Current Outline of Exon Skipping Trials in Duchenne Muscular Dystrophy

Eser, Gökçe; Topaloǧlu, Haluk

doi:10.3390/genes13071241

Cited by 25 publications

(19 citation statements)

References 45 publications

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“…These results highlight some of the caveats of ASO therapies [70,71]. ASOs can also be used to directly introduce splicing modulation, and this has been used to improve functional splicing in disorders, such as SMA, or to limit the effect of deleterious mutations by skipping specific exons, such as in Duchenne muscular dystrophy (DMD) [72][73][74][75]. One drawback of ASO therapies is the need for repeated dosing for a maintained response, which is particularly undesirable for patients if the delivery method is invasive, such as via intrathecal administration.…”

Section: Opportunities For Therapeuticsmentioning

confidence: 99%

The era of cryptic exons: implications for ALS-FTD

Mehta

Brown

Ward

et al. 2023

Mol Neurodegeneration

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TDP-43 is an RNA-binding protein with a crucial nuclear role in splicing, and mislocalises from the nucleus to the cytoplasm in a range of neurodegenerative disorders. TDP-43 proteinopathy spans a spectrum of incurable, heterogeneous, and increasingly prevalent neurodegenerative diseases, including the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum and a significant fraction of Alzheimer’s disease. There are currently no directed disease-modifying therapies for TDP-43 proteinopathies, and no way to distinguish who is affected before death. It is now clear that TDP-43 proteinopathy leads to a number of molecular changes, including the de-repression and inclusion of cryptic exons. Importantly, some of these cryptic exons lead to the loss of crucial neuronal proteins and have been shown to be key pathogenic players in disease pathogenesis (e.g., STMN2), as well as being able to modify disease progression (e.g., UNC13A). Thus, these aberrant splicing events make promising novel therapeutic targets to restore functional gene expression. Moreover, presence of these cryptic exons is highly specific to patients and areas of the brain affected by TDP-43 proteinopathy, offering the potential to develop biomarkers for early detection and stratification of patients. In summary, the discovery of cryptic exons gives hope for novel diagnostics and therapeutics on the horizon for TDP-43 proteinopathies.

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Section: Opportunities For Therapeuticsmentioning

confidence: 99%

The era of cryptic exons: implications for ALS-FTD

Mehta

Brown

Ward

et al. 2023

Mol Neurodegeneration

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“…Additional therapies—not discussed in this review—that could be combined with the listed therapies include specific exercise regimes [ 101 ] and nutritional modifications [ 72 ]. With these many avenues and momentum, it is not surprising that many clinical trials to combat DMD are occurring [ 3 , 102 ].…”

Section: Discussionmentioning

confidence: 99%

A Brief Review of Duchenne Muscular Dystrophy Treatment Options, with an Emphasis on Two Novel Strategies

Heydemann

Siemionow

2023

Biomedicines

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Despite the full cloning of the Dystrophin cDNA 35 years ago, no effective treatment exists for the Duchenne Muscular Dystrophy (DMD) patients who have a mutation in this gene. Many treatment options have been considered, investigated preclinically and some clinically, but none have circumvented all barriers and effectively treated the disease without burdening the patients with severe side-effects. However, currently, many novel therapies are in the pipelines of research labs and pharmaceutical companies and many of these have progressed to clinical trials. A brief review of these promising therapies is presented, followed by a description of two novel technologies that when utilized together effectively treat the disease in the mdx mouse model. One novel technology is to generate chimeric cells from the patient’s own cells and a normal donor. The other technology is to systemically transplant these cells into the femur via the intraosseous route.

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“…The therapeutic fraction may be estimated from clinical observations for diseases in which somatic mosaicism or chimeric transplantation outcomes have been described 230,231 ; in other cases, this threshold may only emerge after therapeutic gene editing studies have been conducted. In addition, targeting a sub-threshold fraction of cells may provide an intermediate clinical benefit and some genetic modifications may partially ameliorate a disease, such as by converting a null to a hypomorphic allele 232 .…”

Section: Considerations On Therapeutic Gene Editing In Patientsmentioning

confidence: 99%

Assessing and advancing the safety of CRISPR-Cas tools: from DNA to RNA editing

2023

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CRISPR-Cas gene editing has revolutionized experimental molecular biology over the past decade and holds great promise for the treatment of human genetic diseases. Here we review the development of CRISPR-Cas9/Cas12/Cas13 nucleases, DNA base editors, prime editors, and RNA base editors, focusing on the assessment and improvement of their editing precision and safety, pushing the limit of editing specificity and efficiency. We summarize the capabilities and limitations of each CRISPR tool from DNA editing to RNA editing, and highlight the opportunities for future improvements and applications in basic research, as well as the therapeutic and clinical considerations for their use in patients.

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Current Outline of Exon Skipping Trials in Duchenne Muscular Dystrophy

Cited by 25 publications

References 45 publications

The era of cryptic exons: implications for ALS-FTD

The era of cryptic exons: implications for ALS-FTD

A Brief Review of Duchenne Muscular Dystrophy Treatment Options, with an Emphasis on Two Novel Strategies

Assessing and advancing the safety of CRISPR-Cas tools: from DNA to RNA editing

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