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
