Can emerging new treatments lead the way to cure Duchenne muscular dystrophy?

Where do we stand in Duchenne muscular dystrophy (DMD) treatment? Drawing on our recent podcast with guest Frank Gleeson, chief executive officer (CEO) of Satellos, a biotech focused on Duchenne muscular dystrophy, this article aims to present an overview of the challenges and advancements in the current and new treatment approaches for this rare disease.

This disease affects 1 in 5,000 male births, very rarely females, and it cannot be identified beforehand. The prognosis is often poor for people suffering from it as Duchenne muscular dystrophy symptoms lead to progressive disability and premature death, signaling how challenging research for treatment options is.

What is Duchenne muscular dystrophy?

Duchenne muscular dystrophy primarily affects boys, due to the dystrophin gene being located on the X chromosome. Since males have only one X chromosome, a single faulty gene on that chromosome results in Duchenne muscular dystrophy. Girls can be carriers and may exhibit mild symptoms but typically do not develop the full spectrum of the disease.

The condition manifests in early childhood, usually between ages three and five, and progresses rapidly. Children with Duchenne muscular dystrophy often begin to show symptoms such as difficulty walking, and many are unable to walk by their early teens. The disease is generally diagnosed through behavioral observation.

Duchenne muscular dystrophy is a genetic disorder caused by mutations in the dystrophin gene, which is vital for maintaining muscle cell integrity. Without dystrophin, muscle cells are damaged during normal activity and eventually deteriorate, leading to progressive muscle weakness and degeneration. 

“In males, skeletal muscle makes up 40% of the body mass, and it is the muscle and the organ that’s responsible for our ability to have posture and strength. As it degenerates and disappears over life, these children will ultimately pass away from complications of respiratory failure or heart failure, often in their mid to late 20s,” said Gleeson.

Despite advances in care improving life expectancy, Duchenne muscular dystrophy remains a life-limiting and life-threatening condition.

Overview of existing treatments for Duchenne muscular dystrophy

The treatment landscape for Duchenne muscular dystrophy has historically centered around managing symptoms and slowing the progression of the disease. Corticosteroids such as prednisone have been the cornerstone of Duchenne muscular dystrophy management. These medications can help improve muscle strength and function and delay the progression of muscle weakness. However, the benefits of corticosteroids come with a range of significant side effects including weight gain, bone fragility, and susceptibility to infections, which can complicate long-term usage.

Gleeson pointed out the limitations of current treatments: “The current standard of care is to recommend that the child begin a course of corticosteroid treatment which, in many countries, is known as prednisone. Then this becomes a lifelong therapy for these children, marked by its own set of challenges.”

Beyond steroids, other treatments have focused on supportive care measures. These include physical therapy to maintain muscle function and mobility, respiratory therapy to assist with breathing difficulties, and various surgical and medical interventions to manage complications such as cardiac issues and scoliosis. Nutritional support and behavioral therapy are also crucial to manage the overall well-being of individuals with Duchenne muscular dystrophy.

In recent years, new therapies aimed directly at the genetic roots of the disease have emerged. For instance, therapies that involve exon skipping, such as Eteplirsen, are designed to modify the processing of the dystrophin mRNA to produce a functional, albeit shorter, dystrophin protein. This approach targets specific mutations within the dystrophin gene and has shown promise, although its applicability is limited to certain genetic profiles within the Duchenne muscular dystrophy population.

The integration of these treatments requires a personalized approach, carefully considering the individual patient’s genetic makeup, disease progression, and overall health status. “Each treatment regimen must be tailored to the individual, balancing efficacy with potential side effects and long-term outcomes,” said Gleeson.

Recent advances in gene therapy for Duchenne muscular dystrophy

The landscape of Duchenne muscular dystrophy treatment has been significantly transformed by recent advancements in gene therapy. One of the most notable developments is the U.S. Food and Drug Administration’s (FDA) approval of ELEVIDYS, a pioneering gene therapy that delivers a truncated version of the dystrophin gene. This treatment, designed for young children, represents the first gene therapy approved for Duchenne muscular dystrophy and has shown promise in stabilizing muscle function, which is a significant breakthrough for the field.

As reported by the University of Rochester Medical Center,  in the Phase 3 EMBARK trial of this gene therapy, children treated with ELEVIDYS showed improved motor functions compared to those who had not received the treatment​​. The therapy uses a viral vector to deliver its genetic material, specifically targeting muscle cells to produce a functional, shorter, version of dystrophin, known as microdystrophin.

However, gene therapy for Duchenne muscular dystrophy is not without its challenges. One of the major hurdles is the immune response to the viral vector used to deliver the gene. Some patients develop neutralizing antibodies, which can limit the effectiveness of the therapy and prevent further treatments​​. Furthermore, the dosing of gene therapies must be carefully managed to balance efficacy with safety, particularly given that the therapy can currently only be administered once in a patient’s lifetime due to these immune responses.

In addition to ELEVIDYS, other gene therapies are under development, targeting different aspects of the dystrophin gene and exploring alternative delivery methods to overcome the challenges associated with viral vectors. These include efforts to enhance muscle trophism and reduce immune system detection, potentially allowing for redosing in patients previously treated with viral-based therapies​.

Non-steroidal advances in treating Duchenne muscular dystrophy

Recent breakthroughs in the treatment of Duchenne muscular dystrophy have included significant non-steroidal advances that offer new hope for managing the disease. Among these, Duvyzat (givinostat) stands out as a noteworthy development. Approved by the FDA in March 2024, Duvyzat is a non-steroidal, histone deacetylase (HDAC) inhibitor that has demonstrated efficacy in reducing muscle deterioration across all genetic forms of Duchenne muscular dystrophy. This oral medication targets the pathogenic processes at the cellular level to mitigate inflammation and the loss of muscle tissue​​.

Duvyzat’s approval came after its phase 3 study which showed statistically significant improvements in muscle function measured by the ability to climb stairs and overall physical function scores. This development is particularly promising as it offers an alternative to steroids, which are commonly used but come with severe side effects. By targeting the broader pathological processes of Duchenne muscular dystrophy, Duvyzat provides a treatment option that is applicable to a wide range of genetic mutations associated with the disease.

“The development of treatments like Duvyzat represents a significant shift in our approach to managing Duchenne muscular dystrophy. By focusing on molecular mechanisms that can be modulated without the use of steroids, we can potentially offer more sustainable and less harmful treatment options,” said Gleeson.

The introduction of non-steroidal treatments like Duvyzat underscores a pivotal shift in Duchenne muscular dystrophy therapy moving towards more targeted and less invasive options that promise to improve quality of life, and possibly alter the course of the disease without the significant side effects associated with traditional steroid treatments. This advancement is a testament to the ongoing innovation in Duchenne muscular dystrophy research and treatment, reflecting a broader trend of personalized medicine that tailors therapies to the specific genetic and pathological profiles of individual patients.

Emerging therapeutic approaches

Emerging therapeutic approaches are showing promise in overcoming the limitations of current Duchenne muscular dystrophy therapies. One approach involves Vamorolone, a drug that functions similarly to corticosteroids but with potentially fewer side effects. Vamorolone has been under investigation for its ability to reduce muscle necrosis, a central issue in Duchenne muscular dystrophy, without the significant side effects typically associated with steroids such as bone density loss and growth impairment​​.

Further expanding the frontier of Duchenne muscular dystrophy treatments are advances in non-viral gene delivery systems. These innovative approaches are being explored to circumvent the challenges posed by viral-based gene therapies, particularly the immune responses that can limit their effectiveness and the feasibility of repeated dosing. Non-viral methods may provide safer, more adaptable delivery mechanisms for gene therapy, potentially including larger or full-length genes that have been difficult to package into viral vectors​​.

In this week’s podcast, Gleeson discusses the potential of new treatments being developed by Satellos Bioscience, which target the regenerative capabilities of muscle tissue. “We have identified a pathway that could be manipulated to enhance muscle repair and regeneration. This is based on our understanding of muscle stem cell behavior in the absence of dystrophin, which has opened the door to potential treatments that could improve muscle function over time,” Gleeson explained.

Satellos Bioscience’s work focuses on manipulating the signaling within muscle stem cells to encourage the formation of new muscle cells, an approach that could fundamentally change the treatment of Duchenne muscular dystrophy by directly addressing the disease’s impact on muscle regeneration. This method represents a shift from managing symptoms to potentially altering the disease’s progression at a cellular level.

Together, these emerging therapies reflect a broader move toward more targeted and biologically nuanced approaches to treating Duchenne muscular dystrophy, offering hope for more effective and less burdensome treatments in the future. By leveraging advanced understanding of genetics and cellular biology, researchers are paving the way for innovations that could significantly improve the lives of those affected by this challenging condition.

Challenges, ethical considerations, and the role of community support

The treatment landscape for Duchenne muscular dystrophy faces significant ethical dilemmas and challenges, particularly concerning the irreversible nature of certain gene therapies. These therapies, while groundbreaking, currently allow for only a single administration, which may prevent patients from accessing more effective treatments developed in the future. This limitation raises ethical concerns about the best timing for intervention and the rights of patients to try subsequent therapies as science progresses.

Additionally, the role of community and advocacy groups such as Parent Project Muscular Dystrophy (PPMD) is crucial in supporting research and providing care guidelines. These organizations not only fund research but also create a supportive network for patients and their families, advocating for better care standards and accessibility to new treatments. PPMD, for example, plays a pivotal role in shaping both the social and regulatory landscape, ensuring that the voices of those affected by Duchenne muscular dystrophy are heard in the research community and beyond.

“Groups like Parent Project Muscular Dystrophy are invaluable. They not only support research financially but also provide a platform for patients and families to unite, share their stories, and push for changes that make real differences in their lives,” said Gleeson.

Looking forward: The future of Duchenne muscular dystrophy treatment

As we look to the future of Duchenne muscular dystrophy treatment, the landscape is marked by a dynamic and evolving research environment where new scientific understandings and technological advancements continually open the door to potentially more effective treatments. Recent progress in gene therapy, non-steroidal medications, and emerging therapeutic approaches highlights a trajectory toward more personalized and less invasive treatment options, aimed at not just managing symptoms but fundamentally altering the course of the disease.

Reflecting on the future, Gleeson offers a perspective rooted in cautious optimism: “The path forward in DMD treatment is illuminated by rapid advancements in genetic medicine and our growing understanding of muscle biology. Each new discovery brings us closer to more sustainable and effective interventions.”