Spinal muscular atrophy (SMA) is a rare genetic condition that impairs a person’s ability to control their muscle movement. Most types of SMA are diagnosed in infants, but the condition sometimes starts in adulthood.
There’s currently no cure for SMA, but the Food and Drug Administration (FDA) has recently approved several new treatments for both type 1 and type 2 SMA, including innovative gene therapies, with many more potential treatments on the horizon.
Mutations in the SMN1 gene cause SMA. The number of copies of another gene, known as SMN2, affects the severity of the condition. SMN1 and SMN2 provide instructions for making a protein called the survival motor neuron (SMN).
SMN is needed to maintain motor neurons, the cells that transmit signals from the brain and spinal cord, telling muscles to contract and allowing the body to move.
Symptoms of SMA include:
- weak arms and legs
- inability to stand or sit up without support
- problems breathing
Depending on the number of copies of SMN2 a person has, there are several different types of SMA.
Type 1 SMA
People with type 1 SMA typically have only two SMN2 genes.
Type 1 SMA is the most common and the most severe form of SMA. Symptoms of type 1 SMA, also known as Werdnig-Hoffman disease, tend to start in the first 6 months after birth.
Life expectancy for children with this type of SMA used to be about 2 years. However, outlooks are improving due to newer treatments. Now, children diagnosed with this type of SMA may survive for a number of years.
Type 2 SMA
People with type 2, or intermediate, SMA typically have three or more SMN2 genes. Symptoms of type 2 SMA usually begin when a baby is between ages 7 and 18 months old.
Less common types
Type 3 SMA, also called late-onset SMA, or Kugelberg-Welander disease, is a less severe form of SMA. Symptoms typically begin after age 18 months.
Symptoms of type 4, or adult-onset, SMA usually begin in early adulthood, most often after age 35 years.
There are also other, less common forms of SMA that are caused by mutations in other genes.
Research for new treatments for SMA is ongoing.
Many researchers believe that it’ll take a combination of treatments to provide the most benefit.
Currently, a variety of different mechanisms are under investigation. These include:
Correcting the SMN1 gene
Pharma company Novartis manufactures onasemnogene abeparvovec-xioi (Zolgensma), an intravenous medication that’s intended to treat SMA in children under age 2 years.
The company is studying a similar drug that would be delivered intrathecally (injected into the fluid surrounding the spinal cord). This delivery method could make this treatment option available to older SMA patients.
Researchers are also looking into the use of novel DNA editing technology called CRISPR/Cpf1 to convert the SMN2 gene to an SMN1-like gene. This research is in its
Modifying SMN2 genes
Novartis is also working on a drug called branaplam (LMI070), which aims to increase the amount of functional SMN protein the SMN2 gene produces. The agent is now being studied in small phase I and phase II trials in infants with Type 1 SMA.
Shift Pharmaceuticals is developing a drug called E1v1.11, which aims to treat all types of SMA by using a person’s own genome to increase the production of SMN protein.
E1v1.11 is an antisense oligonucleotide (ASO) that’s currently in animal testing.
Targeting muscle function
Cytokinetics and Astellas Pharma are developing reldesemtiv, a fast skeletal muscle troponin activator (FSTA) that’s thought to lead to an increase in the ability of skeletal muscles to contract.
The agent has already shown promising results for those with type 2, type 3, and type 4 SMA in a phase II clinical trial.
Apitegromab, which Scholar Rock developed, enhances muscle growth by inhibiting the activation of a muscle growth inhibitor known as myostatin.
This drug aims to improve motor function in people with SMA. A phase II proof-of-concept trial is ongoing in people with types 2 and 3 SMA. An interim analysis of the trial has already shown potential benefits, with more data expected to be released this year.
Biogen, the manufacturer of nusinersen (Spinraza), is also developing BIIB110 (ActRIIA/B ligand trap). This agent inhibits both myostatin and related factors known as activins. It’s currently in phase I development.
It’s important to note that targeting the muscle does not fix the underlying genetic problem that causes SMA. Therefore, drugs that improve muscle function are more likely to be used in combination with other therapies that act on the SMN genes.
Protecting motor neurons
Motor neurons are the nerve cells that deteriorate in people with SMA. Researchers are looking to find new therapies that prevent motor neurons from becoming dysfunctional.
These types of therapies, if successful, will likely be used in combination with other drugs that address the underlying genetic problem in SMA.
Three drugs have been approved for SMA.
It’s an antisense oligonucleotide that works by increasing production of the full-length SMN protein and is administered intrathecally (injected into the fluid surrounding the spinal cord) as a one-time treatment.
Spinraza was shown to be beneficial in about 40 percent of patients with Type 1 infantile-onset SMA who received it.
Onasemnogene abeparovec-xioi (Zolgensma)
Several other therapies may help with muscle weakness and improve independence for those with SMA, including:
- physical therapy
- occupational therapy
- assistive devices, such as braces, orthotics, and wheelchairs
Timing is critical when it comes to SMA treatments. Studies have shown that many new treatments work best before children start to have symptoms, or as soon after diagnosis as possible, compared with those who wait to begin treatment.
New treatments approved within the last few years have offered people with SMA improvements in motor function and prolonged life for those with the most severe forms of SMA.
While there’s currently no cure for SMA, important research is ongoing. As researchers learn more about gene editing and other approaches to treating the underlying genetic causes of SMA, the scenario is likely to change quickly.