How Zolgensma, a Gene Therapy, is Rewriting The Fate of SMA (Spinal Muscular Atrophy) Patients

What is Spinal Muscular Atrophy (SMA)? 1

SMA is a rare inherited disease that weakens muscles over time, making movement difficult. It happens because motor neurons, the nerve cells that control muscles, break down and die.

How does it happen? 1

SMA is caused by a fault in a gene called SMN1. This gene normally produces a protein (SMN protein) that keeps motor neurons healthy.

When the SMN1 gene is broken, the body doesn’t make enough SMN protein, leading to muscle weakness and wasting. The effect? Without enough SMN protein, muscles get weaker, affecting activities like crawling, walking, swallowing, and in some severe cases- even breathing!

Types of SMA: 1

1. Type 1 (Severe) – Symptoms at birth or before 6 months. Weak muscles, breathing/eating difficulties.

2. Type 2 (Intermediate) – Appears at 6–18 months of age. Babies can sit but not walk. There is progressive deterioration in their physical activity.

3. Type 3 (Mild) – Onset after 18 months. Affected kids can walk but may lose the ability to do so over time.

4. Type 4 (Adult-onset) – This type is rare; it starts in adulthood with gradual muscle weakening.

How and When is SMA Diagnosed? 1

SMA is usually diagnosed using one or more of these methods:

1. Genetic Testing (Primary Method)

- A blood test checks for mutations in the SMN1 gene.

- Confirms the diagnosis with >95% accuracy.

2. Newborn Screening (In Some Countries)

- Some places test for SMA at birth (e.g., parts of the U.S., Europe).

- Early detection allows immediate treatment, improving outcomes.

3. Electromyography (EMG) & Muscle Biopsy: These methods were used before genetic testing was available; diagnosis was made based on measuring muscle and nerve activity.

Key Challenges in India: 2

As newborn screening is not yet universal, identifying SMA early remains a task to be navigated in India. We see limited awareness about SMA among pediatricians, while SMA is a very rare genetic disorder. If you have any family history of SMA, you should be sure to mention it to your healthcare provider as well as schedule a carrier screening test before planning a pregnancy. Upon birth, you can request a SMA test & other tests that may help rule out diseases with similar symptoms.

As we progress, Genetic centers and Hospitals in India have begun to test for SMA in newborn screening panels. Genetic tests are also being offered by established labs with a nationwide presence, making these tests more accessible.

A New Chapter in Genetic Medicine 3

Gene therapy represents one of the most exciting breakthroughs in modern medicine, offering the potential to cure diseases at their genetic roots. Among these revolutionary treatments, Zolgensma® (onasemnogene abeparvovec-xioi) stands out as a life-changing therapy for spinal muscular atrophy (SMA). Let’s understand the science behind Zolgensma, its transformative benefits, and crucial considerations for families facing an SMA diagnosis:

Understanding Zolgensma: The Science Simplified 4

What Exactly is Zolgensma?

Zolgensma is:

- The first FDA-approved gene replacement therapy for SMA

- The only one-time intravenous infusion that delivers a functional copy of the SMN1 gene

- Designed to halt disease progression by enabling the production of the crucial SMN protein

How Does It Work? The Brilliant Mechanism 5

The therapy uses a clever biological "delivery truck" system:

1. Viral Vector Technology: A harmless adeno-associated virus (AAV9) serves as the delivery vehicle

2. Gene Replacement: The virus carries a working SMN1 gene to motor neuron cells

3. Protein Production: Once delivered, cells can produce the SMN protein needed for muscle function

The Transformative Benefits of Zolgensma 3, 6

Clinical Advantages

- Single-dose administration: Unlike other SMA treatments requiring regular dosing.

- Dramatically improved survival: 92% of Type 1 patients alive at 14 months vs. <25% historically- that indicates a substantial difference, promising hope to individuals with SMA.

- Motor milestone achievement: Many treated children gain abilities never seen in natural SMA progression without Zolgensma.

Who Can Benefit From Zolgensma? 3, 4

- Pre-symptomatic infants: Best outcomes when treated before symptom onset

- Early symptomatic phase: Still shows significant benefits

- Later stages: May help stabilize the condition, but with more limited improvement

Critical Safety Information: 3

Things to know while considering ZOLGENSMA: 8

- Hospital-based infusion takes about 60 minutes & the pre-treatment preparation requires steroid therapy to prevent immune reactions; reporting of any symptoms to the healthcare provider is crucial. Weekly liver function tests for 3 months post-treatment are recommended for monitoring the liver.

Potential Side Effects 3

• Common reactions:

- Transaminase elevation (63% of patients)

- Vomiting

- Fever

• Serious risks requiring immediate attention:

- Acute liver injury, hepatic impairment

- Thrombocytopenia

- Cardiac complications (rare)

Important Considerations for Families 6

1. Age of the Patient

Best results can be expected when ZOLGENSMA is administered before 6 months of age in symptomatic infants. Although it is FDA-approved for children under 2 years, its effectiveness decreases with age. Older patients still benefit from ZOLGENSMA but typically see more modest improvements.

2. SMA Type and Disease Severity

- Type 1 (most severe): Strongest candidate for immediate treatment

- Type 2: Shows significant benefit when treated early

- Type 3: May help preserve motor function if treated pre-symptomatically

- Type 0: Often treated immediately after birth if identified prenatally

3. Current Motor Function Status: Pre-symptomatic infants are the ideal candidates with the best outcomes. Symptomatic individuals are also good candidates if they receive treatment early- but they may not achieve complete normal development. Patients with advanced symptoms may be able to bring their symptoms to a halt, but are unlikely to regain lost function.

4. SMN2 Copy Number 7

- 1-2 copies: Strongest indication for urgent treatment (more severe progression)

- 3 copies: Variable progression - earlier treatment preferred

- 4+ copies: Milder form but may still benefit from treatment

5. Previous Treatments: Presymptomatic patients who haven't undergone any therapy are the best candidates for Zolgensma monotherapy. Patients on other therapies (Spinraza/Evrysdi) May still benefit from Zolgensma, but require careful transition planning under the supervision of the healthcare provider.

Practical Considerations 6

1. Timing of Administration

- Emergent treatment: For symptomatic infants (especially respiratory involvement)

- Newborn screening: Allows earliest possible intervention

- Logistical planning: Treatment requires specialized center coordination

2. Health Status Evaluation 3

- Liver function: Must be monitored before and after

- Cardiac assessment: Especially important for high-risk infants

- Nutritional status: May need optimization pre-treatment

3. Family Considerations

- Informed consent: Understanding risks/benefits is crucial

- Financial factors and Follow-up commitment: Zolgensma therapy requires long-term monitoring

Contraindications and Special Cases 3

When Zolgensma May Not Be Recommended

- Advanced disease with complete ventilator dependence

- Presence of anti-AAV9 antibodies

- Certain pre-existing liver conditions

- Older patients with established severe disability

Limitations of Zolgensma 3, 6

- Works best if given early (ideally before symptoms start).

- Does not reverse existing nerve damage but prevents further decline.

- Not a cure—some children still need additional therapies (e.g., Spinraza, Evrysdi).

While not the right choice for every SMA patient, Zolgensma represents the best chance for normal development when administered early to appropriate candidates. Families should work closely with their neuromuscular care team to navigate this complex decision-making process.

Conclusion: A Paradigm Shift in SMA Treatment

Zolgensma represents a watershed moment in medicine, transforming SMA from a uniformly fatal condition to one where children can survive and thrive. While not a perfect cure, it offers unprecedented hope. The key takeaways for families:

1. Early diagnosis is critical - pursue newborn screening if available

2. Treatment timing matters - intervene as early as possible

3. Comprehensive care remains essential - physical therapy, nutrition, and monitoring are still needed

Accessing Zolgensma:

Indian Families facing a SMA diagnosis can access ZOLGENSMA through Rx4u, a platform dedicated to bringing life-saving medication directly to your address.

Even when a life-altering drug like ZOLGENSMA is locally unavailable- Rx4u, through heir well established Global Supply Chain & legal team- promises timely delivery of authentic medication from across the world to you, so you can live your healthiest life possible!

Note:

The information provided is for education purpose only and is subjected to prescribing information of the drug and the guidance of your treating physician. Always consult your health care provider before making any medical decision for starting your treatment.

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