Advances in genetic therapeutic strategies for Duchenne muscular dystrophy

Abstract

New Findings What is the topic of this review? This review highlights recent progress in genetically based therapies targeting the primary defect of Duchenne muscular dystrophy. What advances does it highlight? Over the last two decades, considerable progress has been made in understanding the mechanisms underlying Duchenne muscular dystrophy, leading to the development of genetic therapies. These include manipulation of the expression of the gene or related genes, the splicing of the gene and its translation, and replacement of the gene using viral approaches. Duchenne muscular dystrophy is a lethal X‐linked disorder caused by mutations in the dystrophin gene. In the absence of the dystrophin protein, the link between the cytoskeleton and extracellular matrix is destroyed, and this severely compromises the strength, flexibility and stability of muscle fibres. The devastating consequence is progressive muscle wasting and premature death in Duchenne muscular dystrophy patients. There is currently no cure, and despite exhaustive palliative care, patients are restricted to a wheelchair by the age of 12 years and usually succumb to cardiac or respiratory complications in their late 20s. This review provides an update on the current genetically based therapies and clinical trials that target or compensate for the primary defect of this disease. These include dystrophin gene‐replacement strategies, genetic modification techniques to restore dystrophin expression, and modulation of the dystrophin homologue, utrophin, as a surrogate to re‐establish muscle function.

Insights into the Pathogenic Secondary Symptoms Caused by the Primary Loss of Dystrophin

“…Affected boys exhibit symptoms between 2 and 5 years of age, including motor developmental delay, abnormal gait, and muscle weakness [1]. The progressive muscle degeneration leads to loss of ambulation at 8-12 years with premature death due to cardio-respiratory failure [2].…”

CUGC for Duchenne muscular dystrophy (DMD)

“…Histopathology can be useful in providing evidence towards understanding the disease mechanism, although skeletal muscle biopsy is invasive and considered traumatic by some families. Additionally, accurate genetic diagnosis is necessary for inclusion in variant-specific treatments currently in clinical trials (reviewed by Guiraud et al) [48].…”

The advances and challenges of Gene Therapy for Duchenne Muscular Dystrophy

“…The different approaches of gene therapy that we will describe in the following sections, concern the correction of the DMD gene in this region (Figure 2A,B) [48,49]. Gene therapy aims to develop safe and systemic therapeutic approaches capable of restoring dystrophin expression in all skeletal muscles and heart of Duchenne patients [50]. Given the dif iculty in introducing the complete DMD gene into the patient's muscle ibers due to its large size, delivery of a truncated DMD gene or modi ications of the existing DMD gene are being investigated to restore the reading frame either by exon skipping, by exonic knock-out or by the additional deletions of exon fragments.…”

“…Several causes may explain these disappointing results: the lack of effect of ASOs in the cardiac muscle, the low penetration of ASOs into the skeletal muscle ibers, and the rapid elimination of ASOs from the circulation, which required repeated administration [50].…”

“…Meganucleases were used to re-establish the reading frame in the Duchenne dystrophic patient's myoblasts by generating DSBs and micro-insertions or micro-deletions (INDELs) [77]. They were also used in the immortalized myoblasts of the patient to generate DSBs and allow the insertion of exons [45][46][47][48][49][50][51][52]. The sequences of these exons (4.5 kb cDNA) were inserted into a donor lentivirus and integrated into the DMD mutated gene of the patient's myoblasts thus allowing synthesis of a normal dystrophin [71].…”