Therapeutic Strategies for Dystrophin Replacement in Duchenne Muscular Dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked hereditary disease characterized by progressive muscle wasting due to modifications in the DMD gene (exon deletions, nonsense mutations, intra-exonic insertions or deletions, exon duplications, splice site defects, and deep intronic mutations) that result in a lack of functional dystrophin expression. Many therapeutic approaches have so far been attempted to induce dystrophin expression and improve the patient phenotype. In this manuscript, we describe the relevant updates for some therapeutic strategies for DMD aiming to restore dystrophin expression. We also present and analyze in vitro and in vivo ongoing experimental approaches to treat the disease.

Dystrophinopathy Phenotypes and Modifying Factors in DMD Exon 45–55 Deletion

“…Solving these issues would consolidate this mutation as one of the best potential models for DMD gene therapy, comparable to monoexon skipping therapies, with the advantage of being applicable to a broader spectrum of mutations. It also preserves dystrophin functional domains, which is an issue of the minidystrophin gene transfer approach 20 . To achieve this goal, it is essential to overcome the hurdles derived from the usage of MES AO‐cocktails or to the development of gene‐editing therapies.…”

“…Therefore, although rescue of functional dystrophin at the cellular and organismal levels has been achieved by mimicking this mutation by means of multiexon skipping (MES) with cocktails of antisense oligonucleotides (AOs) [14][15][16][17] or applying genomeediting technology, 18,19 it is necessary to deepen the underlying pathogenic mechanisms to make this model a feasible alternative to current advanced therapies. 20 The breakpoint (BP) position of del45-55 in the flanking introns has been invoked as a potential determinant of phenotypic variability. On the one hand, it is known that these introns contain regulatory elements, such as the promoter of dystrophin isoform Dp140, which plays a role in brain development and whose deficiency may entail a risk of cognitive impairment, 21 and also hosts several long noncoding RNAs (lncRNAs) that regulate DMD expression.…”

Update for Duchenne Muscular Dystrophy - Hope for Causal Treatment of a Disorder Presenting in Early Childhood?

“…The dystrophinopathies represent model diseases to understand the personalization of genetic treatment. The many details regarding current approaches would exceed the given frame of a mini-review, therefore, two recent extensive overviews are recommended, also documenting details on current clinical trials [11][12][13][14].…”

Prime editing optimized RTT permits the correction of the c.8713C>T mutation in DMD gene

“… 6 , 7 Different types of mutations leading to DMD have been identified in the DMD gene, which is one of the biggest human genes, 8 and different therapeutic strategies have been developed. 9 , 10 These mutations include exonic and intronic duplications accounting for 10%–15% of DMD mutations, small insertions and deletions (3%), point mutations (nonsense and missense mutations, splice site mutations, and mid intronic mutations, 26%) and single- or multi-exon deletions (60%–70%). 7 , 11 Many research groups have been using CRISPR-Cas9 genome editing to modify the DMD gene to restore the dystrophin expression.…”