Spinal Muscular Atrophy: Progress Continues Against a Grave Neuromuscular Disorder (Podcast)

Spinal muscular atrophy (SMA) is a progressive hereditary disorder with a spectrum of phenotypes that historically have been defined by the patient’s age at onset and motor milestones achieved. While those characteristics remain essential in SMA subtyping, recent insights into the condition’s genetic underpinnings have shaped understanding of SMA in key ways.

There are two important genes in SMA — the survival motor neuron genes, SMN1 and SMN2, notes Alexandra Bonner, MD, a Cleveland Clinic pediatric neurologist specializing in neuromuscular disorders. “SMN1 encodes the survival motor neuron protein, and a patient is diagnosed with SMA when they have homozygous deletions of the SMN1 gene, but it’s the SMN2 gene that really drives the phenotype,” Dr. Bonner explains.

In the latest episode of Cleveland Clinic’s Neuro Pathways podcast, Dr. Bonner updates listeners on the implications of genetic insights into SMA and the latest in diagnosis and treatment more broadly. She explores the following topics, among others:

• Clinical presentations of SMA
• Subtypes of SMA
• SMA genetics and phenotypes, including areas without full overlap
• Policy around newborn screening for SMA
• Current and emerging treatment options and strategies

Click the podcast player above to listen to the 28-minute episode now or read on for a brief excerpt. Check out more Neuro Pathways episodes at clevelandclinic.org/neuropodcast or wherever you get your podcasts.

This activity has been approved for AMA PRA Category 1 Credit™ and ANCC contact hours. After listening to the podcast, you can claim your credit here.

Excerpt from the podcast

Podcast host Glen Stevens, DO, PhD: Is there an age at which it’s too late to give the medications approved for SMA?

Alexandra Bonner, MD: Onasemnogene abeparvovec is approved for children aged 2 years and under. There are studies of it being administered in patients older than this, but one of the concerns is that the risks increase because it’s a weight-based medication. Use after age 2 involves giving a higher dose with potentially higher toxicity. By trying to identify affected children as early as we can through carrier screening and newborn screening, we’re aiming to give gene therapy as early in the clinical course as possible. There are a lot of studies looking at giving therapies presymptomatically and then watching the children over years to evaluate their clinical function over time.

Glen Stevens, DO, PhD: Beyond the approved therapies we’ve discussed, is there anything on the horizon for SMA?

Alexandra Bonner, MD: Another major class of therapies being evaluated is called myostatin inhibitors. Myostatin inhibits the development and function of muscle, so by inhibiting this inhibitor, we can allow for better muscle development and function, in theory. A number of different myostatin inhibitors are being looked at for various muscle and motor neuron disorders, including SMA. Several of these are in clinical trials and are showing some good evidence early on. We'll see where that goes.

There’s also some ongoing work looking at using the therapies we now have in different ways. What if we gave the gene therapy onasemnogene abeparvovec intrathecally? Would that potentially reduce the off-target side effects? What if we gave nusinersen at a higher dose? Would that have higher efficacy? There are also studies looking at dual therapy. How much of an improvement do we see if we give risdiplam after onasemnogene abeparvovec, and what does that look like for all the different types of SMA? A lot of work is happening, yet there are many questions still to be answered.