The treatment landscape for Spinal Muscular Atrophy (SMA) has shifted dramatically in recent years, moving from purely supportive care to targeted, disease-modifying therapies. This transformation means that families and medical teams no longer search for a single “drug of choice” but rather evaluate a suite of options. These treatments are designed to address the underlying genetic cause of SMA by increasing the body’s production of the essential survival motor neuron (SMN) protein.
The Three FDA-Approved Therapies for SMA
There are three FDA-approved medications that target the genetic root of SMA: nusinersen, onasemnogene abeparvovec, and risdiplam. Each has a unique mechanism of action, administration method, and approved patient population.
Nusinersen (Spinraza®)
- Mechanism of Action: Nusinersen is an antisense oligonucleotide (ASO), a type of synthetic genetic material that targets the SMN2 gene. By binding to the SMN2 messenger RNA (mRNA), it corrects the splicing process, prompting the gene to produce more functional, full-length SMN protein.
- Administration: It is administered via intrathecal injection (a spinal tap) directly into the fluid surrounding the spinal cord.
- Approved For: Nusinersen is approved for the treatment of pediatric and adult patients with all types of SMA.
- Dosage Schedule: Treatment begins with a series of initial loading doses, followed by maintenance doses administered every four months for the patient's lifetime.
- Outcomes: Early intervention has shown significant benefits, particularly in infants. Clinical trials have demonstrated improved motor function and survival rates across different SMA types.
Onasemnogene abeparvovec (Zolgensma®)
- Mechanism of Action: This is a one-time gene therapy that uses a harmless viral vector (AAV9) to deliver a functional copy of the missing or mutated SMN1 gene directly into the body's motor neurons.
- Administration: It is given as a single intravenous (IV) infusion that takes approximately one hour.
- Approved For: Zolgensma is approved for pediatric patients under two years of age with bi-allelic mutations in the SMN1 gene.
- Outcomes: Clinical trials have shown significant improvements in motor function and event-free survival, especially when administered in the presymptomatic stage.
- Considerations: Pre-screening for anti-AAV9 antibodies is required, as a high titer can preclude treatment. Close monitoring for potential liver toxicity is also necessary.
Risdiplam (Evrysdi®)
- Mechanism of Action: Risdiplam is a small molecule that also modifies the splicing of the SMN2 gene to increase the production of functional SMN protein. Its key differentiator is that it works systemically, distributing the protein to both the central nervous system and peripheral tissues.
- Administration: It is a daily oral medication, available as a liquid solution or a tablet.
- Approved For: Evrysdi is approved for patients of all ages, from infants to adults.
- Outcomes: Benefits include improved motor function and stabilization of the disease. A key advantage is its non-invasive administration.
Comparison of Major SMA Treatments
| Feature | Nusinersen (Spinraza®) | Onasemnogene Abeparvovec (Zolgensma®) | Risdiplam (Evrysdi®) |
|---|---|---|---|
| Mechanism | SMN2 splicing modifier (ASO) | SMN1 gene replacement (AAV9 vector) | SMN2 splicing modifier (small molecule) |
| Administration | Intrathecal injection (spinal tap) | Single intravenous infusion | Daily oral liquid or tablet |
| Approved Age | All ages (pediatric and adult) | Pediatric patients <2 years of age | All ages (infants to adults) |
| Target | Primarily CNS | Systemic delivery (CNS and periphery) | Systemic delivery (CNS and periphery) |
| Treatment Schedule | Chronic, lifelong (maintenance doses every 4 months) | One-time administration | Chronic, lifelong (once daily) |
| Early Intervention | Greater benefit with earlier treatment | Most effective when given presymptomatically | Strong evidence of benefit with presymptomatic treatment |
Factors Determining the Best SMA Therapy
Since there is no singular drug of choice, a personalized approach is necessary. A multidisciplinary care team, including neurologists and genetic counselors, will consider several factors when recommending a treatment path:
- Patient Age and SMA Type: Age restrictions for certain therapies, such as Zolgensma, are a primary consideration. The severity and type of SMA also influence the selection.
- Genetic Profile: The number of SMN2 gene copies can affect prognosis and help determine which therapy might be most effective.
- Administration Route: Patient and caregiver preference regarding the method of administration (spinal injection, IV, or oral) is a significant factor. Patients with severe scoliosis may face challenges with intrathecal injections, for example.
- Disease Stage: The stage of the disease at diagnosis is critical, as therapies have the most profound effect when initiated early, ideally before symptoms appear.
- Prior Treatments: For patients who have already received one treatment, switching or adding another can be considered based on clinical evidence and trials.
- Insurance Coverage: The cost and coverage provided by insurance plans for these specialized and high-cost therapies are major considerations that the care team can help navigate.
The Importance of Early Diagnosis and Treatment
Thanks to the widespread implementation of newborn screening for SMA, many infants are now diagnosed before the onset of symptoms. Starting treatment in this presymptomatic window can lead to significantly better outcomes, including achieving motor milestones like sitting and walking that would otherwise not be possible. Therefore, rapid diagnosis followed by prompt initiation of the most appropriate therapy is paramount.
Emerging Therapies and Future Directions
The SMA research and development pipeline remains active. In 2025, promising results were reported for apitegromab, an investigational muscle-targeted treatment designed to work alongside existing SMN-enhancing therapies. It aims to improve motor function by inhibiting myostatin, a protein that limits muscle growth. Additionally, clinical trials are investigating a higher-dose regimen of nusinersen to potentially provide enhanced benefits. These ongoing advancements offer future hope and expand the therapeutic toolkit for managing SMA.
Conclusion: A Personalized Treatment Plan Is Essential
In conclusion, there is no one-size-fits-all “drug of choice” for SMA. The advancements in treatment—including Spinraza, Zolgensma, and Evrysdi—represent a new era of proactive and targeted care. The most effective approach is a personalized plan, developed in consultation with a medical team, that takes into account the specific needs and characteristics of the individual patient. Timely diagnosis and intervention are critical for maximizing the therapeutic benefits of any chosen treatment. For further information and patient resources, the Cure SMA website is a valuable resource.
