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Spinal Muscular Atrophy (SMA)

Research

The research picture has brightened considerably in the last decade for people with chromosome 5-related spinal muscular atrophy (SMA) types 0 through 4.

Since 1995, scientists have known that a deficiency of functional SMN protein (SMN stands for survival of motor neuron) is the underlying cause of chromosome 5-related SMA. Two nearly identical genes carry the genetic instructions for making SMN protein: SMN1 and SMN2. Proteins made from the SMN1 gene are full-length, functional, and appear to be necessary for the survival and proper function of motor neurons. By contrast, proteins made using instructions from the SMN2 gene are shorter and tend to be less stable but can compensate for a lack of SMN protein when the SMN1 gene is not functioning.

In SMA types 0 through 4, flaws (mutations) in each of the two copies of the SMN1 genes result in insufficient production of full-length, functional SMN protein. Fortunately, a certain amount of full-length SMN protein can be made from the SMN2 gene. Many people have multiple copies of the SMN2 gene. These extra SMN2 copies can lessen the impact of a flaw in both SMN1 copies. In chromosome 5-related SMA, the more copies of SMN2 a person has, the milder the course of SMA is likely to be.

Researchers are continuing to explore multiple avenues to restore or augment the levels of full-length SMN protein and to address the broader consequences of motor neuron degeneration.

Raising SMN levels through gene replacement

One of the research strategies to treat chromosome 5-related SMA is based on transferring SMN1 genes into the body to raise the level of full-length SMN protein. The US Food and Drug Administration (FDA)-approved therapy onasemnogene abeparvovec (Zolgensma) uses such a strategy to treat pediatric patients with SMA under the age of 2. Zolgensma is a non-infectious viral vector (AAV9) that delivers replacement genes to patients with an SMN1 gene mutation. It is the first-ever gene-replacement therapy approved by the FDA to treat any neuromuscular disease.

Ongoing studies are exploring ways to expand the label (age) eligibility for Zolgensma, evaluate long-term safety and durability of response, and combine gene replacement with other therapeutic approaches to optimize patient outcomes.

Raising SMN levels using antisense oligonucleotides or small molecules

Several research strategies involve manipulating the genetic instructions provided by the SMN2 gene to increase full-length SMN protein production as the SMN2 gene is similar in structure to the SMN1 gene. However, most of the protein made from the SMN2 gene is short and not functional. This research approach uses splicing modifiers, small molecule drugs that change how the SMN2 RNA is processed to encourage production of more full-length, functional SMN protein.

Currently, two FDA-approved therapies follow this approach:

  • Nusinersen (Spinraza) - an antisense oligonucleotide delivered via intrathecal injection
  • Risdiplam (Evrysdi) – an orally administered small molecule that modifies SMN2 splicing

Recent research focuses on optimizing the dosing, improving delivery methods, and assessing combination therapy with gene replacement or muscle-targeted treatments.
Targeting muscle

Motor neurons are the specialized nerve cells that die in people with SMA. These motor neurons are the wires that connect the brain and spinal cord to the muscles, and their death leads to muscle weakness and paralysis in SMA. Newer strategies that researchers are pursuing focus on preserving function or enhancing muscle strength, independent of SMN production. Although this approach does not fix the underlying genetic problem in SMA, drugs that enhance muscle function could likely be used in combination with other therapies that act on the SMN genes.

Neuroprotection

Beyond boosting SMN protein, researchers are exploring strategies to directly protect motor neurons from degeneration. These neuroprotective approaches aim to prevent neuron dysfunction and cell death by addressing metabolic stress, inflammation, or mitochondrial dysfunction. These neuroprotective strategies could be used in combination with SMN-enhancing therapies to provide broader benefit in SMA.

Biomarkers for SMA

A key area of disease research is the identification of biomarkers, biological indicators in the body that can track disease progression and response to therapy. Biomarkers are particularly valuable in infants or in slowly progressing cases where standard motor function assessments may be less reliable. Potential biomarkers have been investigated in blood or urine and in cerebrospinal fluid (such as neurofilament levels), as well as more sophisticated types of testing, such as nerve conduction tests for electrophysiological signals, commonly used to diagnose motor neuron disorders, as well as imaging modalities. Continued progress in this area is essential to accelerate clinical trial evaluation and personalized treatment planning.

X-linked SMA research

An X-chromosome gene has been identified that, when mutated, causes X-linked SMA. The gene codes for the UBE1 protein, which is part of a cellular waste disposal system. Without functional UBE1 protein, cellular waste accumulates, disrupting normal function. Scientists continue to study the UBE1 gene and its role in motor neuron survival, with the goal of identifying therapeutic targets for this rare form of SMA.Chromosome 14-related research

Mutations in the cytoplasmic dynein 1 heavy chain 1 (DYNC1H1) gene on chromosome 14 can cause a rare form of SMA called SMA-LED, which predominantly affects muscles in the legs. DYNC1H1 gene encodes a motor protein responsible for transporting cellular materials. Disruptions in its function due to mutations in the DYNC1H1 gene result in impairment of nerve signal transmission and reduced muscle strength. Ongoing research aims to better understand disease mechanisms and explore potential interventions for this form of SMA.

For more information about ongoing trials in SMA, please visit MDA’s grants at a glance and clinical trial finder or search clinicaltrials.gov for “spinal muscular atrophy” in the condition or disease field.

Last reviewed by July 2025 by Aravindhan Veerapandiyan, MD

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