Duchenne Muscular Dystrophy (DMD) is a rare and severe genetic disorder that primarily affects boys, leading to progressive muscle wasting and weakness. Sarepta Therapeutics stands as a prominent company dedicated to developing treatments for this debilitating condition. Their efforts focus on advanced genetic approaches, including RNA-targeted therapies and gene therapy. This work aims to address the underlying causes of DMD, offering new possibilities for patients.
Understanding Duchenne Muscular Dystrophy
DMD arises from a mutation in the DMD gene, which carries the instructions for producing dystrophin, a protein essential for healthy muscle function. Dystrophin acts as a crucial structural component, providing stability to muscle fibers during contraction and relaxation. Without functional dystrophin, muscle cells become fragile and prone to damage, leading to their gradual degeneration. This ongoing process of muscle breakdown results in progressive weakness, which typically begins in early childhood.
The disease progression often sees children experiencing symptoms such as difficulty walking and running, with most losing the ability to walk independently by their early teenage years. As the condition advances, it can affect the heart and respiratory muscles, leading to serious cardiac and breathing complications.
Sarepta’s Therapeutic Strategies
Sarepta Therapeutics employs distinct scientific strategies to combat DMD, primarily focusing on genetic interventions. One key approach is exon skipping, an RNA-targeted therapy designed to correct errors in the genetic code. This method involves using small synthetic molecules, called antisense oligonucleotides, to “skip” over specific mutated sections (exons) of the DMD gene during the process of converting genetic information into protein. By skipping a problematic exon, the cellular machinery can restore the reading frame of the gene, allowing for the production of a shortened, yet functional, dystrophin protein. This truncated protein can still provide some stability to muscle fibers.
Another innovative strategy utilized by Sarepta is gene therapy. This approach aims to deliver a functional copy of the dystrophin gene directly into muscle cells. Since the natural DMD gene is too large to fit into common viral delivery systems, Sarepta’s gene therapy uses a modified, smaller version of the gene, known as micro-dystrophin. This micro-dystrophin gene is carried into the muscle cells by a harmless adeno-associated virus (AAV) vector, enabling the cells to produce a therapeutic, albeit abbreviated, dystrophin protein. The goal is to provide a one-time treatment that can lead to sustained dystrophin production.
Key Sarepta Treatments for DMD
Sarepta has developed and secured approvals for several treatments addressing specific genetic mutations in DMD. Eteplirsen, marketed as Exondys 51, was the first approved exon-skipping therapy. It targets patients with mutations amenable to exon 51 skipping, representing approximately 13-14% of the DMD population. This therapy promotes the production of a shortened dystrophin protein through weekly intravenous infusions.
Following Exondys 51, Sarepta introduced golodirsen (Vyondys 53) and casimersen (Amondys 45). Golodirsen is designed for patients with mutations amenable to exon 53 skipping, impacting about 8% of individuals with DMD. Casimersen targets mutations amenable to exon 45 skipping, also affecting approximately 8% of the DMD patient population. Both golodirsen and casimersen aim to restore the dystrophin reading frame and enable production of a truncated protein.
In the realm of gene therapy, Sarepta’s delandistrogene moxeparvovec, known as Elevidys, represents a significant advancement. It was granted approval for ambulatory patients aged 4 and older via traditional approval, and non-ambulatory patients aged 4 and older via accelerated approval, provided they do not have specific deletions in exon 8 or 9. Elevidys is a one-time intravenous infusion that delivers a micro-dystrophin gene using an AAVrh74 vector, allowing muscle cells to produce a functional, shorter version of the dystrophin protein.
The Future of DMD Treatment with Sarepta
Sarepta Therapeutics continues to advance its research and development pipeline for Duchenne Muscular Dystrophy. Beyond its currently approved therapies, the company is exploring next-generation approaches within both exon-skipping and gene therapy platforms, investigating therapies that might offer enhanced potency or target additional amenable mutations.
Sarepta’s commitment extends to exploring combination therapies. The ongoing research aims to refine existing treatments and discover novel mechanisms to combat muscle degeneration more effectively. Sarepta is dedicated to improving the lives of individuals living with DMD, striving for more effective and accessible treatment options.