Duchenne muscular dystrophy (DMD), an X-linked, muscle wasting disease that affects 1 in 5000 males, is one of several muscular dystrophies with a genetic underlying pathology. In 2023, the DMD community received a landmark approval as the FDA gave greenlight to Sarepta’s delandistrogene moxeparvovec-rokl (Elevidys) as the first gene therapy for patients living with the disease. Originally approved under the accelerated approval pathway, the drug was later granted traditional approval earlier this year to include patients aged 4 years and older with DMD who have a confirmed mutation in the DMD gene.

At the recently concluded 2024 American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) meeting, held October 15-18, in Savannah, Georgia, Melissa Spencer, PhD, presented on the topic of emerging approaches to treating genetic muscular dystrophies. Spencer, a professor in residence at UCLA Health, has primarily dedicated her craft to understanding pathogenic mechanisms that occur in muscular dystrophies, with a goal of identifying therapeutic interventions. Much of her and her lab’s work has been focused on questions pertaining to the immune system’s contribution to DMD.

During the conference, Spencer sat down with NeurologyLive® to discuss her presentation, which centered around the evolving role of adeno-associated virus (AAV) in gene therapy for treating muscular dystrophies. She emphasized the challenges of evaluating functional benefits in disease like DMD, especially given the paradox of treating early when muscles are still growing but rapidly deteriorating. In addition, Spencer addressed the need for better vectors that are more selective for muscle tissue and immune system considerations, such as pre-existing immunity and potential adverse events like liver toxicity and complement activation.

Challenges of AAV Delivery in DMD Gene Therapy

AAVs are remarkable tools for delivering genes into cells, but they come with challenges specific to treating DMD. Dr. Spencer highlighted several key issues:

• Functional Benefit Assessment: DMD’s degenerative nature makes it difficult to assess the functional benefits of gene therapy. Should treatments be started early, sacrificing durability for potential long-term gain, or later when function is more clearly declining?
• Vector Specificity: Improving the tropism of AAV vectors for skeletal muscle is crucial. The current generation of AAVs can inadvertently target other tissues, like the liver, leading to unwanted side effects. Researchers are actively developing new vectors with higher myotropism to minimize this risk.
• Immune Response: Concern over pre-existing immunity to AAV and the potential for adverse immune reactions, such as liver toxicity and complement activation, is a major focus. This necessitates careful screening for pre-existing immunity and the development of strategies to minimize these risks.

Looking Ahead: Promising Avenues for Gene Therapy

Despite these challenges, Dr. Spencer remains optimistic about the future of AAV-based gene therapy for DMD:

• Novel Vectors:

  Specialized AAV vectors promising higher myotropism and reduced liver targeting, like MyoAAV and AAVMyo, are showing great potential.

• Stem Cell Targeting:

  Critically, incorporating CRISPR technology with AAVs to specifically target and modify muscle stem cells could lead to a permanent cure for DMD.