World Duchenne Awareness Day
September 7 is World Duchenne Awareness Day, established by the international organization United Parent Project Muscular Dystrophy (UPPMD) in 2014 with the hope of raising awareness about this rare disease.
Introduction of Duchenne muscular dystrophy
Duchenne muscular dystrophy (DMD) is a severe X-linked recessive disorder characterized by progressive muscle weakness and degenerative neurological symptoms[1], predominantly affecting males due to a mutation in the DMD gene on the X chromosome[2]. Dystrophin protein is located at the muscle sarcolemma and plays a critical role in maintaining the stability of the muscle sarcolemma. The DMD gene is the largest in the human genome, containing 79 exons and encoding a ~14-kb cDNA. The mutation rate of this gene is high, with exon deletion being the most common mutation, accounting for 55% to 65% of cases.
DMD manifests in early childhood with symptoms like difficulty in walking, running, and the development of a waddling gait. This disorder also impacts the muscles responsible for breathing, potentially leading to respiratory failure and, ultimately, resulting in death during early adulthood.
Therapeutic development for DMD
While there is currently no effective treatment for this disease, there are therapeutics available that can help to slow its progression and improve quality of life, such as corticosteroids and exon-skipping approaches.
Prednisone and Emflaza are two common corticosteroid drugs used to treat DMD. While it can enhance both muscle and lung function in patients, long-term therapy may lead to side effects such as osteoporosis and weight gain. Many exon-skipping medications have been approved in recent years, including Sarepta's Vyondys 53 and Viltepso. Exon-skipping therapy aims to correct the frameshift mutations, which can restore the reading frame of Dmd gene. The resulting reading frame encodes a truncated dystrophin protein that is shorter than usual but may have some function[3]. This therapy can restore partial function in approximately 30% of DMD patients with frameshift mutations in exons 51, 53, and 45. Unfortunately, this therapy faces the limitation of only suitable for a small number of patients with mutations in specific regions of the DMD gene, and the dystrophin produced may have limited function.
Researchers are actively investigating new therapies for DMD, including gene therapy, which can help restore dystrophin production in affected individuals. The FDA has approved Sarepta Therapeutics’ gene therapy Elevidys (delandistrogene moxeparvovec, SRP-9001) for the treatment of ambulatory patients with a confirmed mutation in the DMD gene. Elevidys is the first approved AAV-based investigational gene transfer therapy for DMD. It delivers the gene encoding micro-dystrophin directly to muscle cells, producing a shortened, functional form of dystrophin. Patients with different types of DMD gene mutations may benefit from this treatment and effects may last for a long time even after a single dosage[4]. However, due to its high price of 3.2 million dollars per injection, Elevidys is the second most expensive gene therapy drug in history, significantly limiting its accessibility to patients.
GemPharmatech’s DMD mouse models
Novel treatments for DMD cannot be evaluated without the aid of appropriate animal models. In pursuit of understanding the pathogenesis and therapeutic targets of DMD, GemPharmatech has developed a variety of DMD models utilizing gene editing technology independently. These models can be applied to drug screening and mechanism research.
Strain ID | Strain Name | Characteristics | Application |
Male mice are on a B10 background and exhibit early-onset DMD with muscular lesions (muscle fiber atrophy, inflammatory cell infiltration, etc.) at 9 weeks. | Corticosteroid therapy Gene therapy | ||
Male and female mice are on B10 background and exhibit late-onset DMD with significant motor impairment and more severe muscle damage (muscle fiber degeneration, necrosis, etc.) at 24 weeks. | Gene therapy | ||
In development | Exon-skipping drugs | ||
In development | Exon-skipping drugs | ||
Male mice are on a B6 background and exhibit late-onset DMD with substantial motor deficits and moderate muscle damage (muscle fiber atrophy, degeneration, etc.) at 32 weeks. | Exon-skipping drugs |
References：
1. Bresolin N, Castelli E, Comi GP, Felisari G, Bardoni A, Perani D, et al. Cognitive impairment in Duchenne muscular dystrophy. Neuromuscul Disord. 1994;4:359–69.
2. Kristin Wilson1, Crystal Faelan1, Janet C. Patterson-Kane1, et al. Duchenne and Becker Muscular Dystrophies: A Review of Animal Models, Clinical End Points, and Biomarker Quantification. Toxicol Pathol.2017 Jan 1:192623317734823.
3. What is Duchenne muscular dystrophy? | Duchenne & You (duchenneandyou.eu)
4. FDA Peripheral and Central Nervous System Drugs Advisory Committee Meeting. May 12, 2023. Accessed May, 2023.