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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<ul><li><p>New Ways to Build Muscle for Muscular Dystrophy </p><p>GENE THERAPY to INHIBIT MYOSTATIN </p></li><li><p> MYOSTATIN </p><p> MYOSTATIN Gene discovered in mouse Inhibition or loss leads to muscle enlargement </p><p>Human Gene found in 2004 </p><p>1997 </p><p>Baby at 7 months without myostatin </p><p>Schuelke, Wagner, Stolz, et al N Engl J Med 2004 </p></li><li><p>Can We Harness this as an approach for Gene Therapy ? </p><p>Myostatin Inhibition </p></li><li><p> Smad 3 Smad 2 </p><p>Smad 4 </p><p>Follistatin </p><p>FLRG </p><p>GASP1 </p><p>ActRIIB Alk4 /Alk5 co-receptor P P </p><p>P </p><p>P </p><p>P </p><p>P </p><p>M M </p><p>M M </p><p>M M Propeptide Circulating </p><p>Propeptide Myostatin Complex </p><p>Myostatin Dimer Propeptide Complex </p><p>nucleus </p><p>Smad Complex </p><p>Activation of target genes </p><p> Signal Peptide SP </p><p>Cleavage </p></li><li><p>Candidate Genes for Myostatin Inhibition </p><p>Comparison of hindlimb Strength in C57/B6 mice </p></li><li><p>Follistatin Gene (DNA) 1 2 3 4 5 6a 6b </p><p>1 2 3 4 5 6b </p><p> SP </p><p>Adeno-associated Virus (AAV) </p><p>FS344 </p></li><li><p>Injection of Leg Muscle </p><p>180 days </p><p>Treatment of muscular dystrophy mouse </p><p> Control Gene Therapy Control Gene Therapy </p></li><li><p>None Gene Normal Therapy </p><p>CK </p></li><li><p>MOVING TO NON-HUMAN PRIMATE </p><p>Can the Mouse Studies Predict Safety and Efficacy in a Clinical Trial ? </p></li><li><p>FS344 Gene Transfer to Monkey </p></li><li><p>Follistatin Blood Levels Thigh Circumference Treated </p><p>Untreated </p></li><li><p>AAV1-FS </p><p>Control </p><p> Untreated Low dose high dose </p><p>Gene Therapy </p></li><li><p>The Clinical Problem Quadriceps muscle weakness (Becker Muscular Dystrophy Sporadic Inclusion body myositis) </p><p> Frequent falls/ loss of ambulation </p><p> Clinical trial improving quadriceps muscle strength would result in a </p><p> clinically meaningful outcome </p></li><li><p>Resistant to Muscle Strength Training </p><p> Weight training </p><p> Electrical Stimulation </p><p> Anabolic Steroids </p></li><li><p> Wyeth sponsored 11 Center Trial (10 USA;1GB) Using MYO-029 antibody to myostatin </p><p> No Clinical Benefit Muscle histology showed a trend toward increased muscle fiber size Demonstrated safety of systemic delivery of a </p><p> myostatin inhibitor in a clinical trial </p><p>Ann Neurology March 11, 2008 </p></li><li><p>Can Follistatin Gene Therapy be Done Safely ? </p></li><li><p>Clinical Chemistries Monkeys used in Pre-clinical Studies </p></li><li><p>IMMUNE RESPONSE</p></li><li><p>Full Examination of Non-Human Primates </p><p> Slides on each organ evaluated by a board certified veterinary pathologist blinded to treatment group (control vs FS) </p><p> No treatment-related abnormalities found in heart, liver, lung, spleen, kidney, testis, ovary and uterus (5 &amp;15 months) </p></li><li><p>Cardiac Studies Post AAV1.FS344 Treatment 15 months </p></li><li><p>Moving Forward FDA has given approval to move to a </p><p>clinical trial PPMD has supported studies in Becker </p><p>muscular dystophy Clinical trial will begin in December </p><p>2010 - January 2011 </p></li><li><p>Clinical Trial Design Six BMD patients will undergo direct </p><p>injection of AAV1.MCK.Follistatin into quadriceps muscles (1x1012 vg/muscle) </p><p> Patients will be followed for six months Muscle biopsies will be done at 3 and 6 </p><p>months Muscle size will be assessed and any signs of </p><p>muscle inflammation/damage MRI of quadriceps at 3 and 6 months Muscle strength and 6MWT will be assessed </p></li><li><p>Collaborators Brian Kaspar Louise Rodino K.Reed Clark Kevin Flanigan Zarife Sahenk Chris Walker </p><p>Support Parent Project Muscular Dystrophy </p><p>The Myositis Association </p></li></ul>