Should Treatment for Spinal Muscular Atrophy Be Initiated Earlier?

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Thomas Gillingwater, PhD, discusses how critical it is to start SMA treatment early in infants before the onset of symptoms.

There is a paradigm shift in the way clinicians think about and provide treatment — a shift toward preventative, personalized, and proactive medicine, especially for genetic conditions such as spinal muscular atrophy (SMA).

The rare, neuromuscular, inherited condition affects 1 in every 6000 to 10,000 children. In the United States, an estimated 10,000 to 25,000 children and adults have a SMA diagnosis.1 Due to the genetic nature of the disorder, SMA is always present at birth; however, it may take longer for symptoms to appear, depending on the disease type. In SMA, muscle weakness, fasciculations, and atrophy are due to the loss of motor neurons disrupting nerve signaling to skeletal muscles.2

The 4 known SMA types depend on the number of copies of SMN2, a gene homologous to SMN1. Patients with 2 copies of SMN2 develop SMA type 1. Those with 3 and 4 copies of SMN2 develop SMA types 2 and 3, respectively.3 Patients with SMA type 4 carry between 4 to 8 copies of SMN2.4

SMA type 1 is the most severe with infantile onset of symptoms manifesting within 6 months after birth. Without treatment, these infants do not achieve any major developmental milestones and typically die before age 2.3,5 SMA types 2 and 3 manifest later with intermediate and mild symptom severity, respectively. SMA type 4 is the least severe, manifesting in adulthood usually after age 30.

For conditions such as SMA, tools such as newborn screening, gene therapy, and other effective alternative treatments have shown potential in their ability to indelibly alter the outcomes and quality of life for pediatric patients, especially when treatments are provided prior to symptom onset.

The ability for children to do things like sit unaided, stand unaided, hold their head upright — all these critical milestones of development — can be improved by treating earlier.

Thomas Gillingwater, PhD, professor of anatomy at the University of Edinburgh in Scotland and member of the Scientific Advisory Board for SMA Europe, has researched motor neuron diseases, attempting to unlock the physiological drivers for conditions such as SMA to enable effective treatments. Dr Gillingwater, who is also a study author of a paper published in Cell Reports Medicine5, shared with us the importance of newborn screening programs and early treatment for SMA.

The exact function of the SMN protein is unknown; however, he explained how the SMN protein contributes to the hypothetical model of SMA pathogenesis. “The defective protein is expressed in all cells and tissues throughout prenatal and postnatal life,” he said. “The levels of the protein spike in development, so clearly the SMN protein plays a key role in some developmental aspects of the body.”

Considering Presymptomatic Treatment

Recent clinical trials2,3,6 have raised the question of whether to provide presymptomatic treatment to infants with SMA.

There are three SMA treatments available, including:

  • Onasemnogene abeparvovec (Zolgensma): A gene therapy administered through a single intravenous injection of a genetically modified adenovirus that replaces the deleted SMN1 gene in every cell the virus “infects.”7
  • Nusinersen (Spinraza): An antisense oligonucleotide injected intrathecally into the spinal column every few months, targeting SMN2 to produce more SMN protein.8
  • Risdiplam (Evrysdi): A small molecule powder administered daily in liquid form that also increases SMN protein production by targeting SMN2.9

“The idea of getting in early with therapy is to ameliorate as much of that presymptomatic developmental build-up that seems to set the system up to fail,” said Dr Gillingwater. “Restoring levels of SMN protein early reduces and minimizes the systemic developmental impact [leading] to the symptoms being much [less] when they do appear.”

Early presymptomatic treatment of SMA with gene therapy and nusinersen has improved patient outcomes, allowing many children to achieve major developmental milestones, such as walking independently, and to survive longer without the need for permanent ventilation or nutrition via mechanical support.2,3,5

“The ability for children to do things like sit unaided, stand unaided, hold their head upright — all these critical milestones of development — can be improved by treating earlier,” Dr Gillingwater affirmed.

Newborn Screening for SMA

Newborn screening facilitates presymptomatic treatment of SMA. Newborn genetic screening confirms diagnosis of SMA by detecting SMN1 biallelic deletions or mutations, which prompts rapid initiation of presymptomatic treatment to optimize patient outcomes.

Several countries already have the infrastructure and financial means to support newborn screening programs for many conditions. Countries lacking the infrastructure or financial resources must collaborate with other countries and work continually to improve the infrastructure and procure funding to enable newborn screening programs.

Dr Gillingwater believes that countries with existing capabilities should add SMA to the list of screened conditions if they have not already.

“Now that we have these therapies, and we know that they’re effective, [normalizing newborn screening for SMA] seems ethically the right thing to do to give these patients the best possible chance of benefitting from the therapies, but also from the financial and return-on-investment perspective,” he said.

While SMA therapies are expensive up front, they are cost beneficial in the long run because the cumulative cost to treat progressive SMA symptoms eventually can surpass the cost of presymptomatic treatments, especially the single gene therapy treatment session. Presymptomatic treatment can help reduce the overall economic burden in addition to treatment burden for patients and their caregivers.

Addressing Safety Concerns Over Gene Therapy

Over 30 years ago, when gene therapy first appeared to treat other diseases such as cystic fibrosis, this novel treatment sparked many safety concerns. Researchers and clinicians worried about the promotion of tumor development, hypersensitive immune system responses, incorrect targeting of cellular sites, infection by the modified viral vector, toxicity, and cellular turnover eventually causing diminishing numbers of transfected cells.10,11

“Thankfully, gene therapy technology has been so rigorously tested that we now have designed approaches that, first and foremost, are largely safe, especially given that [clinicians] are delivering this to newborn children,” said Dr Gillingwater.

While the vast majority of patients tolerate gene therapy without serious adverse events, the major safety concern for presymptomatic newborns with SMA is whether they are born with natural antibodies to the viral vector used to deliver the treatment. This antibody is believed to be transferred from mother to infant and is a red flag prior to receiving gene therapy.

If the infant tests positive for the antibody, one strategy is to wait and see if these natural antibodies decrease over time after birth. Infants can receive 1 of the alternative SMA treatments in the interim until they are deemed safe to receive gene therapy. Consequently, if a patient cannot tolerate or safely receive a specific treatment, it is critical to have multiple treatment options available to improve that patient’s chance of success.

Rarely, patients receiving gene therapy develop liver problems due to hepatotoxicity. While adverse events are uncommon, patients must undergo monitoring to catch these side effects following administration of gene therapy.

“As clinical teams become more familiar with seeing patients and delivering treatments, they learn more about things to look out for and ways to improve, so that patients get the best possible outcome with the minimal possible risk,” Dr Gillingwater asserted.

For some gene therapies, cells such as hepatocytes, have high turnover rates which may exhibit the decreasing number of transfected cells. According to Dr Gillingwater, high turnover rate leading to reduced therapeutic benefit is not as much of a problem in SMA. Gene therapy for SMA targets motor neurons. “Neurons are terminally differentiated cells,” he explained. “Once that gene is in those cells, theoretically, they should be producing that gene for the rest of that cell’s life [and] for the lifetime of the patient.”

Dr Gillingwater cautioned that receiving gene therapy early does not guarantee uptake of the gene by every cell in the body, nor does it guarantee that every cell will continue producing that gene. Every patient responds differently to therapy, even when provided presymptomatically; therefore, accurately predicting treatment outcomes is difficult.

A Community for Change

One aspect that is often overlooked is the critical role that patient advocacy groups, charities, patients, and caregivers play in becoming agents of health care change.

“Incredibly dedicated families and advocacy support groups have fought tooth and nail for these therapies,” said Dr Gillingwater. “These groups have been absolutely instrumental in bringing these therapies to patients quickly and have been at the heart of advocacy for patients to get things like newborn screening, access to early therapy, and [approval of the therapy] on insurance protocols.” “It is because of their commitment and willingness to engage that these treatments and newborn screening have become a reality, and that is a really powerful thing,” he said.


  1. National Institute of Neurological Disorders and Stroke. Spinal muscular atrophy fact sheet. Updated July 25, 2022. Accessed September 22, 2022.
  2. Strauss KA, Farrar MA, Muntoni F, et al. Onasemnogene abeparvovec for presymptomatic infants with two copies of SMN2 at risk for spinal muscular atrophy type 1: the Phase III SPR1NT trial. Nat Med. Published online June 17, 2022. doi:10.1038/s41591-022-01866-4
  3. Strauss KA, Farrar MA, Muntoni F, et al. Onasemnogene abeparvovec for presymptomatic infants with three copies of SMN2 at risk for spinal muscular atrophy: the Phase III SPR1NT trial. Nat Med. Published online June 17, 2022. doi:10.1038/s41591-022-01867-3
  4. Butchbach MER. Copy number variations in the survival motor neuron genes: implications for spinal muscular atrophy and other neurodegenerative diseases. Front. Mol. Biosci. Published online March 10, 2016.
  5. Motyl AAL, Gillingwater TH. Timing is everything: clinical evidence supports pre-symptomatic treatment for spinal muscular atrophy. CR Med. Published online August 16, 2022. doi:10.1016/j.xcrm.2022.100725
  6. Albrechtsen SS, Born AP, Boesen MS. Nusinersen treatment of spinal muscular atrophy – a systematic review. Dan Med J. 2020;67(9):A02200100
  7. Important Safety Information. Novaritis; 2020. Updated May 2022. Accessed September 22, 2022.
  8. Important Safety Information & Indication. Biogen; 2016. Accessed September 22, 2022.
  9. Learn About Evrysdi® (Risdiplam), Approved Pediatric & Adult Spinal Muscular Atrophy (SMA) Treatment. Genentech; 2022. Accessed September 22, 2022.
  10. National Library of Medicine (US). Is Gene Therapy Safe? Updated February 28, 2022. Accessed September 22, 2022.
  11. Ferrari S, Geddes DM, Alton EWFW. Barriers to and new approaches for gene therapy and gene delivery in cystic fibrosis. Adv Drug Deliv Rev. 2002;54(11):1373-1393. doi:10.1016/S0169-409X(02)00145-X