Understanding the Genetic Basis of SMA
Spinal Muscular Atrophy (SMA) is a rare, inherited neuromuscular disorder caused by a missing or mutated survival motor neuron 1 (SMN1) gene, leading to a deficiency in the Survival Motor Neuron (SMN) protein. The SMN2 gene provides a backup, but produces less functional SMN protein, and the number of SMN2 copies can influence disease severity. FDA-approved treatments aim to increase SMN protein production or replace the missing gene function.
FDA-Approved Treatments for SMA
Since 2016, the FDA has approved three treatments for SMA with different mechanisms and administration methods. The optimal choice depends on factors like age, SMA type, and overall health.
Nusinersen (Brand Name: Spinraza)
Approved in December 2016, nusinersen was the first FDA-approved SMA treatment. It is an antisense oligonucleotide (ASO) that modifies SMN2 gene splicing to increase functional SMN protein production. Administered via intrathecal injection into the cerebrospinal fluid, it is approved for all ages with genetically confirmed SMA. Treatment involves initial loading doses followed by maintenance doses every four months.
Onasemnogene Abeparvovec (Brand Name: Zolgensma)
Zolgensma, approved in May 2019, is a one-time gene therapy that uses a viral vector to deliver a functional SMN1 gene to motor neurons, enabling the body to produce SMN protein. This single intravenous infusion is approved for pediatric patients under two with genetically confirmed SMA. Due to potential liver injury, monitoring and corticosteroids may be necessary.
Risdiplam (Brand Name: Evrysdi)
Risdiplam, approved in August 2020, is the first oral SMA medication. It is an SMN2 splicing modifier that increases functional SMN protein. Taken daily by mouth as a liquid or tablet, Evrysdi is approved for all ages with SMA.
A Comparison of SMA Treatments
Selecting the right treatment considers age, SMA type, administration, and other medical factors. The table below compares the three FDA-approved options.
| Feature | Nusinersen (Spinraza) | Onasemnogene Abeparvovec (Zolgensma) | Risdiplam (Evrysdi) |
|---|---|---|---|
| Mechanism | SMN2 splicing modifier (ASO) | Gene replacement therapy (SMN1 gene) | SMN2 splicing modifier (oral) |
| Administration | Intrathecal (spinal) injection | Single intravenous (IV) infusion | Daily oral medication (liquid or tablet) |
| Frequency | 4 loading doses over 2 months, then every 4 months | One-time treatment | Daily |
| Approved Population | All ages (pediatric and adult) | Pediatric patients under 2 years of age | All ages (pediatric and adult) |
| Key Benefit | Changes the course of SMA for many patients | Single administration can provide long-term benefit | Non-invasive, daily oral administration |
Important Considerations and Future Directions
Early diagnosis through newborn screening is vital for prompt treatment to preserve motor neuron function. Research is ongoing to explore new SMA therapies, including combination approaches and drugs like apitegromab that enhance muscle growth. Higher-dose Spinraza and an intrathecal version of Zolgensma are also being investigated.
Conclusion
The availability of FDA-approved treatments like nusinersen, risdiplam, and onasemnogene abeparvovec has significantly improved the prognosis for individuals with SMA by targeting the underlying genetic cause. While a cure is not yet available, these advancements have dramatically altered the disease's course and enhanced the quality of life for those affected. Ongoing research holds promise for future therapeutic breakthroughs.
For more information on spinal muscular atrophy, the Muscular Dystrophy Association is a valuable resource that supports research and provides patient advocacy.
