Phylomer® hits show significant neuroprotection

                        100
                                                                                       ** p < 0.0001




          % Neuronal viability
                                 80                                                                      **
                                                                                           **                                                **


                                 60

                                                                             **
                                 40                                                                                    **
                                                               **


                                 20

                                                               L-PYC19-TAT
                                  0
                                                                             L-PYC35-TAT

                                                                                           L-PYC36-TAT

                                                                                                         L-PYC38-TAT

                                                                                                                       L-PYC41-TAT
                                      No insult




                                                                                                                                     TAT-D
                                                  No peptide




                                                                                                                                             D-JNKI-1 -TAT
Dose-dependent neuroprotection
     L & D Phylomers® inhibit glutamate-induced apoptosis



         PYC35                           PYC36
NMDA excitotoxicity model
                             protection against NMDA-induced apoptosis


                             Exposure                      Measure
               Synthesised            Culture
                             to 200!M                      neuronal
                 peptide              at 37°C
                               NMDA                        survival




 Rat neuronal cells
Rat neuronal cells     15 min     15 min        24 hours
Phylomers® confer neuroprotection
                                                 inhibition of NMDA-induced apoptosis

                                                    p < 0.0001




         % Neuronal survival
                               100

                               80

                               60

                               40

                               20

                                0



                                                 No peptide




                                                                                      Blockers
                                     No insult




                                                              PYC35-TAT


                                                                          PYC36-TAT
Transient oxygen-glucose deprivation model
                    mimicking conditions following cerebral ischemia
            Pre-insult                              Post-insult
            Synthesised                              Synthesised
              peptide                                  peptide


                      Wash;                    Re-supply
                   Incubation in Anaerobic      culture                   Measure
                   Glucose-free/ incubator     medium;                    neuronal
                   Deoxyglucose                Glucose/                   survival
                       BSS                      Oxygen




Rat neuronal cells 15 min             35 min                   24 hours
Protection from ischemia-induced death
    inhibiting cell death pre-and post oxygen-glucose deprivation




            % Neuronal survival
                                                                   p < 0.0001
                                  100


                                  80


                                  60


                                  40


                                  20


                                   0
                                                    No peptide
                                        No insult




                                                                                                            Post-insult
                                                                                 Post-insult
                                                                    Pre-insult




                                                                                               Pre-insult
                                                                 D-PYC35-TAT D-PYC36-TAT
Pharmacological properties of Phylomers®:
   stability, pharmacokinetics, and immunogenicity
Stability of Phylomers®
                  high stability of modified and unmodified peptides
Plasma stability of unmodified lead Phylomers® range from 10 minutes to 30
minutes in rat plasma
 - Unmodified Phylomers® are stable in buffer, but are degraded by
   proteases in plasma as with many other peptides


Plasma stability of modified (retroinverted) Phylomer® peptides is greatly
improved with more than 50% of the Phylomer® peptides present after 12 hrs
incubation in human plasma
 - Retroinverted Phylomers® are stable and protease-resistant in human
   plasma
 - Retroinverted Phylomers® show greatly extended in vivo half-life of up
   to 100 min in rat plasma without further modification (e.g.PEGylation)


Retroinverted Phylomer® peptides have also been demonstrated to be highly
stable in physiological buffer
Stabilities of Phylomers are compatible with     infusion for acute treatment
settings (eg stroke,TBI, severe burns)
In vitro stability
                              Phylomer® half-life in human plasma
Quantitation of Phylomer® peptides using High Performance Liquid
Chromatography (HPLC) and Mass Spectrometry (MS) for the duration of
the study (up to 12 hrs)
       Phylomer® [!g/ml]




                              Time [min]
     InSymbiosis, Canada
In vivo stability
                                        pharmacokinetic studies in rats
Quantitation of Phylomer® peptides levels by HPLC/MS in blood samples
over a period of time following intravenous injection

In vivo half-lives of approx 100 minutes for two unPEGylated retro-inverted
Phylomer® peptides
     •   Half life of PEGylated Phylomers are being tested currently
Immunogenicity potential of Phylomers®
  in silico and ex vivo approaches to assess immunogenic potential
In silico testing of 28 Phylomer® peptides tested against multiple HLA
haplotypes
    - Only a few Phylomers® have a high chance of being immunogenic


Phylomer® hits were aligned to known MHC Class II epitopes and then
docked to MHC allotypes to rank degree of likelihood of immunogenicity
    - More than 60% of Phylomer® peptides were not modeled as significantly
      immunogenic
    - More than 85% of Phylomer® peptides, including PYC35 and PYC36 were
      potentially less immunogenic than currently marketed peptide drugs


Phylomers with greater risk of immunogenicity were generally larger
    - More likely to contain MHC epitopes


Ex vivo human mixed lymphocyte assay identifies Phylomers
with minimal proliferative activity (2-10%) against PBMC
across 40 different UK human MHC allotypes
                       Modeling Phylomer® immunogenicity
                                                                              low immunogenic potential




                                                                                                      Calcitonin (32)
                                                                                                      r-Insulin (51)

                                                                                                                        Fuzeon (36)
                                                 Phylomer® peptides
                                                      (14-80 aa)

                       +++
 MHC Ligands/Peptide




                        ++

                         +
                                                                                                                                             es
                                                                                                                                         t yp ide
                                                                                                                                      llo ept
                                                                                                                                     A /p
                                                                                                                                  HC nd
                                                                                                                                 M ou
                             1   3   5   7   9   11   13   15      17   19   21   23   25   27   29    31                          b
                                                       Peptide No.

Accuro Biologics Ltd, UK
              Phylomer function in vivo:
In vivo validation of Phylomer peptide delivery by the intravenous,
             topical and intranasal inhalation routes
                        In vivo efficacy:
assessing Phylomers® for treatment of stroke, head trauma and burns
Phylomer® efficacy in vivo
                   models of head trauma, stroke and burns




     Global model of ischemic stroke

     Focal models of CNS injury (include IV delivery)

     Full thickness burns model (topical delivery)

     Inhaled LPS model of ARDS (inhaled delivery)
Global model of ischemic stroke
                                In vivo rat model of cerebral ischemia
Rat two vessel occlusion with hypotension model: both carotid arteries are
occluded lowering the blood pressure to 45mmHg, followed by reperfusion
and restoration of blood pressure


                          11nmoles
   Global                  peptide                               Assess CA1
  cerebral                                                       7 days post
 ischemia                intracerebro-
                                                                  ischemia
                           ventricular




  8 min       1 hr                              7 days
Neuroprotection in a global ischemia model
                                                   post insult treatment with Phylomers®




         Hippocampal CA1 Cell Count
                                      350   n=3
                                                   *p<0.05 compared with NaCl
                                      300

                                      250

                                      200                              n=6
                                      150                                *
                                      100
                                                              n=3
                                       50           n=5

                                        0
                                            Sham    NaCl     PYC36      D-PYC36
                                                             scram

                                                       8 minute global cerebral
                                                             ischaemia
                                                       11nmoles peptide (ICV)
                                                      added 1 h post-ischaemia
      Phylomer Protection from brain damage of
       Permanent Focal Ischaemia - PYC36-D
          Intravenous administration of peptide
                            *
                                      400

                                      350



               (Infarct volume mm3)
                    Brain Damage      300


                                      250    N=4
                                                       N=3

                                      200

                                      150

                                      100
                                                                  N=4
                                      50

                                       0
                                            Saline    PYC36D     PYC36D
                                                     Scrambled
                                                      Control
500 nMol/Kg Phylomer peptide administered IV 1 hour Post-ischaemia
Focal model of cortical CNS injury
                                in vivo rat model of traumatic brain injury
There are currently no effective treatment available for Traumatic Brain
injury (TBI); e.g. invasive head injuries

Similar pathways of neuronal cell death are
activated in the case of stroke and TBI

                                                           1.5mm




     Chung RS et al,
     The Journal of Neuroscience (2003)
Protection from neuronal death
                                         significantly reduced cortical lesions
Extent of neuronal death measured as loss of MAP immunoreactivity in
representative cortical lesions 24 hrs post injury and concomitant treatment
with Phylomers®


                                                                      2.5




                                                       Loss of MAP2 (mm2)
                                                                            2

                                                                      1.5

                                                                            1
                                                                                      *
                                                                      0.5

                                                                            0
                                                                                  D-PYC35T    D-PYC35scr

                                                                                * P < 0.05 compared with the
                                                                                (scrambled D-PYC35) control
Adrian K West, NeuroRepair Group, UTAS
Phylomer® efficacy in vitro and in vivo
              Skin burns (apoptosis and wound healing models)
  Immediately following a burn injury, the cells surrounding
  the injury site undergo cell death which inhibits wound
  healing and increases scaring (first 12 hours critical)

  Phylomer treatment to minimise burns induced cell death
      • emergency therapy for severe burns

  UV induced apoptosis model
  Mouse full-thickness burns model
     • topical application of Phylomers under a dressing
Full thickness burns model
                                   in vivo mouse model of burn injuries
Burn injuries are the third leading cause of accidental death in the US

After a burn injury, the cells surrounding the injury site undergo cell death
similar to the damage following a stroke

 1) Full-thickness burn    2) Addition of peptide      3) Skin analysis

    10 mm (2% TBSA)          20mM peptide in PBS          Skin sample taken
    9 sec contact burn       Injected under Tegapore      on days 1, 3, 7 and
    95°C                     membrane                     11 post burn
                             Wound contact – 5min




                                                            FACS            Histology
Histology of burn site
                         mouse full thickness burns model

         Day 1




         Control 2x           Control 20x




         PYC35B
         Treated 2x           Treated 20x
                                        Treatment of burns with Phylomers®
                                             topical application of Phylomers® improves wound healing
                  Treated wounds close faster: from day 7, treated 2cm burns have
                  significantly more re-epithelialised and the distance between the wound
                  edges is significantly smaller                         Day 11
                                                                                                                          Untreated
                  Reduced scars following Phylomer treatment
                                                                                                            p<0.05
                                       Re-epithelisation of 2cm burn injury treated with PYC35B
re-epithelialised/micrometres




                                                     (3 micromolar concentration)                                    0.2 mm
                         25000
                                                                 Statistically significant p=0.008
        Distance not




                         20000                               *
                                                                                                                     PYC35B treated
                         15000                                                                    PBS
                                                                                                  3uM   *
                         10000                                                                                       0.11 mm

                                5000

                                  0
                                              0                 7               15
                                                      time post-injury/days
PYC35B treated wound has less scarring (dose of 3!M)




                                                     * p=0.002


                                                       *




    Scar is bisected and histology sections used to measure
    distance between hair follicles on either side of the wound
    equating to the scar
   Experiment 4 – Toxicity of SP35 toxicity of lead Phylomer for burns
No evidence of in vitro on human NHEK cells
    Method                                            Trypan         b lue dye exclusion and cell counting
       Trypan Blue dye exclusion assay with
    Result
       normal human epidermal keratinocytes

                                               Toxicity Assay of SP35 on NHEK cell in
     Percentage of Dead Cells                                  DMEM
                                          100.00
                                              80.00                                          Control

                                              60.00                                          0.5 uM

                                              40.00                                          1 uM
                                                                                             500 uM
                                              20.00
                                                                                             1000 uM
                                               0.00
                                                      4 hrs     24 hrs         48 hrs
                                                                Time



                                                              Total Cell counts


                                              250


                                              200
                                                                                                    C
                                Cell number




                                              150                                                   0.5
                                                                                                    1
                                              100                                                   500
                                                                                                    1000
                                              50


                                               0
                                                      4              24                 48
                                                                 tim e/hours
Minimal evidence of systemic toxicity of D-PYC35-TAT

   Intended to be delivered topically to burns sites

   Rat IV dose range finding study (preliminary results):

   • Escalating IV doses: 1, 3, 10, 30 and 100 mg/kg

   • Toxicity only reported at 100 mg/kg IV

   • No effects seen at lower doses (i.e 1, 3, 10 or 30 mg/kg IV)

   Screening bank of radioligand cell binding and enzyme
   assays for off-target effects show no significant interactions
   with common markers
Treatment of ARDS with Phylomers®
Animals were either untreated (control), given LPS alone (open bars), given LPS and treated
with scrambled peptide (filled bar), or treated with Phylomers (hatched bars) and BAL
performed 6 hour post LPS administration.

Treatment was by intranasal inhalation of peptide before and upon LPS challenge

Readout is neutraphils as % of Bronchoalveolar lavage (BAL) performed 6 hours
after LPS administration.

                                             total number of neutrophils recovered from BAL
                                        30
                                        20
          Total # of neutrophils x104




                                                               P=0.0096



                                                                            P=0.0297




                                                                                        P=0.0011
                                        10
                                        10
                                        8
                                        6
                                        4
                                        2
                                        0
                                              control   LPS   #36          #35         #38         Control
                                                                                                   peptide


                                                                          LPS + phylomer
            Intellectual Property
                  An integrated patent portfolio
to establish dominant ownership of the entire Phylomer drug class
          Phylogica owns the most comprehensive
          collection of peptide shapes found in
          nature
          Patents cover methods of making and
          screening Phylomer libraries and
          composition-of-matter on peptides
          12 patent families, 25 granted/ allowed
          patents and 24 patent applications
          covering the markets of US, Europe,Japan
          and Australia
         Phylomer peptides as target validation tools
                                  Acting at the level of protein interactions
     Exploiting high functional hit rates of Phylomers for protein interference




Watt, PM et al., (2006) Expert Opin. Drug Discov. 1:492-502
                      Summary of Phylomers
What are Phylomers?
           Peptides from biodiverse genomic fragments
Phylomer peptides offer significant advantages as
a new class of biologics:
           Able to hit intracellular targets which antibodies can’t
                      eg.                                                  factors,kinases
                    - eg. intracellular signalling adaptors, transcription factors,kinases


            Able to block targets which small molecules can’t
                      eg.
                    - eg. transcription factors, protein interactions etc.


            Reduced cost of goods (synthetic production)

            No antibody IP-associated royalty stack (increases profit margin)

            Alternative patient friendly delivery potential (inhaled, intranasal)

            Phylomer approach is validated in multiple diseases

            Could be useful for diagnostics and imaging
                                                                              www.phylogica.com
                                                                              www.phylogica.com
  Phylogica’s team, collaborators & co-development partners
                        Paul Watt         Marie Scobie           Vanessa Cull
                       Nadia Milech        Daniel Shaw         Katharine Adcroft
                     Richard Hopkins       Clinton Hall          Ryan Jeffries
                     Michelle Schaffer    Scott Winslow         Darryl D’Souza
                     Katrin Hoffmann                            Darcelle Dixon
                                            Patrick Holt
                                         Deborah Strickland
Australian Neuromuscular            University of Western Australia       McComb Foundation
      Research Institute                     Renae Barr
         Bruno Meloni                      Marie Bogoyevitch
                                                                                Mark Fear
         Amanda Meade                                                          Fiona Wood



  Erica Golemis
 Ilya Serebriiskii
Roland Dunbrack




                            PHYLOGICA (www.phylogica.com)

								
To top