Effects of Chronic, Maximal Phosphorodiamidate Morpholino Oligomer (PMO) Dosing on Muscle Function and Dystrophin Restoration in a Mouse Model of Duchenne Muscular Dystrophy.

Abstract

BACKGROUND:

Phosphorodiamidate morpholino oligomer (PMO)-mediated exon skipping is currently used in clinical development to treat Duchenne muscular dystrophy (DMD), with four exon-skipping drugs achieving regulatory approval. Exon skipping elicits a truncated, but semi-functional dystrophin protein, similar to the truncated dystrophin expressed in patients with Becker Muscular dystrophy (BMD) where the disease phenotype is less severe than DMD. Despite promising results in both dystrophic animal models and DMD boys, restoration of dystrophin by exon skipping is highly variable, leading to contradictory functional outcomes in clinical trials.

OBJECTIVE:

To develop optimal PMO dosing protocols that result in increased dystrophin and improved outcome measures in preclinical models of DMD.

METHODS:

Tested effectiveness of multiple chronic, high dose PMO regimens using biochemical, histological, molecular, and imaging techniques in mdx mice.

RESULTS:

A chronic, monthly regimen of high dose PMO increased dystrophin rescue in mdx mice and improved specific force in the extensor digitorum longus (EDL) muscle. However, monthly high dose PMO administration still results in variable dystrophin expression localized throughout various muscles.

CONCLUSIONS:

High dose monthly PMO administration restores dystrophin expression and increases muscle force; however, the variability of dystrophin expression at both the inter-and intramuscular level remains. Additional strategies to optimize PMO uptake including increased dosing frequencies or combination treatments with other yet-to-be-defined therapies may be necessary to achieve uniform dystrophin restoration and increases in muscle function.

• Authors: Margaret E Benny Klimek, Maria Candida Vila, Katie Edwards, Jessica Boehler, James Novak, Aiping Zhang, Jack Van der Meulen, Kathleen Tatum, James Quinn, Alyson Fiorillo, Umar Burki, Volker Straub, Qi Long Lu, Yetrib Hathout, John van Den Anker, Terence A Partridge, Melissa Morales, Eric Hoffman, Kanneboyina Nagaraju
• Journal: Journal of neuromuscular diseases (J Neuromuscul Dis) Vol. 8 Issue s2 Pg. S369-S381 ( 2021) ISSN: 2214-3602 [Electronic] Netherlands
• PMID: 34569970 (Publication Type: Journal Article)

Chemical References

• Dystrophin
• Morpholinos

Topics

• Animals
• Disease Models, Animal
• Dystrophin (drug effects)
• Exons
• Genetic Therapy
• Male
• Mice
• Mice, Inbred mdx
• Morpholinos (administration & dosage)
• Muscle, Skeletal (drug effects)
• Muscular Dystrophy, Duchenne (drug therapy)