Despite Progress in SMA Identification and Treatment, More Work Remains

The most severe forms of the neurodegenerative disorder spinal muscular atrophy (SMA) were formerly universally fatal in childhood, but in recent years SMA has seen novel treatments approved and new phenotypes and complications identified. A review of current and emerging research, as well as new questions surrounding the disease, calls for redefinition of its natural history and a more proactive approach to SMA management.

It is known that SMA is caused by homozygous loss of function of the SMN1 gene, which produces a crucial survival motor neuron (SMN) that the SMN2 gene cannot sufficiently provide when the SMN1 gene is not functioning properly. But the phenotypes of SMA are typically stratified based on patients’ motor ability. Infants with type 1 SMA, the most common form, are unable to sit independently; patients with type 2 SMA can sit without assistance; patients with type 3 can walk without assistance; type 4 SMA was added to the spectrum to classify those whose disease onset occurs after age 30 years. Type 0 is the fifth and most severe form, which is prenatal onset.

The review, published in The Journal of Pediatrics, notes that although all patients with SMA share the common cause of mutated or nonfunctional SMN1, the number of copies of SMN2 does vary between patients and generally correlates inversely to the type of SMA a patient has. But this is not always the case with every patient, so there may be other modifying factors or genes. Newborns are often screened for the disease with genetic testing, so the study authors stress the importance of utilizing any genetic characteristics that may guide recommendations for disease management rather than stratifying patients by maximum motor function alone.

SMA Treatment

The review notes that 3 treatments are FDA approved for SMA:

• Nusinersen (an intrathecally dosed antisense oligonucleotide)
• Risdiplam (an oral small molecule splice modifier)
• Onasemnogene abeparvovec-xioi (an intravenous gene replacement therapy [GRT])

These treatments all work by different mechanisms, and have some other differences: Nusinersen has been used for the longest time after its FDA approval and gene therapy is approved only for patients under 2 years old. GRT is a one-time dose, whereas the other 2 are systematic. Data on combination therapies and therapy after GRT are very limited.

“At present, there is not sufficient evidence indicating superiority of one treatment over the others,” the authors wrote. “Age of onset, current functional status, scoliosis/contractures, AAV9 antibody status, and SMN2 copy number are the primary factors that guide treatment choice.”

Other treatments under investigation include reldesemtiv, which modulates fast troponin activity, and SRK-015, which is an antimyostatin antibody that targets skeletal muscle rather than increased SMN expression in motor neurons. Reliable biomarkers are also needed to help gauge patient response to treatments.

There has also been a decrease in respiratory failure, a significant contributor to mortality in patients with SMA. But close monitoring and proactive care are still necessary throughout treatment because the effects of therapy on respiratory strength have not been described.

Classic rehabilitation and orthopedic management must also be revisited now that disease-modifying therapies exist. For example, treated infants with SMA type 1 have more mobility than they would have before the advent of therapies. In these infants, kyphoscoliosis can progress quickly and researchers suggest that earlier and more aggressive bracing should be considered in weak sitters and nonsitters.

The review also addresses issues in special populations, including prenatal and neonatal care. Pregnant women are often screened to determine whether they are carriers, but some carriers are missed in current testing, including those whose 2 SMN1 copies are on the same allele. Newborn screening is another recommended measure for infants within the first 3 to 7 days of life. The goal is to then begin treatment as soon as possible, but ideally within the first 3 to 4 weeks.

Room for Progress

Despite the progress made thus far, there is still much room for improvement in the identification, classification, and treatment of SMA, the authors conclude.

“As SMA treatments continue to advance, providers will need to redefine its natural history, adopt a more proactive approach to rehabilitation and multidisciplinary management, and use biomarkers to create personalized treatment approaches for their patients,” they wrote. “Ultimately, combination therapies and rehabilitation may be needed to optimize outcomes for certain patients with SMA, but further research is needed to identify whether there is added benefit and, if so, which patients require multiple treatments.”

Reference

Klotz J, Rocha C, Young S, et al. Advances in the therapy of spinal muscular atrophy. J Pediatr. 2021;236:13-20.e1. doi:10.1016/j.jpeds.2021.06.033