Safety concerns surrounding AAV and CRISPR therapies in neuromuscular treatment.

Gene therapies, notably those leveraging CRISPR and adeno-associated virus vectors (AAVs), have risen to the forefront of potential treatments for neuromuscular disorders. The recent demise of a Duchenne muscular dystrophy (DMD) patient following a trial utilizing CRISPR transactivation with AAV has cast a spotlight on the potential risks associated with these approaches.1.

Advancing Epidemiology and Genetic Approaches for the Treatment of Spinal and Bulbar Muscular Atrophy: Focus on Prevalence in the Indigenous Population of Western Canada.

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is a debilitating neuromuscular disease characterized by progressive muscular weakness and neuronal degeneration, affecting 1-2 individuals per 100,000 globally. While SBMA is relatively rare, recent studies have shown a significantly higher prevalence of the disease among the indigenous population of Western Canada compared to the general population. The disease is caused by a pathogenic expansion of polyglutamine residues in the androgen receptor protein, which acts as a key transcriptional regulator for numerous genes. SBMA has no cure, and current treatments are primarily supportive and focused on symptom management. Recently, a form of precision medicine known as antisense therapy has gained traction as a promising therapeutic option for numerous neuromuscular diseases. Antisense therapy uses small synthetic oligonucleotides to confer therapeutic benefit by acting on pathogenic mRNA molecules, serving to either degrade pathogenic mRNA transcripts or helping to modulate splicing. Recent studies have explored the suitability of antisense therapy for the treatment of SBMA, primarily focused on gene therapy and antisense-mediated mRNA knockdown approaches. Advancements in understanding the pathogenesis of SBMA and the development of targeted therapies offer hope for improved quality of life for individuals affected by this debilitating condition. Continued research is essential to optimize these genetic approaches, ensuring their safety and efficacy.

Recent Trends in Antisense Therapies for Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a debilitating and fatal genetic disease affecting 1/5000 boys globally, characterized by progressive muscle breakdown and eventual death, with an average lifespan in the mid-late twenties. While no cure yet exists for DMD, gene and antisense therapies have been heavily explored in recent years to better treat this disease. Four antisense therapies have received conditional FDA approval, and many more exist in varying stages of clinical trials. These upcoming therapies often utilize novel drug chemistries to address limitations of existing therapies, and their development could herald the next generation of antisense therapy. This review article aims to summarize the current state of development for antisense-based therapies for the treatment of Duchenne muscular dystrophy, exploring candidates designed for both exon skipping and gene knockdown.

Biological and genetic therapies for the treatment of Duchenne muscular dystrophy.

INTRODUCTION: Duchenne muscular dystrophy is a lethal genetic disease which currently has no cure, and poor standard treatment options largely focused on symptom relief. The development of multiple biological and genetic therapies is underway across various stages of clinical progress which could markedly affect how DMD patients are treated in the future. AREAS COVERED: The purpose of this review is to provide an introduction to the different therapeutic modalities currently being studied, as well as a brief description of their progress to date and relative advantages and disadvantages for the treatment of DMD. This review discusses exon skipping therapy, microdystrophin therapy, stop codon readthrough therapy, CRISPR-based gene editing, cell-based therapy, and utrophin upregulation. Secondary therapies addressing nonspecific symptoms of DMD were excluded. EXPERT OPINION: Despite the vast potential held by gene replacement therapy options such as microdystrophin production and utrophin upregulation, safety risks inherent to the adeno-associated virus delivery vector might hamper the clinical viability of these approaches until further improvements can be made. Of the mutation-specific therapies, exon skipping therapy remains the most extensively validated and explored option, and the cell-based CAP-1002 therapy may prove to be a suitable adjunct therapy filling the urgent need for cardiac-specific therapies.

Antisense and Gene Therapy Options for Duchenne Muscular Dystrophy Arising from Mutations in the N-Terminal Hotspot.

Duchenne muscular dystrophy (DMD) is a fatal genetic disease affecting children that is caused by a mutation in the gene encoding for dystrophin. In the absence of functional dystrophin, patients experience progressive muscle deterioration, leaving them wheelchair-bound by age 12 and with few patients surviving beyond their third decade of life as the disease advances and causes cardiac and respiratory difficulties. In recent years, an increasing number of antisense and gene therapies have been studied for the treatment of muscular dystrophy; however, few of these therapies focus on treating mutations arising in the N-terminal encoding region of the dystrophin gene. This review summarizes the current state of development of N-terminal antisense and gene therapies for DMD, mainly focusing on exon-skipping therapy for duplications and deletions, as well as microdystrophin therapy.

Natural History of a Mouse Model Overexpressing the Dp71 Dystrophin Isoform.

Dystrophin is a 427 kDa protein that stabilizes muscle cell membranes through interactions with the cytoskeleton and various membrane-associated proteins. Loss of dystrophin as in Duchenne muscular dystrophy (DMD) causes progressive skeletal muscle weakness and cardiac dysfunction. Multiple promoters along the dystrophin gene (DMD) give rise to a number of shorter isoforms. Of interest is Dp71, a 71 kDa isoform implicated in DMD pathology by various animal and patient studies. Strong evidence supporting such a role for Dp71, however, is lacking. Here, we use del52;WT mice to understand how Dp71 overexpression affects skeletal and cardiac muscle phenotypes. Apart from the mouse Dmd gene, del52;WT mice are heterozygous for a full-length, exon 52-deleted human DMD transgene expected to only permit Dp71 expression in muscle. Thus, del52;WT mice overexpress Dp71 through both the human and murine dystrophin genes. We observed elevated Dp71 protein in del52;WT mice, significantly higher than wild-type in the heart but not the tibialis anterior. Moreover, del52;WT mice had generally normal skeletal muscle but impaired cardiac function, exhibiting significant systolic dysfunction as early as 3 months. No histological abnormalities were found in the tibialis anterior and heart. Our results suggest that Dp71 overexpression may have more detrimental effects on the heart than on skeletal muscles, providing insight into the role of Dp71 in DMD pathogenesis.