Myostatin Inhibition Gene Therapy — Gene Therapy & Genetic Interventions
Gene therapy to inhibit myostatin (GDF8) signaling for prevention of age-related muscle wasting and sarcopenia.
Overview
Myostatin (GDF8) is a TGF-beta superfamily member that negatively regulates skeletal muscle growth. Natural myostatin loss-of-function mutations result in dramatic muscle hypertrophy in cattle (Belgian Blue), dogs (whippets), and at least one documented human case. Gene therapy approaches include AAV-delivered follistatin (myostatin antagonist), anti-myostatin antibodies, and direct myostatin gene knockout. AAV1-follistatin gene therapy (Milo Biotechnology) has been tested in Phase 1/2 trials for Becker muscular dystrophy and inclusion body myositis, demonstrating muscle growth and functional improvements.
Indications
- Sarcopenia (age-related muscle loss)
- Becker muscular dystrophy
- Inclusion body myositis
- Spinal muscular atrophy
- Cachexia and muscle wasting
Mechanism of Action
Follistatin binds and neutralizes myostatin (GDF8) and activin A, preventing their interaction with ActRIIB receptors
Dosing
| Compound | Dose | Frequency | Notes |
|---|---|---|---|
| AAV1-Follistatin (FS344) | 2 x 10^11 - 6 x 10^11 vg per muscle | Single intramuscular injection | Bilateral quadriceps injection; Phase 1/2 data available |
| AAV-anti-myostatin (systemic) | Study-specific | Single IV infusion | Systemic approach under preclinical investigation |
Safety & Contraindications
- Follistatin inhibits activin A as well as myostatin, potentially affecting reproductive function
- Cardiac effects of myostatin inhibition require monitoring (cardiac muscle hypertrophy)
- Tendon and ligament strength may not keep pace with muscle growth
- AAV1-follistatin Phase 1/2 trials showed acceptable safety profile
- Long-term effects of sustained myostatin inhibition in humans unknown
- Antibody approaches (bimagrumab, trevogrumab) have failed Phase 2/3 trials