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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 1997 Baby at 7 months without myostatin

• Human Gene found in 2004

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


Can We Harness this as an approach for Gene Therapy ? Myostatin Inhibition


Circulating Propeptide Myostatin Complex

MM

SP

Propeptide Signal Peptide

Cleavage Myostatin Dimer Propeptide Complex

MM Follistatin

GASP1

MM

FLRG

P

ActRIIB

P

Alk4 /Alk5 co-receptor P P

Smad 2

Smad 3

P P

Smad Complex

Smad 4

Activation of target genes

nucleus


Candidate Genes for Myostatin Inhibition

Comparison of hindlimb Strength in C57/B6 mice


Follistatin Gene (DNA) 1

2

1

3

2

3

4

4

5

5

6b

6a

6b

FS344

SP

Adeno-associated Virus (AAV)


Treatment of muscular dystrophy mouse Control Control

Gene Gene Therapy Therapy

Injection of Leg Muscle 180 days


CK

None Gene Normal Therapy


Can the Mouse Studies Predict Safety and Efficacy in a Clinical Trial ? MOVING TO NON-HUMAN PRIMATE


FS344 Gene Transfer to Monkey


Follistatin Blood Levels Treated

Untreated

Thigh Circumference


Gene AAV1-FS Therapy

Control

Untreated

Low dose

high dose


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


Ann Neurology March 11, 2008

•  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


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

New Ways to Build Muscle for Muscular Dystrophy  

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