Omigapil Ameliorates the Pathology of Muscle Dystrophy Caused by Laminin-α2 Deficiency

doi:10.1124/jpet.109.160754

Paper

Omigapil Ameliorates the Pathology of Muscle Dystrophy Caused by Laminin-α2 Deficiency

Published Dec 1, 2009 · M. Erb, S. Meinen, P. Barzaghi

Journal of Pharmacology and Experimental Therapeutics

Q2 SJR score

85

Citations

2

Influential Citations

Full textSemantic Scholar

Abstract

Laminin α2-deficient congenital muscular dystrophy, called MDC1A, is a rare, devastating genetic disease characterized by severe neonatal hypotonia (“floppy infant syndrome”), peripheral neuropathy, inability to stand or walk, respiratory distress, and premature death in early life. Transgenic overexpression of the apoptosis inhibitor protein BCL-2, or deletion of the proapoptotic Bax gene in a mouse model for MDC1A prolongs survival and mitigates pathology, indicating that apoptotic events are involved in the pathology. Here we demonstrate that the proapoptotic glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-Siah1-CBP/p300-p53 pathway is activated in a mouse model for MDC1A. Moreover, we show that omigapil, which inhibits GAPDH-Siah1-mediated apoptosis, ameliorates several pathological hallmarks in the MDC1A mouse model. Specifically, we demonstrate that treatment with omigapil inhibits apoptosis in muscle, reduces body weight loss and skeletal deformation, increases locomotive activity, and protects from early mortality. These data qualify omigapil, which is in late phase of clinical development for human use, as a drug candidate for the treatment of MDC1A.

Non-RCT

Animal Study

Highly Cited

Study Snapshot

Omigapil, a drug candidate for MDC1A, reduces muscle apoptosis, increases locomotive activity, and protects against early mortality in a mouse model.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

Sign up to use Study Snapshot

Consensus is limited without an account. Create an account or sign in to get more searches and use the Study Snapshot.

Create an account

Paper

Omigapil Ameliorates the Pathology of Muscle Dystrophy Caused by Laminin-α2 Deficiency

Sign up to use Study Snapshot

References

GOSPEL: A Neuroprotective Protein that Binds to GAPDH upon S-Nitrosylation

GOSPEL, a neuroprotective protein, prevents NMDA-glutamate excitotoxicity and may regulate cell viability by binding to GAPDH and preventing its nuclear translocation.

EM.P.5.04 Genetic ablation of cyclophilin D rescues mitochondrial defects and prevents muscle apoptosis in collagen VI myopathic mice

Cyp-D inactivation in mice rescues mitochondrial dysfunction and prevents muscle apoptosis, suggesting potential therapeutic targets for human ColVI myopathies.

Pathology is alleviated by doxycycline in a laminin‐α2–null model of congenital muscular dystrophy

Doxycycline treatment significantly increases lifespan and improves neuromuscular function in a laminin-2-deficient mouse model of congenital muscular dystrophy type 1A.

Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis

Nitric oxide-induced nuclear GAPDH activates p300/CBP, leading to cell death through p53-dependent pathways.

Genetic and pharmacologic inhibition of mitochondrial-dependent necrosis attenuates muscular dystrophy

Inhibiting cyclophilin D could provide a new pharmacologic treatment strategy for muscular dystrophy, as it reduces muscle wasting and necrosis in various models.

Citations

A Multicenter Cross-Sectional Study of the Swiss Cohort of LAMA2-Related Muscular Dystrophy

Swiss cohort of LAMA2-related muscular dystrophy patients provides insights into disease severity and progression, aiding future clinical trials and better clinical understanding and management of the condition.

Pharmacological Treatments and Therapeutic Targets in Muscle Dystrophies Generated by Alterations in Dystrophin-Associated Proteins

Pharmacological treatments with potential for muscle dystrophies caused by alterations in dystrophin-associated proteins show promising results in experimental models.

Phase 1 Open-Label Study of Omigapil in Patients With LAMA2- or COL6-Related Dystrophy.

Omigapil is a safe and well-tolerated oral drug for pediatric patients with LAMA2-related and COL6-related muscular dystrophy, but no significant changes in disease-relevant clinical assessments were observed.

Apelin stimulation of the vascular skeletal muscle stem cell niche enhances endogenous repair in dystrophic mice

Apelin-13 stimulation of the vascular muscle stem cell niche improves tissue regeneration and muscle strength in dystrophic mice, suggesting it as a potential therapeutic strategy for muscular dystrophy.

Pharmacotherapeutic Approaches to Treatment of Muscular Dystrophies

New pharmacotherapeutic approaches are needed to limit inflammation and fibrosis in muscular dystrophies, reducing muscle damage and promoting repair.

Merosin-deficient congenital muscular dystrophy type 1a: detection of LAMA2 variants in Vietnamese patients

Vietnamese patients with merosin-deficient congenital muscular dystrophy type 1A have identified seven LAMA2 variants, providing genetic counseling for parents with offspring.

S-Glutathionylation and S-Nitrosylation in Mitochondria: Focus on Homeostasis and Neurodegenerative Diseases

S-glutathionylation and S-nitrosylation play key roles in mitochondrial homeostasis and are associated with neurodegenerative diseases like Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Friedreich's ataxia.

Apelin Stimulation of the Perivascular MuSC Niche Enhances Endogenous Repair in Muscular Dystrophy

Apelin stimulation of the perivascular muscle stem cell niche improves tissue regeneration, muscle strength, and physical performance in muscular dystrophy patients.