Duchenne Muscular Dystrophy

THERAPEUTIC APPROACHES

Duchenne is a complex, multi-system disorder caused by a pathogenic variant in one of the largest genes in the human body, the dystrophin gene.

It is likely that no single treatment will cure Duchenne, but that a combination approach will be required to successfully treat Duchenne. This approach includes:

• Restoring or replacing dystrophin, the underlying cause of Duchenne; and
• Treating symptoms that arise from the absence of dystrophin.

RESTORING OR REPLACING DYSTROPHIN

Dystrophin restoration or replacement aims to treat the underlying cause of the disease which is the lack of dystrophin, the protein that provides stability to the muscles. Exon skipping, nonsense mutation readthrough, and gene therapy are all ways that dystrophin restoration/replacement is being explored.

Exon Skipping  

A common variant in the dystrophin gene occurs when a piece of the code in the middle of the gene is missing or deleted. In-frame deletions allow some dystrophin protein to be produced and usually result in Becker muscular dystrophy, whereas out-of-frame deletions do not allow any dystrophin protein production and usually result in Duchenne muscular dystrophy.

Researchers are using antisense oligonucleotides (“AONs”) to help muscle cells turn an out-of-frame deletion into an in-frame deletion, potentially allowing for the production of a smaller, functional dystrophin protein. Different gene deletions require specific sets of AONs to correct the reading frame. There are FDA-approved therapies for skipping exons 51, 53, and 45, as well as ongoing clinical trials for skipping of other exons. Second generation exon skipping therapies are also in development, with the goal of even greater dystrophin expression in the muscle cells.

Nonsense Mutation Readthrough

In Duchenne, sometimes the dystrophin gene mutation causes a premature stop in the reading of the gene. This results in no full-length functional dystrophin at all. Strategies involving small molecules that enable the production of full-length dystrophin by “reading through” or reading over this premature stop are being developed and are in clinical trials. One nonsense mutation readthrough therapy has been approved in several countries for use in Duchenne.

Gene Therapy

Gene therapy for Duchenne muscular dystrophy aims to introduce the correct genetic code into muscle cells to produce the dystrophin protein and/or support muscle stability. Researchers are currently using adeno-associated viruses (AAV) for this delivery due to their ability to insert genetic material into cells. There is an FDA-approved micro-dystrophin gene therapy for Duchenne, and other gene therapies in clinical trials. Learn more about gene therapy for Duchenne.

TREATING DUCHENNE SYMPTOMS

In the absence of dystrophin, muscle damage occurs, leading to a cycle of degeneration and regeneration that results in downstream effects such as fibrosis, inflammation, calcium imbalance, muscle wasting, energy depletion, and cardiac dysfunction. Various therapeutic strategies are being developed to address these effects.

Many of these therapeutic approaches are in clinical trials for Duchenne, including many that are not variant-specific so they would benefit all patients regardless of their genetic variant.

Please visit the Parent Project Muscular Dystrophy website to learn more about the various therapeutic approaches for treating Duchenne, the robust pipeline for Duchenne and to view a comprehensive list of clinical trials.

Steroids

One primary treatment for Duchenne muscular dystrophy is corticosteroids. These steroids may help slow down the progression of muscle deterioration, and recent studies have confirmed the benefits of starting glucocorticoids in younger children, ideally before significant physical decline. However, steroid use can cause various side effects, including increased susceptibility to infections, meaning administration of flu and pneumonia vaccinations is crucial.

Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by progressive muscle weakness and atrophy. SMA is caused by a homozygous deletion of the survival motor neuron 1 (SMN1) gene, which is associated with reduction of functional SMN protein. The survival motor neuron 2 (SMN2) gene, often termed the “back-up” gene, may produce insufficient amounts of the fully functional SMN protein, which is necessary for motor neuron survival. Someone with SMA who has more copies of the back-up (SMN2) gene may present with a milder phenotype.

SMA is the number one genetic cause of death for infants. Traditionally, it has been classified into five clinical phenotypes (SMA type 0-4) based on severity and age of onset of symptoms. Type I, the most severe and common form, presents early in infancy, before the age of 6 months. In 2022, SMA was added to the recommended uniform screening panel, or RUSP, which is a list of disorders recommended for state newborn screening. The newborn screen is a tool used for all newborns in the United States, and uses a bloodspot taken from the baby’s heel at birth to screen for numerous conditions. Following a positive newborn screen for SMA, a doctor will order more tests to confirm the diagnosis. Newborn screening can lead to early detection and intervention to prevent the rapid and irreversible loss of motor function caused by SMA. However, even with newborn screening, approximately 5% of children with SMA have a genetic change that is not picked up by the screening technology. These children will be diagnosed later when they present with symptoms.

THERAPEUTIC APPROACHES

Currently, there are multiple FDA-approved treatments for SMA that are all SMN-enhancing therapies. Some of these therapies aim to replace or correct the faulty SMN1 gene whereas others work to modulate the expression of the “back-up” SMN2 gene.

These treatments are available for all types and ages of SMA, but it is important that individuals with SMA begin therapy as soon after diagnosis as possible. In clinical trials of SMN-based therapies, infants and children who began SMA treatment earlier had better results than those who began treatment later. There is an FDA-approved gene therapy for SMA which has been approved for patients who are under the age of 2 years.

Outside of FDA-approved treatments, there are several treatments being tested in clinical trials. Learn more about SMA treatments at CureSMA.org and the SMA Drug Pipeline page. Some of the therapies in development are not SMN-enhancing and are considered SMN-independent. Many researchers believe that it will take a combination of SMN-dependent and SMN-independent treatments to provide the most benefit for those with SMA. This could mean that individuals with SMA will take two or more drugs together. Or, they may take one type of drug at one stage of the disease and then another drug at a different stage. For these reasons, SMN-independent treatments are sometimes referred to as “combination” or “add-on” therapies. There are many SMN-dependent and SMN-independent therapies at various stages of development for SMA.

Other Neuromuscular Disorders

Beyond Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), there are several other forms of childhood neuromuscular disorders that also pose significant treatment challenges. Some of these include muscular dystrophies such as limb-girdle muscular dystrophy (LGMD) and facioscapulohumeral muscular dystrophy (FSHD), and mitochondrial myopathies such as TK2 deficiency (TK2D).

Though cures for these conditions remain elusive, managing symptoms is crucial for improving patients’ quality of life.

• For LGMD, FSHD, and TK2D, symptom management often includes physical and occupational therapies, corticosteroids to help control inflammation, and the use of mobility aids to maintain function. Nutritional support is also an essential aspect of care.
• In the case of LGMD, there are clinical trials exploring medications and gene therapies for patients.

As the science behind neuromuscular disorders and other genetic conditions continues to advance, there is growing hope that ongoing and future clinical trials will expand treatment options and offer new possibilities for managing all of these conditions.