Revolutionary Therapies Offer Hope to Patients with Neuromuscular Diseases

Amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy (DMD), and spinal muscular atrophy (SMA) are devastating disorders that affect nerve and muscle function. Until recently, they have been difficult, if not impossible, to treat. Myasthenia gravis (MG) has been treatable but early therapies generated significant side effects.

After decades of research, groundbreaking treatments have finally emerged.

“These new therapies are radically changing the outlook for some patients and their families,” said Michael Benatar, M.D., Ph.D., chief of the University of Miami Miller School of Medicine’s Neuromuscular Division and executive director of the University of Miami ALS Center. “We can now offer hope to many of our patients with neuromuscular diseases.”

New Therapies for Spinal Muscular Atrophy

Driven by mutations in the SMN1 gene, SMA affects motor neuron survival, causing progressive muscle weakness.

“When I was a resident, SMA was a death sentence for young children,” said Mario Saporta, M.D., Ph.D., associate professor of clinical neurology and director of the Muscular Dystrophy Association/Cure SMA Care Center. “Even adult patients, with less severe disease, had limited motor function. There was nothing that could help them.”

But starting in 2016, revolutionary new therapies began to emerge. Now, many SMA babies can have more normal lives and adults are regaining function.  

The drug nusinersen (SPINRAZA^®) uses antisense technology—short pieces of genetic material that can favorably modulate genes. In this case, it boosts a redundant form of SMN1, SMN2, that normally produces the missing protein at low levels. SPINRAZA kicks that up a notch, helping to compensate for SMN1 loss.

The drug must be periodically infused via spinal tap, which can be a difficult procedure for adult patients who often have a history of spinal surgeries and metal implants. Patients taking SPINRAZA must be hospitalized every few months for infusions.

An oral drug, risdiplam (Evrysdi®), alleviates that burden.

A third drug for SMA, onasemnogene abeparvovec (ZOLGENSMA^®), is a gene therapy for children with severe cases. The drug uses the viral system AAV9 to deliver healthy SMN1 genes and make the necessary protein. Infants in most states, including Florida, are tested for SMN1 deficiencies soon after birth. Many South Florida babies with SMA are referred to UHealth—University of Miami Health System for this advanced treatment.

“This used to be a horrible disease,” said Dr. Saporta. “These babies were given supportive care, which meant having them on a ventilator with a feeding tube, but none would live past their second year. There was almost nothing we could do, but that has totally changed.”

Treating Duchenne Muscular Dystrophy

DMD is caused by mutations in the dystrophin gene that contributes to muscle damage prevention. Without this protection, muscles decay each time they are used. Until recently, DMD patients could optimistically expect to live into their 30s.

Dystrophin is one of the largest human genes. It can mutate in multiple ways and early therapies could only address a few.

In June 2023, the FDA approved delandistrogene moxeparvovec (ELEVIDYS), which uses AAV9 to deliver a healthy “dystrophin gene.”

ELEVIDYS required some complex engineering. Because the gene is so large, scientists couldn’t fit it into the virus for delivery. Researchers developed an abbreviated version of the gene that produces a smaller functional protein.

“These new drugs have been life-changing for patients and a gigantic boost for people who treat neuromuscular diseases,” said Dr. Saporta. “In addition, these early drugs are creating a powerful momentum in the field. We can expect to see new and even better therapies emerge over time.”  

Progress for Myasthenia Gravis Patients

MG is an autoimmune disease in which antibodies mistakenly target neuromuscular connections. When it affects the breathing muscles, the disease can be life threatening.

In the past few years, new classes of drugs have emerged to regulate specific aspects of the autoimmune response. Most treat generalized acetylcholine receptor antibody-positive MG, the most prevalent form of the disease.

“For many years, treatment options were limited and patients either had to wait months to years for their symptoms to get better or face serious side effects from faster-acting drugs,” said Olimpia Carbunar, M.D., M.S., assistant professor of clinical neurology at the Miller School. “But now, with advances in our ability to target discrete aspects of the aberrant immune response in myasthenia, we have many more therapeutic options.”

The MG medication eculizumab (SOLIRIS®) works rapidly. Patients experience improvements within weeks of their first infusions. However, it must be given frequently.

“The drug can be administered at home or an infusion center, but it must be infused every two weeks,” said Dr. Carbunar. “That was the major issue, the frequency of administration. Later, the company developed a more extended-release version, called ravulizumab (ULTOMIRIS®).”

Zilucoplan (ZILBRYSQ®) allows patients to self-administer, an enormous benefit. Rozanolixizumab (RYSTIGGO®) has been approved to treat both the common form of the disease and MuSK-associated MG.

This series of new drugs has a profound impact on some patients’ quality of life. One patient suffered from ophthalmoplegia, a weakening of the eye muscles that sometimes results in eye muscle paralysis.

“He could not move his eyes at all,” said Dr. Carbunar. “He tried everything and finally had an amazing response with eculizumab. He went from not being able to move his eyes to full function. That was amazing.”

A New Era for Amyotrophic Lateral Sclerosis Patients

ALS, or Lou Gehrig’s Disease, patients experience motor neuron degeneration that leads to progressive weakness and paralysis. Patients lose the ability to walk, swallow and, ultimately, breathe. But a genetic therapy, tofersen (QALSODY^®), is signaling a new era for a subset of ALS patients.

Tofersen is an antisense drug that inhibits production of the SOD1 protein. In patients with SOD1 gene mutations, the abnormal protein is toxic, leading to neuronal death. The pivotal clinical trial VALOR showed the drug reduced neurofilament light chains, a neurodegeneration marker. The trial’s extension phase showed clinical benefits in patients who received early tofersen.

“This is a groundbreaking therapy, but it must be administered intrathecally (into the space around the spinal cord) once each month,” said Nathan Carberry, M.D., assistant professor of clinical neurology and part of the Miller School’s Neuromuscular Division. “The University of Miami is one of the few facilities to offer this cutting-edge treatment.”

This is the first genetic therapy for ALS and early treatment is important. Many of the patients who participated in the VALOR trial had relatively advanced disease. Dr. Benatar is leading a new study, ATLAS, focused on early treatment. In this trial, people with disease-causing variants in their SOD1 genes receive tofersen before they evince symptoms. The goal is to determine if the drug can prevent ALS when initiated early.

The Future of Neuromuscular Disease Treatment

Many of these treatments are not widely available, requiring infusion at specialized neuromuscular clinics like those at UHealth. However, this is just the beginning.

But there are dozens of neuromuscular therapies in development that may help patients who have not benefitted from initial treatments. These second-generation treatments are expected to be more cost-effective and easier to administer.

“We now have a lot of new treatments for a range of neuromuscular diseases,” said Dr. Benatar, “but these therapies are expensive, and they do not help all patients who need them. While it’s important to celebrate these successes—10 years ago, almost none of these conditions had effective treatments—we can and must do even better.”

Tags: ALS, ALS Center, Dr. Mario Saporta, Dr. Michael Benatar, Dr. Nathan Carberry, Dr. Olimpia Carbunar, neurology, neuromuscular division, spinal muscular atrophy