A Brief Review of Duchenne Muscular Dystrophy Treatment Options, with an Emphasis on Two Novel Strategies

Abstract

Despite the full cloning of the Dystrophin cDNA 35 years ago, no effective treatment exists for the Duchenne Muscular Dystrophy (DMD) patients who have a mutation in this gene. Many treatment options have been considered, investigated preclinically and some clinically, but none have circumvented all barriers and effectively treated the disease without burdening the patients with severe side-effects. However, currently, many novel therapies are in the pipelines of research labs and pharmaceutical companies and many of these have progressed to clinical trials. A brief review of these promising therapies is presented, followed by a description of two novel technologies that when utilized together effectively treat the disease in the mdx mouse model. One novel technology is to generate chimeric cells from the patient’s own cells and a normal donor. The other technology is to systemically transplant these cells into the femur via the intraosseous route.

Cross-species modeling of muscular dystrophy in Caenorhabditis elegans using patient-derived extracellular vesicles

“…Additional treatments are being developed for DMD ( Duan et al, 2021 ), including anti-inflammatory and anti-fibrotic agents ( Bushby et al, 2010 ; Heier et al, 2013 ; Huebner et al, 2008 ; Levi et al, 2015 ) and agents increasing muscle regeneration ( Bogdanovich et al, 2002 ). A number of treatments that alter dystrophin expression have been recently approved for the treatment of DMD, including exon-skipping antisense oligonucleotides ( Aartsma-Rus et al, 2017 ), such as Exondys51 and Viltepso, and the adeno-associated viral vector-based gene therapy, ELEVIDYS ( Heydemann and Siemionow, 2023 ). Despite these efforts, there is currently no cure for these diseases.…”

mCherry on Top: A Positive Read-Out Cellular Platform for Screening DMD Exon Skipping Xenopeptide–PMO Conjugates

“…ASOs that modulate splicing are termed splice-switching oligonucleotides (SSOs) and can induce specific exclusion or inclusion of one or more exons as well as modulation of the equilibrium between splicing isoforms. − A specific ASO chemistry is represented by phosphorodiamidate morpholino oligomers (PMOs) that are artificial nucleic acid analogues consisting of uncharged phosphorodiamidates and morpholine rings in the backbone. PMOs represent promising candidates for the treatment of several diseases such as viral infections, thalassemia, , neuromuscular disorders, − inflammation, retinopathies, and cancer. , Eteplirsen, golodirsen, viltolarsen, and casimersen are approved PMO therapeutics used for the treatment of different genetic variants of Duchenne muscular dystrophy (DMD) via skipping of specific exon sequences. − The synthetic uncharged character of PMOs has beneficial effects on stability, nuclease resistance, immunogenicity, and toxicity, , but also influences the cellular uptake of naked PMO and compatibility with conventional nucleic-acid transfecting agents . To overcome these limitations, PMO conjugates with cell-penetrating peptides, − dendrimers, , cationic backbone modifications, and ionizable xenopeptides were established.…”