Experiments in dystrophin gene transgenic mice have supported the concept of treating Duchenne muscular dystrophy (DMD) by demonstrating that regional expression of recombinant dystrophin in dystrophic muscle leads to regional restoration of normal muscle morphology and that dystrophin mini-genes driven by muscle specific regulatory elements are probably more effective than the full-length dystrophin gene.
Using antisense oligonucleotides (AONs), the disrupted DMD reading frame is restored, allowing generation of partially functional dystrophin and conversion of a severe Duchenne into a milder Becker muscular dystrophy phenotype.
In the Duchenne muscular dystrophy (DMD) syndrome, mutations affecting expression of Dp71, the main dystrophin isoform of the multipromoter dmd gene in brain, have been associated with intellectual disability and neuropsychiatric disturbances.
DMD is associated with specific learning and behavioral disabilities that are more prominent in patients with mutations in the distal part of the DMD gene, predicted to affect expression of shorter protein isoforms.
We have previously shown that supra-physiological expression of nNOS-binding mini-dystrophin restores normal blood flow regulation and prevents functional ischemia in transgenic mdx mice, a DMD model.
The total absence of dystrophin observed in DMD patients is generally caused by mutations that disrupt the reading frame of the DMD gene, and about 80% of cases harbour deletions or duplications of one or more exons.
An unusual case of infantile onset Duchenne muscular dystrophy (DMD) with an internal 3' genomic deletion, and a membrane localized non-functional dystrophin protein, was used to explore the functional activity of this region.
Antisense oligonucleotide-mediated exon skipping is a promising therapeutic approach aimed at restoring the DMD reading frame and allowing expression of an intact dystrophin glycoprotein complex.
Since it has recently been suggested that the upregulation of utrophin might functionally compensate for the lack of dystrophin in DMD, considerable interest is now directed toward the elucidation of the various regulatory mechanisms presiding over expression of utrophin in normal and dystrophic skeletal muscle fibers.
Because utrophin can functionally substitute dystrophin, the identification and characterization of new regulatory elements provide new targets for possible therapies of Duchenne muscular dystrophy aiming at the up-regulation of the utrophin expression in muscle cells.
Recent studies using antisense oligonucleotide-targeted exon skipping to induce near normal dystrophin in vivo in animal models, and in vitro in DMD cell lines, highlight the promise of this approach.
The relationship between the severe Duchenne muscular dystrophy-like phenotype and the milder limb girdle muscular dystrophy phenotype is therefore similar to that of Duchenne muscular dystrophy to Becker muscular dystrophy, where there is absence of dystrophin in Duchenne muscular dystrophy and reduced amounts in Becker muscular dystrophy.
Searching for therapeutic strategies for Duchenne muscular dystrophy, it is of great interest to understand the responsible molecular pathways down-stream of dystrophin completely.
DMD murine MABs were transfected with transposable expression vectors for full-length dystrophin and transplanted intramuscularly or intra-arterially into mdx/SCID mice.
We undertook an open-label, phase 2, dose-escalation study (0·5, 1·0, 2·0, 4·0, 10·0, and 20·0 mg/kg bodyweight) in ambulant patients with Duchenne muscular dystrophy aged 5-15 years with amenable deletions in DMD.
Thus, 15 revertant fibers in a DMD patient with a frameshift deletion of exon 45 were shown to correct the frameshift by the additional deletion of exon 44 (or perhaps exon 46 in some fibers) from the dystrophin mRNA, but not by larger deletions.
The exon skipping of DMD mRNA aims to restore the disrupted reading frame using antisense oligonucleotides (AONs), allowing the production of truncated but partly functional dystrophin proteins, and slow down the progression of the disease.