It’s been a little over a year since the FDA granted approval to onasemnogene abeparvovec-xioi (Zolgensma), the first approved gene therapy for the treatment of spinal muscular atrophy (SMA) in children under the age of 2. At the same time, antisense oligonucleotides (ASOs) are available for both SMA and Duchenne muscular dystrophy (DMD), and additional small molecule and gene therapies are in development.

Reflecting on this innovative period, researchers provided an overview of what they deem a hopeful future for SMA and DMD.

“Precision medicine for neuromuscular disorders has transformed in the past decade with commercially available gene replacement therapy for SMA and ASOs for both SMA and DMD,” authors said.

While gene therapies deliver an intact copy of the disrupted gene for conditions like SMA and DMD in order to express a functional protein to alleviate disease, ASOs are an RNA-based treatment strategy that alter expression of existing genes, researchers explained.

Treatment Landscape of SMA

In May 2019, the FDA approved Zolgensma, a one-time intravenously administered treatment of SMN complementary DNA, from which full-length SMN protein can be produced. The landmark phase 1/2a, open-label, dose escalation trial of the treatment in 15 children with Type 1 SMA and 2 copies of SMN2 demonstrated significant improvement in motor milestones. Every patient also had event-free survival compared with just 8% of natural history controls.

While the trial studied the use of Zolgensma in infants, the drug’s indication includes all children under the age of 2 years without end-stage disease.

Currently, there are phase 3 trials being conducted around the globe, as well as studies assessing pre-symptomatic treatment and Zolgensma in patients with more SMN2 copies, which have produced encouraging interim results.

Once considered an incurable disease, SMA until recently had no approved disease-modifying therapies. In 2016, the FDA approved the first treatment for the disease: nusinersen, a 2-methoxyethyl modified ASO designed to target the intronic splicing silencer N1 to suppress the routine splicing out of exon 7 from SMN2 pre-mRNA. In August, the FDA approved an alternative to nusinersen, the orally bioavailable small molecule risdiplam.

Treatment landscape of DMD

The use of gene therapy also holds promise in DMD, according to the researchers, who outlined the potential of emerging therapies that directly provide a functional, although shortened, copy of the DMD gene, which addresses the underlying genetic defect regardless of the underlying mutation.

Currently there are 3 active studies in the United States assessing microdystrophin. Results from an open-label phase 1/2a trial of the treatment in 4 children with DMD showed high levels of microdystrophin expression 12 weeks following gene transfer and functional improvements in motor outcomes that were sustained over a 1-year period. Results also showed that the treatment was safe, with self-limited vomiting and transient enzyme elevations being the most common adverse events.

“Surrogate gene therapy represents another mutation-independent therapeutic avenue by

delivery of genes via AAV vectors that can substitute for dystrophin,” added the researchers. “Utrophin bears much of the structural and functional elements of dystrophin, and its upregulation via AAV-mediated gene transfer has been successful at restoring muscle function in animal models.”

Since 1974, glucocorticoids have demonstrated an ability to offer neuromuscular care in DMD. However, since this discovery, novel treatments targeting the underlying pathophysiology of the condition have only recently emerged, despite decades of research.

In 2016, the FDA approved the first-generation morpholino ASO eteplirsen, which in clinical studies demonstrated a small but significant amount of dystrophin expression, attenuation of respiratory decline based on forced vital capacity, and improved ambulation in the majority of treated patients compared with historical controls. Since then, the administration has also approved 2 exon 53-skipping ASOs, phosphorodiamidate morpholino oligomer golodirsen and viltolarsen.

Reference: Abreu NJ, Waldrop MA. Overview of gene therapy in spinal muscular atrophy and Duchenne muscular dystrophy. Pediatr Pulm. Published online September 4, 2020. doi:10.1002/ppul.25055