new ways to build muscle for muscular dystrophy

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New Ways to Build Muscle for Muscular Dystrophy: GENE THERAPY to INHIBIT MYOSTATIN presented at PPMD's 2010 Annual Connect Conference

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  • New Ways to Build Muscle for Muscular Dystrophy

    GENE THERAPY to INHIBIT MYOSTATIN

  • MYOSTATIN

    MYOSTATIN Gene discovered in mouse Inhibition or loss leads to muscle enlargement

    Human Gene found in 2004

    1997

    Baby at 7 months without myostatin

    Schuelke, Wagner, Stolz, et al N Engl J Med 2004

  • Can We Harness this as an approach for Gene Therapy ?

    Myostatin Inhibition

  • Smad 3 Smad 2

    Smad 4

    Follistatin

    FLRG

    GASP1

    ActRIIB Alk4 /Alk5 co-receptor P P

    P

    P

    P

    P

    M M

    M M

    M M Propeptide Circulating

    Propeptide Myostatin Complex

    Myostatin Dimer Propeptide Complex

    nucleus

    Smad Complex

    Activation of target genes

    Signal Peptide SP

    Cleavage

  • Candidate Genes for Myostatin Inhibition

    Comparison of hindlimb Strength in C57/B6 mice

  • Follistatin Gene (DNA) 1 2 3 4 5 6a 6b

    1 2 3 4 5 6b

    SP

    Adeno-associated Virus (AAV)

    FS344

  • Injection of Leg Muscle

    180 days

    Treatment of muscular dystrophy mouse

    Control Gene Therapy Control Gene Therapy

  • None Gene Normal Therapy

    CK

  • MOVING TO NON-HUMAN PRIMATE

    Can the Mouse Studies Predict Safety and Efficacy in a Clinical Trial ?

  • FS344 Gene Transfer to Monkey

  • Follistatin Blood Levels Thigh Circumference Treated

    Untreated

  • AAV1-FS

    Control

    Untreated Low dose high dose

    Gene Therapy

  • The Clinical Problem Quadriceps muscle weakness (Becker Muscular Dystrophy Sporadic Inclusion body myositis)

    Frequent falls/ loss of ambulation

    Clinical trial improving quadriceps muscle strength would result in a

    clinically meaningful outcome

  • Resistant to Muscle Strength Training

    Weight training

    Electrical Stimulation

    Anabolic Steroids

  • Wyeth sponsored 11 Center Trial (10 USA;1GB) Using MYO-029 antibody to myostatin

    No Clinical Benefit Muscle histology showed a trend toward increased muscle fiber size Demonstrated safety of systemic delivery of a

    myostatin inhibitor in a clinical trial

    Ann Neurology March 11, 2008

  • Can Follistatin Gene Therapy be Done Safely ?

  • Clinical Chemistries Monkeys used in Pre-clinical Studies

  • IMMUNE RESPONSE

  • Full Examination of Non-Human Primates

    Slides on each organ evaluated by a board certified veterinary pathologist blinded to treatment group (control vs FS)

    No treatment-related abnormalities found in heart, liver, lung, spleen, kidney, testis, ovary and uterus (5 &15 months)

  • Cardiac Studies Post AAV1.FS344 Treatment 15 months

  • Moving Forward FDA has given approval to move to a

    clinical trial PPMD has supported studies in Becker

    muscular dystophy Clinical trial will begin in December

    2010 - January 2011

  • Clinical Trial Design Six BMD patients will undergo direct

    injection of AAV1.MCK.Follistatin into quadriceps muscles (1x1012 vg/muscle)

    Patients will be followed for six months Muscle biopsies will be done at 3 and 6

    months Muscle size will be assessed and any signs of

    muscle inflammation/damage MRI of quadriceps at 3 and 6 months Muscle strength and 6MWT will be assessed

  • Collaborators Brian Kaspar Louise Rodino K.Reed Clark Kevin Flanigan Zarife Sahenk Chris Walker

    Support Parent Project Muscular Dystrophy

    The Myositis Association