Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease

Louise R. Rodino-Klapac, Amanda M. Haidet, Janaiah Kota, Chalonda Handy, Brian K. Kaspar, Jerry R. Mendell

Research output: Contribution to journalReview article

115 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)283-296
Number of pages14
JournalMuscle and Nerve
Volume39
Issue number3
DOIs
StatePublished - Mar 2009
Externally publishedYes

Fingerprint

Myostatin
Follistatin
Dependovirus
Muscle Strength
Muscles
Inclusion Body Myositis
Neuromuscular Diseases
Inborn Genetic Diseases
Follicle Stimulating Hormone
Muscular Diseases
Transgenes
Genetic Therapy
Haplorhini
Ovary
Therapeutics
Complementary DNA
Binding Sites
Clinical Trials
Pathology
Amino Acids

Keywords

  • Follistatin
  • Muscle disease
  • Muscle enhancement
  • Myostatin inhibition

ASJC Scopus subject areas

  • Clinical Neurology
  • Cellular and Molecular Neuroscience
  • Physiology (medical)
  • Physiology

Cite this

Rodino-Klapac, L. R., Haidet, A. M., Kota, J., Handy, C., Kaspar, B. K., & Mendell, J. R. (2009). Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease. Muscle and Nerve, 39(3), 283-296. https://doi.org/10.1002/mus.21244

Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease. / Rodino-Klapac, Louise R.; Haidet, Amanda M.; Kota, Janaiah; Handy, Chalonda; Kaspar, Brian K.; Mendell, Jerry R.

In: Muscle and Nerve, Vol. 39, No. 3, 03.2009, p. 283-296.

Research output: Contribution to journalReview article

Rodino-Klapac, LR, Haidet, AM, Kota, J, Handy, C, Kaspar, BK & Mendell, JR 2009, 'Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease', Muscle and Nerve, vol. 39, no. 3, pp. 283-296. https://doi.org/10.1002/mus.21244
Rodino-Klapac, Louise R. ; Haidet, Amanda M. ; Kota, Janaiah ; Handy, Chalonda ; Kaspar, Brian K. ; Mendell, Jerry R. / Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease. In: Muscle and Nerve. 2009 ; Vol. 39, No. 3. pp. 283-296.
@article{b66e50e405c14305b2c25496ca494061,
title = "Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease",
abstract = "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, Muscle disease, Muscle enhancement, Myostatin inhibition",
author = "Rodino-Klapac, {Louise R.} and Haidet, {Amanda M.} and Janaiah Kota and Chalonda Handy and Kaspar, {Brian K.} and Mendell, {Jerry R.}",
year = "2009",
month = "3",
doi = "10.1002/mus.21244",
language = "English (US)",
volume = "39",
pages = "283--296",
journal = "Muscle and Nerve",
issn = "0148-639X",
publisher = "John Wiley and Sons Inc.",
number = "3",

}

TY - JOUR

T1 - Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease

AU - Rodino-Klapac, Louise R.

AU - Haidet, Amanda M.

AU - Kota, Janaiah

AU - Handy, Chalonda

AU - Kaspar, Brian K.

AU - Mendell, Jerry R.

PY - 2009/3

Y1 - 2009/3

N2 - 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.

AB - 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.

KW - Follistatin

KW - Muscle disease

KW - Muscle enhancement

KW - Myostatin inhibition

UR - http://www.scopus.com/inward/record.url?scp=62849108016&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=62849108016&partnerID=8YFLogxK

U2 - 10.1002/mus.21244

DO - 10.1002/mus.21244

M3 - Review article

VL - 39

SP - 283

EP - 296

JO - Muscle and Nerve

JF - Muscle and Nerve

SN - 0148-639X

IS - 3

ER -