Evidence of isoform restoration, immune activation following treatment, and a framework to evaluate exon-skipping therapies in the CNS using spatial transcriptomics are presented.
Abstract
Summary Duchenne muscular dystrophy (DMD) causes progressive muscle degeneration due to dystrophin deficiency. Dystrophin is also expressed in the brain during development and postnatally, yet a characterization of dystrophin isoform expression across brain cells and regions is lacking, limiting our understanding of the cognitive impairment affecting one-third of the patients and hampering the development of dystrophin-restoring drugs in the central nervous system (CNS). Here, we applied spatial transcriptomics to map Dmd isoforms across mouse brain regions and cell types. Mdx52 mice received exon 51-skipping therapies restoring the Dp427-sized isoform at the transcript and protein levels. We observed distinct spatial patterns: full-length isoforms localized to deeper cortical layers and CA1, while shorter isoforms were enriched in cortical layer 1 and dentate gyrus. We present evidence of isoform restoration, immune activation following treatment, and a framework to evaluate exon-skipping therapies in the CNS using spatial transcriptomics.
Through multidisciplinary treatment and continuous scientific progress, individualized precision medicine that integrates therapies targeting secondary pathogenic pathways with dystrophin-restoration techniques can finally convert this devastating illness into a tolerable chronic ailment.
Shahjad Ansari, M. Saifi, Sarfaraz Ahmed et al.· Current pharmaceutical desig...· 0 citations
ABSTRACT Background Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X‐linked dystrophinopathies caused by mutations in the dystrophin (DMD) gene. A common DMD‐causing mutation in humans is exon 52 deletion (DMDΔ52), which disrupts the reading frame and abolishes dystrophin expression. Therapeu...
Sarah Reschke, Alexander Graf, F. Hadlich et al.· Journal of Cachexia, Sarcope...· 0 citations
Duchenne muscular dystrophy (DMD) is a fatal disorder caused by dystrophin mutations, leading to progressive muscle degeneration and cardiac failure. Although AAV-based DMD therapies with innovative designs to overcome the cargo limits of the virus are effective in animal models, these current systems may face clinical...
Ryan H. Hsu, Claire E. Williams, Geraldine Maier et al.· bioRxiv· 0 citations
BACKGROUND
Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disease caused by mutations in the DMD gene, leading to the absence or dysfunction of dystrophin. Although cardiac and skeletal muscles are both affected, tissue-specific differences in disease manifestation and dystrophin regulation remain...
M. Białobrzeska, M. Przymuszała, Paweł E. Ferdek et al.· Circulation Genomic and Prec...· 0 citations
Huntington's disease is an inherited neurodegenerative disorder characterized by the progressive loss of neurons, particularly in the basal ganglia, resulting from a mutation in the Huntingtin gene. Recently, skeletal muscle defects have emerged as a contributing factor in HD pathogenesis. However, the mechanistic role...
Athira M. Sarath, Naorem Tarundas Singh, B. Sahu et al.· Biochemical and Biophysical...· 0 citations
It is suggested that even modest levels of base editing-mediated exon skipping may ameliorate the DMD cardiac phenotype toward a BMD-like state, supporting the translational potential of this dual rAAV base editing approach for DMD cardiomyopathy.
Ina Luksch, Christine M. Poch, Aylin Mayer et al.· Human Gene Therapy· 0 citations
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