First, do no harm: the role of preclinical animal models in predicting adverse events in gene therapy clinical trials for Duchenne muscular dystrophy and X-Linked myotubular myopathy DOI Open Access
Joe N. Kornegay, Hansell H. Stedman, Michael W. Lawlor

et al.

Rare Disease and Orphan Drugs Journal, Journal Year: 2024, Volume and Issue: 3(4)

Published: Nov. 4, 2024

The occurrence of severe adverse events (SAEs) in patients with Duchenne muscular dystrophy (DMD), X-linked myotubular myopathy (XLMTM), and other neuromuscular diseases treated adeno-associated virus (AAV) constructs has prompted studies to improve the safety efficacy gene therapy. Physicians have weighed medical tenet “first, do no harm” against perspective progressive life-threatening conditions who may accept greater risk. Regarding SAE pathogenesis, discussion focused on total AAV exposure patient mutations more likely induce immunity, while stressing limitations animal models predicting events. Therapeutic strategies for reducing side effects employed myotropic serotypes efficient transgenes. Other recommendations include excluding certain DMD associated SAEs substituting less immunogenic transgenes such as utrophin (DMD) myotubularin-related protein (XLMTM). For sake preclinical studies, emphasis been placed outbred rodents larger animals that better predict immunity. Here, absence canine XLMTM might be explained partly by phenotypic differences between affected humans dogs. Specifically, dystrophin- myotubularin-deficient dogs exhibit milder lesions, including muscle fat deposition hepatopathy, respectively, which could lead reduced immune responses constructs. To future problems, thought should given tracking early subclinical markers innate response, especially complement activation. Regardless steps taken predictive value SAEs, some questions will only answered through human clinical trials after carefully considering risk-benefit ratio.

Language: Английский

Gene therapy for ultrarare diseases: a geneticist’s perspective DOI Creative Commons
Wuh‐Liang Hwu

Journal of Biomedical Science, Journal Year: 2024, Volume and Issue: 31(1)

Published: Aug. 13, 2024

Abstract Gene therapy has made considerable strides in recent years. More than 4000 protein-coding genes have been implicated more 6000 genetic diseases; next-generation sequencing dramatically revolutionized the diagnosis of diseases. Most diseases are considered very rare or ultrarare, defined here as having fewer 1:100,000 cases, but only one 12 approved gene therapies (excluding RNA therapies) targets an ultrarare disease. This article explores three supplementation approaches suitable for various diseases: lentiviral vector-modified autologous CD34 + hematopoietic stem cell transplantation, systemic delivery adeno-associated virus (AAV) vectors to liver, and local AAV cerebrospinal fluid brain. Together with therapies, we propose a potential business model these therapies.

Language: Английский

Citations

7
Anticoagulants for atrial fibrillation: from warfarin and DOACs to the promise of factor XI inhibitors DOI Creative Commons
Vineet Kumar, Leonard Ilkhanoff

Frontiers in Cardiovascular Medicine, Journal Year: 2024, Volume and Issue: 11

Published: Feb. 5, 2024

Anticoagulation is the mainstay of stroke prevention in appropriate patients with atrial fibrillation. Due to advances pharmacotherapy anticoagulants used for this purpose have evolved significantly over past decades aim optimizing effectiveness while minimizing bleeding risks. Though significant improvements been made toward goal, risk remains major concern these therapies. An investigational class agents which inhibit Factor XI shown promise pre-clinical and early clinical trials minimize maintaining efficacy against systemic embolism. This mini-review will discuss currently fibrillation including warfarin direct oral anticoagulants. We also review mechanism action data from inhibitors their potential advantages shortcomings.

Language: Английский

Citations

5
Amelioration of Morphological Pathology in Cardiac, Respiratory, and Skeletal Muscles Following Intraosseous Administration of Human Dystrophin Expressing Chimeric (DEC) Cells in Duchenne Muscular Dystrophy Model DOI Creative Commons
Maria Siemionow, Katarzyna Budzynska, Kristina Zalants

et al.

Biomedicines, Journal Year: 2024, Volume and Issue: 12(3), P. 586 - 586

Published: March 6, 2024

Duchenne Muscular Dystrophy (DMD) is a lethal disease caused by mutation in the dystrophin gene. Currently there no cure for DMD. We introduced novel human Dystrophin Expressing Chimeric (DEC) cell therapy of myoblast origin and confirmed safety efficacy DEC

Language: Английский

Citations

4
The latest developments in synthetic approaches to duchenne muscular dystrophy DOI

Lucy M. Johnson,

Tariq G. Pulskamp,

Daniel J. Berlau

et al.

Expert Review of Neurotherapeutics, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 3, 2025

Duchenne muscular dystrophy (DMD) is a rare X-linked genetic disorder caused by mutations in the dystrophin gene, leading to an almost complete absence of dystrophin, which essential for muscle cell structure and function. This resulting deterioration fibrosis, eventually causes respiratory failure cardiomyopathy. While there currently no cure, existing therapies aim prolong survival alleviate symptoms. paper reviews current emerging DMD, focusing on their safety efficacy. Although corticosteroids remain standard treatment, newly approved drugs such as exon-skipping therapies, vamorolone, delandistrogene moxeparvovec, givinostat provide new treatment options. Additionally, future including gene therapy, stem treatments, anti-fibrotic agents, show promise clinical application. Advancements DMD treatments have expanded patient therapy offers potential correcting defect alleviating symptoms, most cost-effective well-researched treatment. partly due lack compelling long-term efficacy data therapies. The accelerated FDA review process has enabled faster approval medications; however many provided minimal benefit patients. Despite these challenges, continued drug development innovative research offer hope

Language: Английский

Citations

0
Awareness of doctors as a component of medical determinant of public health (on the example of determining the level of knowledge of pediatricians about early diagnosis and treatment of Duchenne muscular dystrophy) DOI Creative Commons
G. E. Sakbaeva, Sergey V. Russkikh,

Tatyana P. Vasilyeva

et al.

Сибирский научный медицинский журнал, Journal Year: 2025, Volume and Issue: 45(1), P. 212 - 220

Published: Feb. 28, 2025

Duchenne muscular dystrophy is a rare progressive neuromuscular disease that diagnosed in early childhood and leads to significant reduction life expectancy. Based on clinical guidelines, the authors of this article developed questionnaire for pediatricians determine knowledge primary care physicians about diagnosis treatment patients with genetic disease. Material methods. Using method quantitative sociological survey, we determined awareness The basis analysis was data from an online survey 609 respondents who were pediatricians. Results its discussion. Less than half (48 %) showed high level knowledge, ready diagnose correctly, carry out dispensary monitoring patients. Every third respondent has insufficient manage dystrophy. Also, during found opinion sufficiency and/or insufficiency their management patients, as well preferences channels obtaining new information Conclusions. Pediatricians play major role In regard, training accordance guidelines should be included improvement doctors’ knowledge. Addressing issue could lead economic benefits.

Language: Английский

Citations

0
Preclinical development of genome editing to treat Duchenne muscular dystrophy by exon skipping DOI Creative Commons
Made Harumi Padmaswari, Shilpi Agrawal, Christopher E. Nelson

et al.

Journal of Neuromuscular Diseases, Journal Year: 2025, Volume and Issue: unknown

Published: March 19, 2025

Duchenne muscular dystrophy (DMD) is caused by loss-of-function mutations to the gene encoding dystrophin. Restoring reading frame of dystrophin removing internal out-of-frame exons may address symptoms DMD. Therefore, principle exon skipping has been at center stage in drug development for over past two decades. Antisense oligonucleotides (AONs) have proven effective modulating splicing sites skipping, resulting FDA approval several drugs using this technique recent years. However, due temporary nature AON, researchers are actively exploring genome editing as a potential long-term, single-administration treatment. The advancements genome-editing technology last decade boosted transition. While no clinical trials DMD via conducted writing, preclinical studies show encouraging results. This review describes landscape Along with highlighting adaptability also delivery challenges and outlines future research directions that could set new enhanced therapeutic

Language: Английский

Citations

0
Dystrophinopathies DOI

L.H. Hayes,

Anthony A. Amato

Elsevier eBooks, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

0
Enhanced Diaphragm Muscle Function upon Satellite Cell Transplantation in Dystrophic Mice DOI Open Access

Karim Azzag,

Heather M. Gransee, Alessandro Magli

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(5), P. 2503 - 2503

Published: Feb. 21, 2024

The diaphragm muscle is essential for breathing, and its dysfunctions can be fatal. Many disorders affect the diaphragm, including muscular dystrophies. Despite clinical relevance of targeting there have been few studies evaluating function following a given experimental treatment, with most these involving anti-inflammatory drugs or gene therapy. Cell-based therapeutic approaches shown success promoting regeneration in several mouse models dystrophy, but focused mainly on limb muscles. Here we show that transplantation as 5000 satellite cells directly into results consistent robust myofiber engraftment dystrophin- fukutin-related protein-mutant dystrophic mice. Transplanted also seed stem cell reservoir, by presence donor-derived cells. Force measurements showed enhanced strength engrafted These findings demonstrate feasibility to target diseased improve contractility.

Language: Английский

Citations

0
Medical Statistics in Drug Development and Regulatory Approval DOI
Bancha Yingngam

Advances in bioinformatics and biomedical engineering book series, Journal Year: 2024, Volume and Issue: unknown, P. 57 - 110

Published: June 7, 2024

In the rapidly evolving field of pharmaceuticals, application medical statistics has become increasingly important. This chapter provides an insightful overview integral role that statistical analysis plays in journey drug development, highlighting its impact from preclinical trials to phase III studies as well significance regulatory decision-making. begins by establishing foundational principles methods clinical research. Specific models and techniques used ensure safety efficacy new drugs have been explored. Key topics include experimental design, hypothesis testing, data interpretation, management potential biases. highlights indispensability robust practices for achieving reliable scientifically sound results, which are critical gaining approval. future, this discusses emerging trends biostatistics their on future development approval processes.

Language: Английский

Citations

0
Uncovering the Embryonic Origins of Duchenne Muscular Dystrophy DOI
Philip Barrett, Ke’ale Louie, Jean‐Baptiste Dupont

et al.

WIREs Mechanisms of Disease, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 23, 2024

ABSTRACT Duchenne muscular dystrophy (DMD) is a severe degenerative muscle disease caused by mutations in the DMD gene, which encodes dystrophin. Despite its initial description late 19th century French neurologist Guillaume de Boulogne, and identification of causal genetic 1980s, therapeutics remain challenging. The current standard care corticosteroid treatment, delays progression dysfunction but associated with significant adverse effects. Emerging therapeutic approaches, including AAV‐mediated gene transfer, CRISPR editing, small molecule interventions, are under development face considerable obstacles. Although viewed as progressive disease, damage abnormal molecular signatures already evident during fetal myogenesis. This early onset pathology suggests that limited success therapies may partly be due to their administration after aberrant embryonic myogenesis has occurred absence Consequently, identifying optimal strategies intervention windows for depend on better understanding earliest mechanisms. As newer techniques applied, field gaining increasingly detailed insights into developmental abnormalities DMD. A comprehensive events pathogenesis will facilitate generation testing effective interventions.

Language: Английский

Citations

0