One of the strengths of Cure SMA’s drug discovery program is how we attack SMA from multiple angles. This also gives us great reason for hope. We know that if one approach fails, we have several others we can pursue.

Due to a mutation in the survival motor neuron gene 1 (SMN1), individuals with spinal muscular atrophy (SMA) don’t produce survival motor neuron (SMN) protein at high enough levels. Without this protein, the motor neuron cells shrink and eventually die. This causes debilitating and potentially fatal muscle weakness.

One way to treat SMA is to increase the amount of SMN protein in the body. These ways of treating SMA are often called “SMN-based” or “SMN-enhancing” approaches, including:

  • Replacement or correction of the faulty SMN1 gene.

  • Modulation of the low functioning SMN2 “back-up gene.”

But increasing the amount of SMN protein in the body is not the only way to treat SMA. The loss of SMN protein also impacts other systems, pathways, and processes, and other treatments target these systems. Often called “non-SMN,” these approaches include:

  • Muscle protection to prevent or restore the loss of muscle function in SMA.

  • Neuroprotection of the motor neurons affected by loss of SMN protein.

  • Newer approaches that identify additional systems and pathways affected by SMA.

Many researchers believe that it will take a combination of SMN-based and non-SMN treatments to provide the most benefit for those with SMA. This could mean that individuals with SMA will take two drugs together. Or, they may take one type of drug at one stage of the disease, and then another drug at a different stage.

Replacement or Correction of the SMN1 Gene

One way of treating SMA is by replacing or correcting the faulty SMN1 gene through an approach called “gene therapy” or “gene replacement therapy.” Gene replacement therapy uses a piece of DNA from a particular gene, such as SMN1 for SMA. It isn’t possible to insert the gene directly into a cell, so scientists use a carrier, called a vector, to deliver the gene to the cell. A vector is a virus that “infects” the cell with the new DNA. The virus is modified so that it doesn’t make the person sick.

One gene therapy, Zolgensma, has been approved by the U.S. Food and Drug Administration (FDA) for infants with all types of SMA under 2 years of age. Zolgensma was developed and is marketed by Novartis Gene Therapies. It is a one-time intravenous (IV) infusion.

Novartis Gene Therapies is also developing a second gene therapy program. This second program works similarly to Zolgensma. However, instead of an IV delivery, this program delivers gene therapy via an intrathecal (IT) injection, which is an injection directly into the cerebrospinal fluid through the lower back. This method of delivery could eventually make this treatment available to older and larger patients.

Currently, this method of delivery is being studied in a Phase 3 clinical trial in patients from 2 up to 18 years who have SMA Type 2, and who have never walked, and who have never received a prior treatment for SMA. If the results are positive, Novartis Gene Therapies may file for FDA approval of this delivery method.

Modulation of the SMN2 “Back-Up Gene”

All individuals with SMA have at least one, and often multiple, copies of a second gene, called survival motor neuron gene 2 (SMN2), or the “SMA back-up gene.” SMN2 also produces SMN protein, but only a small percentage of the protein produced by SMN2 can be used by the body.

Most of the SMN protein made by SMN2 is missing an important piece, called exon 7. A number of strategies that target SMN2 are being explored. These treatment approaches may:

  • Correct SMN2 mRNA splicing, meaning SMN2 could produce a complete protein.

  • Prompt SMN2 to make more protein.

  • Make the protein produced by SMN2 last longer.

Spinraza, the first FDA-approved therapy for SMA, is a treatment that targets the SMN2 gene. Spinraza is an antisense oligonucleotide (ASO) approved for all ages and types of SMA. Antisense drugs are small snippets of synthetic genetic material that bind to ribonucleic acid (RNA), so they can be used to fix the splicing of genes like SMN2.

Evrysdi, FDA-approved for the treatment of SMA in adults and children 2 months and older, is another treatment that works by correcting the splicing of SMN2. Evrysdi is a small molecule that is taken daily by mouth or by g-tube. It must be taken for the duration of the individual’s life.

Muscle Protection

When low levels of SMN protein disrupt the proper function of motor neurons, the loss of nerve stimulation causes the skeletal muscles to atrophy. As the name would suggest, the goal of muscle protection is to protect these muscles from atrophy, increase muscle mass, and perhaps even restore some muscle function.

While this strategy does not address the underlying genetics of SMA, it may help slow or stop the progression of SMA and it can be used in combination with SMN-enhancing approaches. These approaches may include the use of small molecules that enhance the muscle’s ability to contract, or regulators of muscle mass that may improve muscle strength.

Currently, two muscle protectors are being studied in clinical trials.

  • The first is SRK-015, a myostatin inhibitor that may help increase muscle mass. Scholar Rock, the company developing SRK-015, is testing SRK-015 by itself, and in combination with approved SMN-enhancing therapies.
  • The second is reldesemtiv, a skeletal muscle activator developed by Cytokinetics/Astellas. A Phase 2 trial tested reldesmetiv in individuals with SMA Types 2, 3, or 4 who were over the age of 12 years.
child standing using musculoskeletal equipment


Motor neurons are one of the primary cell types affected in SMA. The goal of neuroprotection is to protect motor neurons by restoring their function and/or preventing their death. Similar to muscle protection, researchers believe that neuroprotection could be used in combination with SMN-enhancing therapies that fix the SMN1 or SMN2 gene. Two main neuroprotective strategies are being studied for SMA:

  • Neuroprotective small molecules that help cells stay alive.

  • Stem cells transplants that provide growth factors to motor neurons.