Progress in the Treatment of Duchenne Muscular Dystrophy
Duchenne muscular dystrophy (DMD) is a rare and severe X-linked recessive disorder characterized by progressive muscle weakness and degenerative neurological symptoms[1, 2], predominantly affecting males due to a mutation in the DMD gene on the X chromosome. The ensuing lack of functional dystrophin protein in afflicted patients destabilizes cell membrane, increases intracellular and extracellular permeability, and promotes protein and calcium ion influx as well as the efflux of intracellular enzymes such as creatine kinase. These lead to the degeneration of muscle fibers, necrosis, and hyperplasia of fibrous tissues, which activates inflammatory and apoptotic pathways.
DMD affects 1 in 3,500 to 1 in 5,000 people worldwide. Symptoms typically appear between the ages of 3 and 5. Patients with DMD may have difficulties walking, running, and climbing stairs and develop a waddling gait. The disorder causes the muscles to weaken and waste away over time, resulting in a loss of mobility and independence. It also affects the muscles that control breathing, which can lead to respiratory failure. This is the most prevalent cause of death in DMD.
DMD disease progression[3]
Therapeutic development for DMD
While there is currently no cure for Duchenne muscular dystrophy, there are treatments available that can help to slow the progression of the disease and improve quality of life, such as corticosteroids and antisense oligonucleotide (ASO).
Prednisone and Emflaza are two common corticosteroid drugs used to treat DMD. While they can slow the progression of muscular weakening and loss of mobility, long-term therapy may cause bone fragility and weight gain. Many ASO medications have been approved in recent years, including Sarepta's Vyondys 53 and Dyne Therapeutics' DYNE-251. As a result of the 2016 approval of Eteplirsen, a therapy for exon 51 skipping, such ASOs have risen to prominence as a potential treatment for DMD. Exon-skipping therapy causes the deletion of certain exons, which can restore the reading frame of Dmd gene despite of frameshift mutations. The resulting reading frame encodes a truncated dystrophin protein, partially restoring function[4]. 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 working for a small number of patients with those specific mutations in DMD.
Researchers are actively investigating new therapies for DMD, including gene therapy, which can help restore dystrophin production in affected individuals. PF-06939926, for example, uses a benign adenovirus (AAV9) to deliver a microdystrophin gene into muscle cells, allowing the muscles to synthesize a recombinant protein with partial anti-muscle atrophy function, thereby improving muscle’s ability to contract. Patients with different types of DMD gene mutations may benefit from this treatment. The effects may last for a long time even after a single dosage.
GemPharmatech’s DMD mouse models
Novel treatments for DMD cannot be evaluated without the aid of appropriate animal models. GemPharmatech has produced various DMD models employing gene editing technology. These models can be applied to drug screening and mechanistic 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 and motor impairment at 18 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. |
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. |
Gene therapy |
References:
1. Bresolin N, Castelli E, Comi GP, Felisari G, Bardoni A, Perani D, Grassi F, Turconi A, Mazzucchelli F, Gallotti D, et al. Cognitive impairment in Duchenne muscular dystrophy. Neuromuscul Disord. 1994 Jul;4(4):359-69.
2. Wilson K, Faelan C, Patterson-Kane JC, Rudmann DG, Moore SA, Frank D, Charleston J, Tinsley J, Young GD, Milici AJ. Duchenne and Becker Muscular Dystrophies: A Review of Animal Models, Clinical End Points, and Biomarker Quantification. Toxicol Pathol. 2017 Oct;45(7):961-976.
3. Asher DR, Thapa K, Dharia SD, Khan N, Potter RA, Rodino-Klapac LR, Mendell JR. Clinical development on the frontier: gene therapy for duchenne muscular dystrophy. Expert Opin Biol Ther. 2020 Mar;20(3):263-274.
4. What is Duchenne muscular dystrophy? | Duchenne & You (duchenneandyou.eu)