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

Issue title: Special Issue Dedicated to Professor Terence Partridge

Guest editors: Jyoti Jaiswal and Kanneboyina Nagaraju

Article type: Research Article

Authors: Benny Klimek, Margaret E.^{a; 1} | Vila, Maria Candida^{a; b; 1} | Edwards, Katie^f | Boehler, Jessica^{a; b} | Novak, James^a | Zhang, Aiping^a | Van der Meulen, Jack^a | Tatum, Kathleen^a | Quinn, James^a | Fiorillo, Alyson^a | Burki, Umar^a | Straub, Volker^c | Lu, Qi Long^d | Hathout, Yetrib^{a; b; f} | van Den Anker, John^{a; e} | Partridge, Terence A.^{a; b} | Morales, Melissa^f | Hoffman, Eric^{a; b; f} | Nagaraju, Kanneboyina^{a; b; f; *}

Affiliations: [a] Center for Genetic Medicine, Children’s National Health System, Washington, DC, USA | [b] The George Washington University, Institute of Biomedical Sciences, Washington, DC, USA | [c] The John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases at Newcastle, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom | [d] McColl-Lockwood Laboratory for Muscular Dystrophy Research, Neuromuscular/ALS Center, Department of Neurology, Carolinas Medical Center, Charlotte, NC, USA | [e] Center for Translational Science, Children’s National Health System, Washington, DC, USA | [f] School of Pharmacy and Pharmaceutical Sciences, Binghamton University, Binghamton, NY, USA

Correspondence: [*] Correspondence to: Kanneboyina Nagaraju, Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Binghamton University, PO Box 6000; Binghamton, NY 13902-6000, USA. E-mail: [email protected].

Note: [1] These authors contributed equally to this work

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.

Keywords: KeywordsMorpholinos, dystrophin quantitation, specific force of muscle, dystrophin deficiency

DOI: 10.3233/JND-210701

Journal: Journal of Neuromuscular Diseases, vol. 8, no. s2, pp. S369-S381, 2021