CRISPR-Based Therapeutic Gene Editing for Duchenne Muscular Dystrophy: Advances, Challenges and Perspectives

Abstract

Duchenne muscular dystrophy (DMD) is a severe neuromuscular disease arising from loss-of-function mutations in the dystrophin gene and characterized by progressive muscle degeneration, respiratory insufficiency, cardiac failure, and premature death by the age of thirty. Albeit DMD is one of the most common types of fatal genetic diseases, there is no curative treatment for this devastating disorder. In recent years, gene editing via the clustered regularly interspaced short palindromic repeats (CRISPR) system has paved a new path toward correcting pathological mutations at the genetic source, thus enabling the permanent restoration of dystrophin expression and function throughout the musculature. To date, the therapeutic benefits of CRISPR genome-editing systems have been successfully demonstrated in human cells, rodents, canines, and piglets with diverse DMD mutations. Nevertheless, there remain some nonignorable challenges to be solved before the clinical application of CRISPR-based gene therapy. Herein, we provide an overview of therapeutic CRISPR genome-editing systems, summarize recent advancements in their applications in DMD contexts, and discuss several potential obstacles lying ahead of clinical translation.

Satellite cell contribution to disease pathology in Duchenne muscular dystrophy

“…One challenge of CRISPR/Cas9 mediated gene editing in correcting the genetic defect of DMD cells is the long-term maintenance of the edited gene ( Chen et al, 2022a ). Satellite cell transduction and editing by CRISPR/Cas9 have traditionally been limited, and consequently, the edited nuclei may be diluted out as new muscle cells are generated.…”

Regulation of Satellite Cells Functions during Skeletal Muscle Regeneration: A Critical Step in Physiological and Pathological Conditions

“…Despite this debate, the scientific community agrees that skeletal muscle must be preserved by correcting the genetic defect of DMD. Any proposal to restore dystrophin expression by gene editing in vivo or stem cell transplantation requires a synergistic approach to preserve skeletal muscle in order to cure the disease [ 165 , 166 , 167 , 168 ].…”

Correction of human nonsense mutation via adenine base editing for Duchenne muscular dystrophy treatment in mouse

“…Therefore, DMD patients gradually experience ambulation loss, pulmonary insufficiency, heart failure, and early death in their twenties. 5 , 6 DMD still cannot be completely cured. Recent Food and Drug Administration (FDA)-approved mini-dystrophin, in principle, only changes DMD into the milder phenotype of Becker muscular dystrophy and does not cure it.…”