Treatment Of Duchenne Muscular Dystrophy Research Articles

Exon-Skipping Therapy for Duchenne Muscular Dystrophy: 30 Years Since Its Proposal and the Future of Pseudoexon Skipping

Thirty years ago, in 1995, I proposed a fundamental treatment for Duchenne Muscular Dystrophy (DMD) using antisense oligonucleotides (ASOs) to induce exon skipping and restore dystrophin expression. DMD is a progressive and fatal muscular dystrophy, and the establishment of an effective therapy has been a pressing demand among patients worldwide. Exon-skipping therapy utilizing ASOs has garnered significant attention as one of the most promising treatments for DMD, stimulating global research and development efforts in ASO technology. Two decades later, in 2016, one ASO was conditionally approved by the U.S. FDA as the first DMD treatment. This review summarizes the current status and challenges of ASO-based exon-skipping therapies for DMD and explores the prospects of pseudoexon skipping using ASOs, which holds the potential for achieving a complete cure for DMD.

Real-world treatment and health care utilization among patients with Duchenne muscular dystrophy by race and ethnicity in a Medicaid population.

Duchenne muscular dystrophy (DMD) is a rare neuromuscular disorder, and data on the impact of patients' race on treatment outcomes and health care resource utilization are lacking. To describe the real-world treatment and health care utilization among patients with DMD, by race, in a Medicaid population. This was a retrospective cohort study of patients with DMD in the Merative Multi-State Medicaid Database between January 2017 and June 2021. Patients with DMD were identified using a validated algorithm and included male patients with at least 2 DMD diagnoses (earliest DMD diagnosis date = index date), aged 40years or younger, with at least 12 months of continuous enrollment prior to index date, and with at least 12 months (or evidence of death) following the index date were selected. Demographics, clinical characteristics, treatment utilization, and health care utilization and costs were reported by race and ethnicity in the 12-month baseline and 12-month follow-up periods. A total of 561 patients were included in the study, of which 360 (64.2%) were White, 50 (8.9%) were Black, 33 (5.9%) were Hispanic, and 118 (21.0%) were of other/unknown race and ethnicity. The median age on the index date was 16, 13, 14, and 15years among the race and ethnicity categories, respectively. In the follow-up, period clinical characteristics were similar across cohorts. Corticosteroids were the most commonly received treatment, with the highest use among Hispanic patients (73%) and lowest use among Black patients (52%). A third of patients treated with corticosteroids received deflazacort, with similar utilization across groups. Exon-skipping therapy use was rare, with 3% utilization overall, and highest use among White patients (4.2%). In both the baseline and follow-up periods, differences in health care costs were not statistically significant. White patients had the highest total costs in the follow-up period (mean [SD] = $108,895 [$346,934]) compared with $59,501 [$85,758] in the Black cohort, $61,199 [$67,021] in the Hispanic cohort, and $65,247 [$119,733] in the unknown/other cohort. Differences in total health care costs were driven by outpatient pharmacy costs, likely because of the larger proportion of White patients having a prescription for an exon-skipping therapy. Differences were seen across race and ethnicities in select clinical characteristics, DMD treatments, and health care utilization and costs in a Medicaid population.

Safety and efficacy of tamoxifen in non-ambulant patients with Duchenne muscular dystrophy: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial (TAMDMD Group B).

Most patients with Duchenne muscular dystrophy (DMD) are non-ambulant. Preserving proximal motor function is crucial, rarely studied. Tamoxifen, a selective oestrogen receptor modulator, reduced signs of muscular pathology in a DMD mouse model. Our objective was to assess the safety and efficacy of tamoxifen over 48 weeks in non-ambulant DMD patients. In this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at six European centres boys aged 10-16 years with genetically diagnosed DMD, non-ambulant and off corticosteroid treatment for ≥6 months, randomly assigned (1:1) to either 20 mg/day tamoxifen orally or placebo were included. The primary outcome was change in D2 motor function measure from baseline to week 48. Of 15 non-ambulant male patients with DMD screened, 14 were enrolled from January 24th, 2019, to January 6th, 2021. Eight patients were randomised to the treatment and six to the placebo group. The primary efficacy outcome did not differ significantly between tamoxifen and placebo (7.8 percentage points, 95 % CI, -26.82 to 11.22, p=0.359) with a trend not favouring tamoxifen. No deaths or life-threatening serious AEs occurred. Tamoxifen was safe but due to insufficient clinical evidence, it cannot be recommended as a treatment option for DMD. Trial registration: ClinicalTrials.gov (NCT03354039).

Scientific and Technological Prospecting on Polymeric Particles Containing Extracellular Matrix Peptides for the Treatment of Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy is a neuromuscular disease with an overall incidence of between 1 in 5,000 newborn males. Carriers may manifest progressive muscle weakness, resulting from the progressive degeneration of skeletal muscles, generating cardiac and respiratory disorders. Considering the lack of effective treatments, different therapeutic approaches have been developed, such as protein synthesis and extracellular matrix derivatives that can be used to improve muscle regeneration, maintenance, or repair. At the same time, the use of other anti-inflammatory drugs or biological agents to replace corticosteroids conjugated to these extracellular matrix derivatives may act more effectively in controlling the progression of Duchenne muscular dystrophy. Extracellular matrix-derived peptides (eg laminin-111 derivatives) and the use of essential oils with antiinflammatory activity in polymeric particles for application in the treatment of Duchenne muscular dystrophy are discussed. For this purpose, the literature of patents and scientific articles from 2012- 2024 on LM-111 peptides and Duchenne muscular dystrophy was reviewed. Many patents focus on palliative technologies that seek to prolong the progressive effects of the disease, considering the control of the inflammatory process. The technological and scientific prospecting suggests the need for continuous research on systems that can serve as a treatment for Dystrophy.

Phase 1 Mass Balance Study of Pizuglanstat: An Investigational Hematopoietic Prostaglandin D Synthase Inhibitor.

Pizuglanstat is a novel hematopoietic prostaglandin D synthase inhibitor and investigational treatment for Duchenne muscular dystrophy. This Phase 1 mass balance study aimed to characterize the absorption, metabolism, and excretion of carbon-14 (14C)-labeled pizuglanstat in healthy adults (ClinicalTrials.gov, NCT04825431). After administering a single oral dose of [14C]pizuglanstat solution containing 400mg of pizuglanstat and 1 megabecquerel of radioactivity to 6 healthy men (median age, 26years), pizuglanstat in plasma reached a maximal concentration after a median of 0.5hour and declined with a geometric mean half-life of 7.7hours. Pizuglanstat and its metabolites were primarily excreted via the fecal route; on average, 66.1% of administered radioactivity was excreted in feces after 168hours, compared with 32.2% excreted in urine. Pizuglanstat was mostly present as the unchanged parent molecule in plasma, urine, and feces, while the sulfate conjugate of hydroxyl pizuglanstat was the major metabolite in each sample type. Two adverse drug reactions of urticaria were reported in 2 participants (33.3%); both events were nonsevere and manageable with treatment, and no other clinically significant safety events were observed. Overall, this study provides important pharmacokinetic, mass balance, and safety data to support the development of pizuglanstat as a new treatment for Duchenne muscular dystrophy.

Histone deacetylase inhibition with givinostat: a multi-targeted mode of action with the potential to halt the pathological cascade of Duchenne muscular dystrophy.

Muscle repair and regeneration are complex processes. In Duchenne muscular dystrophy (DMD), these processes are disrupted by the loss of functional dystrophin, a key part of the transmembrane dystrophin-associated glycoprotein complex that stabilizes myofibers, indirectly leading to progressive muscle wasting, subsequent loss of ambulation, respiratory and cardiac insufficiency, and premature death. As part of the DMD pathology, histone deacetylase (HDAC) activity is constitutively increased, leading to epigenetic changes and inhibition of muscle regeneration factors, chronic inflammation, fibrosis, and adipogenesis. HDAC inhibition has consequently been investigated as a therapeutic approach for muscular dystrophies that, significantly, works independently from specific genetic mutations, making it potentially suitable for all patients with DMD. This review discusses how HDAC inhibition addresses DMD pathophysiology in a multi-targeted mode of action and summarizes the recent evidence on the rationale for HDAC inhibition with givinostat, which is now approved by the United States Food and Drug Administration for the treatment of DMD in patients aged 6years and older.

Hydroxyapatite nanoparticle mediated delivery of full length dystrophin gene as a potential therapeutic for the treatment of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a severe genetic disorder characterized by progressive muscle degeneration, primarily affecting young males. In this study, we investigated arginine-modified hydroxyapatite nanoparticles (R-HAp) as a novel non-viral vector for DMD gene therapy, particularly for delivering the large 18.8 kb dystrophin gene. Addressing the limitations of traditional adeno-associated viral vectors, R-HAp demonstrated efficient binding and delivery of the dystrophin plasmid to DMD patient-derived skeletal muscle cells. Using confocal imaging and RT-PCR analysis, our results showed effective gene delivery and expression in both mouse myotubes and patient-derived cells, with sustained expression evident up to 5 days post transfection. The patient-derived myotubes also showed dystrophin protein production 7 days post transfection. These findings suggest R-HAp nanoparticles as a promising and cost-effective alternative for DMD treatment, highlighting their potential for overcoming current gene therapy challenges.

Optimizing DMD management in Asia: Current challenges and future directions

Background Since 1970, advances in Duchenne muscular dystrophy (DMD) management have significantly extended the patients’ life expectancy. However, DMD remains universally fatal. Objective To understand the current DMD management standards and practices in Asia and to evaluate inconsistencies, unmet needs, and future directions for DMD patient management in the region. Methods Clinical experts from Hong Kong, Singapore, and Taiwan convened in September 2023 to discuss DMD diagnosis, assessment, treatment, and management best practices. A pre-meeting survey was also administered to explore professional perspectives and practices and refine the discussion focus. Results Genetic profiling has become the pivotal diagnostic tool and has been universally adopted by experts. Steroid therapy is recognized as the cornerstone of DMD care. However, there are various opinions regarding the timing of its initiation and whether it should be continued after the loss of ambulation. Gene therapy has the potential to significantly improve outcomes in patients with DMD. However, its adoption is hampered by high costs, the potential for serious adverse events, and difficulties with patient selection. Governments and manufacturers must work together to improve its affordability. Establishing a centralized DMD registry garnered strong support from the experts as it promised to provide insights into unique DMD subtypes, standardize treatment protocols, and facilitate the conduct of clinical trials. Furthermore, the introduction of gene therapy has highlighted the need for generating long-term safety and effectiveness data in patients with DMD. Lastly, a centralized patient registry can be used to inform policy decisions. Conclusions DMD care in Asia is characterized by substantial heterogeneity, with financial and reimbursement issues playing a major role in management decisions. A centralized patient registry has the potential to address these concerns by providing a valuable source of information.

Height development and multiple bone health indicators in children aged 2-12 years with Duchenne muscular dystrophy (DMD).

Short stature is a frequent complication of DMD, and its pathomechanisms and influencing factors are specific to this disease and the idiosyncratic treatment for DMD. To establish the height growth curve of early DMD, and evaluate the potential influencing markers on height growth, provide further evidence for pathological mechanism, height growth management and bone health in DMD. A retrospective, cross-sectional study of 348 participants with DMD aged 2-12 years was conducted at West China Second Hospital of Sichuan University from January 2023 to October 2023. The growth curve for 2-12 years old boys with DMD indicates a slower growth rate compared to the average population. At age two, children with DMD have a similar height to their peers, but gradually falls behind afterwards. Short stature was observed in children with DMD before and after GC exposure, and prolonged GC use exacerbated the retardation. BMI (β = -0.47, p = 0.007), BMD (β = -0.005, p = 0.014), β-CTX (β = 0.001, p = 0.002), delayed BA (β = 0.417, p < .001), GC duration (β = -0.006, p = 0.047) were independent influencing factors of height. Relevant bone health markers showed different sequential changing patterns. The high proportion and progression of short stature are associated with the broad bone health status. Different bone indicators have different sensitivities and specificities and need to be considered together for clinical monitoring of bone health. This study provides evidence for the early monitoring of height development and relevant factors as part of bone health management in DMD, to minimize the occurrence of bone-related complications later in life.

Inhibition of Mitochondrial Fission Protein Drp1 Ameliorates Myopathy in the D2-mdx Model of Duchenne Muscular Dystrophy.

Although current treatments for Duchenne Muscular Dystrophy (DMD) have proven to be effective in delaying myopathy, there remains a strong need to identify novel targets to develop additional therapies. Mitochondrial dysfunction is an early pathological feature of DMD. A fine balance of mitochondrial dynamics (fission and fusion) is crucial to maintain mitochondrial function and skeletal muscle health. Excessive activation of Dynamin-Related Protein 1 (Drp1)-mediated mitochondrial fission was reported in animal models of DMD. However, whether Drp1-mediated mitochondrial fission is a viable target for treating myopathy in DMD remains unknown. Here, we treated a D2-mdx model of DMD (9-10 weeks old) with Mdivi-1, a selective Drp1 inhibitor, every other day (i.p. injection) for 5 weeks. We demonstrated that Mdivi-1 effectively improved skeletal muscle strength and reduced serum creatine kinase concentration. Mdivi-1 treatment also effectively inhibited mitochondrial fission regulatory protein markers, Drp1(Ser616) phosphorylation and Fis1 in skeletal muscles from D2-mdx mice, which resulted in reduced content of damaged and fragmented mitochondria. Furthermore, Mdivi-1 treatment attenuated lipid peroxidation product, 4-HNE, in skeletal muscle from D2-mdx mice, which was inversely correlated with muscle grip strength. Finally, we revealed that Mdivi-1 treatment downregulated Alpha 1 Type I Collagen (Col1a1) protein expression, a marker of fibrosis, and Interleukin-6 (IL-6) mRNA expression, a marker of inflammation. In summary, these results demonstrate that inhibition of Drp1-mediated mitochondrial fission by Mdivi-1 is effective in improving muscle strength and alleviating muscle damage in D2-mdx mice. These improvements are associated with improved skeletal muscle mitochondrial integrity, leading to attenuated lipid peroxidation.

Duchenne Muscular Dystrophy: An Overview of Diagnosis, Management, and Pharmacological Treatment

Background: Duchenne muscular dystrophy (DMD) is a severe inherited neuromuscular disorder, primarily affecting males, characterized by progressive muscle weakness due to mutations in the dystrophin gene. This gene encodes dystrophin, a protein crucial for maintaining muscle cell integrity. DMD leads to the progressive loss of muscle function, cardiac complications, and intellectual disability. The disease typically results in wheelchair dependence by the early teens and early mortality due to respiratory or cardiac complications in the twenties. Aim: This overview aims to examine the diagnosis, management strategies, and pharmacological treatments for Duchenne muscular dystrophy. Methods: The article reviews current literature on the genetic basis, epidemiology, pathophysiology, and clinical manifestations of DMD. It also explores diagnostic methods including serum biomarkers, genetic testing, and muscle biopsy, as well as treatment options, particularly glucocorticoid therapy, and ongoing pharmacological interventions. Results: Early detection of elevated serum creatine kinase (CK) levels, along with genetic testing, is key to confirming DMD. Current pharmacological treatments primarily focus on corticosteroids to slow muscle degeneration, and new investigational therapies are exploring gene editing and protein restoration. Additionally, cardiomyopathy, a major complication, requires regular monitoring and management. Conclusion: Duchenne muscular dystrophy remains a challenging condition with significant impact on patients and their families. Early diagnosis and intervention are essential for improving outcomes, while ongoing research offers hope for more effective therapies. Effective management includes a multidisciplinary approach focusing on pharmacological, physical, and cardiac care.

Histone Deacetylase (HDAC) Inhibitors as a Novel Therapeutic Option Against Fibrotic and Inflammatory Diseases.

Histone deacetylases (HDACs) are enzymes that play an essential role in the onset and progression of cancer. As a consequence, a variety of HDAC inhibitors (HDACis) have been developed as potent anticancer agents, several of which have been approved by the FDA for cancer treatment. However, recent accumulated research results have suggested that HDACs are also involved in several other pathophysiological conditions, such as fibrotic, inflammatory, neurodegenerative, and autoimmune diseases. Very recently, the HDAC inhibitor givinostat has been approved by the FDA for an indication beyond cancer: the treatment of Duchenne muscular dystrophy. In recent years, more and more HDACis have been developed as tools to understand the role that HDACs play in various disorders and as a novel therapeutic approach to fight various diseases other than cancer. In the present perspective article, we discuss the development and study of HDACis as anti-fibrotic and anti-inflammatory agents, covering the period from 2020-2024. We envision that the discovery of selective inhibitors targeting specific HDAC isozymes will allow the elucidation of the role of HDACs in various pathological processes and will lead to the development of promising treatments for such diseases.

Mechanism-based approach in designing patient-specific combination therapies for nonsense mutation diseases.

Premature termination codon (PTC) diseases, arising as a consequence of nonsense mutations in patient DNA, account for approximately 12% of all human disease mutations. Currently there are no FDA approved treatments for increasing PTC readthrough in nonsense mutation diseases, although one translational readthrough inducing drug, ataluren, has had conditional approval for treatment of Duchenne muscular dystrophy in Europe and elsewhere for 10 years. Ataluren displays consistent low toxicity in clinical trials for treatment of several different PTC diseases, but its therapeutic effects on such diseases are inconsistent. The identity of the stop codon and its sequence context are major determinants of PTC readthrough efficiency in both the absence and presence of nonsense suppressors. Previously we have shown that ataluren stimulates readthrough exclusively by competitively inhibiting release factor complex (RFC, eRF1.eRF3.GTP)-dependent catalysis of translation termination. Here, using an in vitro reconstituted system (PURE-LITE) and both ensemble and single molecule assays, we demonstrate that PTC identity and the immediately adjacent mRNA sequence contexts modulate the catalytic activity of RFC in terminating peptide elongation. Such modulation largely determines the effectiveness of ataluren in stimulating readthrough, whether added alone or in combination with either the aminoglycoside G418 or an anticodon edited aa-tRNA, each of which stimulate readthrough by mechanisms orthogonal to that of ataluren. Our results provide an attractive rationale for the variability of ataluren effectiveness in stimulating readthrough in clinical trials. Patients harboring a PTC mutation with a sequence context promoting strong interaction with RFC are predicted to be resistant to ataluren, whereas ataluren treatment should be more effective for patient sequences conferring weaker interaction with RFC.

Digital outcome measures in Duchene muscular dystrophy: Lessons learnt from clinical trials

Duchenne muscular dystrophy is a severe neuromuscular disorder characterized by progressive muscle degeneration resulting from mutations in the dystrophin gene. Digital outcome measures offer a promising alternative to traditional outcome measures used in clinical trials. This review explores the development and application of digital outcome measures in Duchenne muscular dystrophy, emphasizing the feasibility, reliability, sensitivity, and validity of these measures. The stride velocity 95th centile has been validated as a robust endpoint and has been approved for use in clinical evaluation of drugs for the treatment of Duchenne muscular dystrophy by the European Medicines Agency. Although digital outcome measures have the potential to enhance the efficiency and accuracy of clinical trials, challenges such as limited sample sizes and patient compliance persist. The integration of artificial intelligence into the data analysis is in progress, but further validation is required before these analysis strategies can be incorporated into future clinical trial methodologies.

A154: MyoAAV 2a-Mediated Neurturin Improves the Pathological and Motor Function of Mdx Mice

Background/Purpose: Neurturin is a muscle secretory factor mediated by PGC-1Α1. Studies have shown that Neurturin has the function of coordinating the integrity of muscle fibers and their motor neurons and improving motor ability. Duchenne muscular dystrophy is a neuromuscular disease in which people gradually lose their mobility. Therefore, the aim of this study was to explore the pathological improvement of mdx mice treated with Neurturin. Methods: (1) MyoAAV 2A-Neurturin viral tool was prepared by HEK293T three-plasmid system. (2) Three male and three female SPF newborn C57BL/10ScSn mice and six male and six female C57BL/10scsn-Dmdmdx/J mice were used in the experiment. C57 mice were used as the control group (C57+PBS), and mdx mice were divided into virus injection group (mdx+Ntrn) and control group (mdx+PBS). The mice in the mdx+Ntrn were injected with 1.0E+13 vg/kg MyoAAV 2A-Neurturin, and the mice in the C57+PBS and mdx+Ntrn were injected with the same volume of PBS. (3) Grip strength, treadmill running performance, and creatine kinase were measured after 4 weeks. (4) Statistical methods: The results were expressed as mean ± standard error, a one-way ANCOVA test was used between groups, and P &lt; 0.05 was considered statistically significant. Results: (1) The titer of MyoAAV 2A-Neurturin was 1.0E+13 vg/ml. The migration distance of VP1:VP2:VP3 bands in silver staining was consistent with that of the corresponding molecular weight bands in Marker, and the ratio was close to 1:1:10. (2) In the grip strength test, compared with the mdx+PBS, the relative grip strength of the mdx+Ntrn increased (P = 0.022). Compared with the C57+PBS, relative grip strength of the mdx+Ntrn increased, but the difference was not statistically significant (P = 0.122). (3) In the treadmill running performance test, compared with the mdx+PBS, the exhaustion time of the mdx+Ntrn significantly increased (P &lt; 0.05). (4) Compared with the mdx+PBS, the CK level of the mdx+Ntrn significantly decreased (P &lt; 0.05). The CK level of the mdx+Ntrn showed a downward trend, but the difference was not statistically significant (P = 0.099). Conclusion/Discussion: The grip strength and exhaustion time of mdx mice were improved, and the level of creatine kinase decreased. Neurturin improved the pathological and motor function of mdx mice. This study provided a new attempt for the application of Neurturin in mdx mice and provides a new idea for the treatment of Duchenne muscular dystrophy.

Safety and effectiveness of ataluren in patients with Duchenne muscular dystrophy: single-center experience from Saudi Arabia

Objective Duchenne muscular dystrophy (DMD) is a rare X-linked neurodegenerative disorder caused by mutations in the DMD gene. This study examined the efficacy and safety of ataluren, the first oral treatment for DMD with nonsense mutations (nmDMD), in patients in the Middle East. Methods This retrospective longitudinal study assessed the outcomes of seven boys with nmDMD who received treatment with ataluren and follow-up at a single center since 2016. Results The median patient age at treatment initiation was 8.04 years (range: 3.3–9.92), and the median duration of exposure was 3.95 years (interquartile range = 4.42 years). Five patients were still ambulatory at the last follow-up. Ataluren was more effective in individuals with baseline 6-min walking distance (6MWD) ≥300 m, as these patients had smaller declines in 6MWD and North Star Ambulatory Assessment scores. Pulmonary function was well preserved in all patients, with no patients having forced vital capacity &lt;60% at their last follow-up. Six patients maintained normal cardiac function, whereas one patient developed heart failure before starting ataluren treatment. Conclusions Our results demonstrated both the efficacy and safety of ataluren. Early initiation of ataluren treatment delayed the loss of ambulation and cardiorespiratory milestones.

RWD83 What Are the Key Themes and Sentiments Captured Through Social Listening in Response to Recent Changes in the Duchenne Muscular Dystrophy Treatment Landscape?

RWD83 What Are the Key Themes and Sentiments Captured Through Social Listening in Response to Recent Changes in the Duchenne Muscular Dystrophy Treatment Landscape?

Golodirsen restores DMD transcript imbalance in Duchenne Muscular Dystrophy patient muscle cells

BackgroundAntisense oligonucleotides (AON) represent a promising treatment for Duchenne muscular dystrophy (DMD) carrying out-of-frame deletions, but also show limitations. In a completed clinical trial golodirsen, approved by FDA to induce skipping of DMD gene exon 53 in eligible patients, we demonstrated increase in DMD expression and protein production, albeit with inter-patient variability.MethodsHere, we investigate further the golodirsen mechanism of action using myotubes derived from MyoD transfected fibroblasts isolated from DMD patients at the baseline of the clinical trial SRP-4053.ResultsWe confirm golodirsen’s selectivity and efficiency in removing only exon 53. For the first time in human cells, we revealed a significant reduction in the so called DMD “transcript imbalance”, in golodirsen-treated DMD muscle cultures. The transcript imbalance is a unique DMD phenomenon characterized by non-homogeneous transcript expression along its entire length and responsible for the reduced stability of the transcript. Our in-vivo study also showed that the efficiency of exon skipping did not always correspond to a proportional restoration of the dystrophin protein. Predominant nuclear localization of the DMD transcript, observed in patients and animal models, persists even after exon skipping.ConclusionAll these findings suggest challenges other than AON delivery for high level of protein restoration in DMD, highlighting the importance of investigating the biological mechanisms upstream of protein production to further enhance the efficiency of any AON treatment in this condition.

An Updated Analysis of Exon-Skipping Applicability for Duchenne Muscular Dystrophy Using the UMD-DMD Database.

Antisense oligonucleotide (ASO)-mediated exon-skipping is an effective approach to restore the disrupted reading frame of the dystrophin gene for the treatment of Duchenne muscular dystrophy (DMD). Currently, four FDA-approved ASOs can target three different exons, but these therapies are mutation-specific and only benefit a subset of patients. Understanding the broad applicability of exon-skipping approaches is essential for prioritizing the development of additional therapies with the greatest potential impact on the DMD population. This review offers an updated analysis of all theoretical exon-skipping strategies and their applicability across the patient population, with a specific focus on DMD-associated mutations documented in the UMD-DMD database. Unlike previous studies, this approach leverages the inclusion of phenotypic data for each mutation, providing a more comprehensive and clinically relevant perspective. The theoretical applicability of all single and double exon-skipping strategies, along with multi exon-skipping strategies targeting exons 3-9 and 45-55, was evaluated for all DMD mutations reported in the UMD-DMD database. Single and double exon-skipping approaches were applicable for 92.8% of large deletions, 93.7% of small lesions, 72.4% of duplications, and 90.3% of all mutations analyzed. Exon 51 was the most relevant target and was applicable for 10.6% of all mutations and 17.2% of large deletions. Additionally, two multi-exon-skipping approaches, targeting exons 45-55 and 3-9, were relevant for 70.6% of large deletions and 19.2% of small lesions. Current FDA-approved ASOs were applicable to 27% of the UMD-DMD population analyzed, leaving a significant portion of patients without access to exon-skipping therapies. The clinical translation of alternative approaches is critical to expanding the accessibility of these therapies for the DMD population.

The potential applications of CRISPR/Cas9 in treating Duchenne Muscular Dystrophy

Abstract. The Duchenne Muscular Dystrophy (DMD) is a widespread genetic disorder caused by a mutation in the dystrophin gene. Current treatments, such as corticosteroids and genetic therapies like exon skipping, offer some symptom management but fall short of providing a cure. The CRISPR/Cas9 technology, which is related with Clustered Regularly Interspaced Short Palindromic Repeats-associated protein 9, could edit the genome with great precision. This technique holds potential in tackling the underlying issue of DMD by rectifying mutations in the dystrophin gene. Various strategies, including exon skipping, frame remodeling, and expression regulation, have demonstrated the potential to resumption dystrophin expression and improve muscle fitness in preclinical models. Even with these developments, there are still a number of important obstacles to overcome, such as enhancing the effectiveness of delivery, reducing off-target effects, and managing immune reactions. Future research will focus on refining these techniques and ensuring their safe and effective translation to clinical therapies, potentially revolutionizing the treatment of DMD and other genetic disorders.