kevnycmuscle
New member
here is a link and abstract from the NIH website. interesting reading. Thought it might help. there are other references to other researd as well.
Muscle Nerve. Author manuscript; available in PMC 2009 July 29.
Published in final edited form as:
Muscle Nerve. 2009 March; 39(3): 283–296.
doi: 10.1002/mus.21244
PMCID: PMC2717722
NIHMSID: NIHMS118670
Copyright notice and Disclaimer
INHIBITION OF MYOSTATIN WITH EMPHASIS ON FOLLISTATIN AS A THERAPY FOR MUSCLE DISEASE
LOUISE R. RODINO-KLAPAC, PhD,1,2 AMANDA M. HAIDET, BS,1,2 JANAIAH KOTA, PhD,1,2 CHALONDA HANDY, BS,1,2 BRIAN K. KASPAR, PhD,1,2 and JERRY R. MENDELL, MD1,3
1 Center for Gene Therapy, Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, Ohio 43205 USA
2 Department of Pediatrics, Ohio State University, Columbus, Ohio USA
3 Department of Neurology, Ohio State University, Columbus, Ohio USA
Correspondence to: J.R. Mendell; Email: [email protected]
The publisher's final edited version of this article is available at Muscle Nerve
See other articles in PMC that cite the published article.
In most cases, pharmacologic strategies to treat genetic muscle disorders and certain acquired disorders, such as sporadic inclusion body myositis, have produced modest clinical benefits. In these conditions, inhibition of the myostatin pathway represents an alternative strategy to improve functional outcomes. Preclinical data that support this approach clearly demonstrate the potential for blocking the myostatin pathway. Follistatin has emerged as a powerful antagonist of myostatin that can increase muscle mass and strength. Follistatin was first isolated from the ovary and is known to suppress follicle-stimulating hormone. This raises concerns for potential adverse effects on the hypothalamic–pituitary–gonadal axis and possible reproductive capabilities. In this review we demonstrate a strategy to bypass off-target effects using an alternatively spliced cDNA of follistatin (FS344) delivered by adeno-associated virus (AAV) to muscle. The transgene product is a peptide of 315 amino acids that is secreted from the muscle and circulates in the serum, thus avoiding cell-surface binding sites. Using this approach our translational studies show increased muscle size and strength in species ranging from mice to monkeys. Adverse effects are avoided, and no organ system pathology or change in reproductive capabilities has been seen. These findings provide the impetus to move toward gene therapy clinical trials with delivery of AAV-FS344 to increase size and function of muscle in patients with neuromuscular disease.
Keywords: follistatin, myostatin inhibition, muscle disease, muscle enhancement
INHIBITION OF MYOSTATIN WITH EMPHASIS ON FOLLISTATIN AS A THERAPY FOR MUSCLE DISEASE
Muscle Nerve. Author manuscript; available in PMC 2009 July 29.
Published in final edited form as:
Muscle Nerve. 2009 March; 39(3): 283–296.
doi: 10.1002/mus.21244
PMCID: PMC2717722
NIHMSID: NIHMS118670
Copyright notice and Disclaimer
INHIBITION OF MYOSTATIN WITH EMPHASIS ON FOLLISTATIN AS A THERAPY FOR MUSCLE DISEASE
LOUISE R. RODINO-KLAPAC, PhD,1,2 AMANDA M. HAIDET, BS,1,2 JANAIAH KOTA, PhD,1,2 CHALONDA HANDY, BS,1,2 BRIAN K. KASPAR, PhD,1,2 and JERRY R. MENDELL, MD1,3
1 Center for Gene Therapy, Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, Ohio 43205 USA
2 Department of Pediatrics, Ohio State University, Columbus, Ohio USA
3 Department of Neurology, Ohio State University, Columbus, Ohio USA
Correspondence to: J.R. Mendell; Email: [email protected]
- Other Sections▼
- Abstract
- MYOSTATIN PATHWAY
- MYOSTATIN SYNTHESIS
- FOLLISTATIN SYNTHESIS,
ISOFORMS, AND PHYSIOLOGIC ROLE - GENETICALLY ALTERED MICE OVER- AND UNDEREXPRESSING FOLLISTATIN
- TRANSLATIONAL APPROACHES THAT INHIBIT MYOSTATIN IN MUSCULAR DYSTROPHY
- FOLLISTATIN EFFECTS ON MUSCLE ENHANCEMENT THROUGH GENE THERAPY
- REFERENCES
In most cases, pharmacologic strategies to treat genetic muscle disorders and certain acquired disorders, such as sporadic inclusion body myositis, have produced modest clinical benefits. In these conditions, inhibition of the myostatin pathway represents an alternative strategy to improve functional outcomes. Preclinical data that support this approach clearly demonstrate the potential for blocking the myostatin pathway. Follistatin has emerged as a powerful antagonist of myostatin that can increase muscle mass and strength. Follistatin was first isolated from the ovary and is known to suppress follicle-stimulating hormone. This raises concerns for potential adverse effects on the hypothalamic–pituitary–gonadal axis and possible reproductive capabilities. In this review we demonstrate a strategy to bypass off-target effects using an alternatively spliced cDNA of follistatin (FS344) delivered by adeno-associated virus (AAV) to muscle. The transgene product is a peptide of 315 amino acids that is secreted from the muscle and circulates in the serum, thus avoiding cell-surface binding sites. Using this approach our translational studies show increased muscle size and strength in species ranging from mice to monkeys. Adverse effects are avoided, and no organ system pathology or change in reproductive capabilities has been seen. These findings provide the impetus to move toward gene therapy clinical trials with delivery of AAV-FS344 to increase size and function of muscle in patients with neuromuscular disease.
Keywords: follistatin, myostatin inhibition, muscle disease, muscle enhancement
INHIBITION OF MYOSTATIN WITH EMPHASIS ON FOLLISTATIN AS A THERAPY FOR MUSCLE DISEASE
