Generic Name

Elevidys

Mechanism

• Vector‑mediated SMN restoration – AAV9 particles enter motor neuron nuclei and release a functional *SMN1* cDNA.
• Sustained SMN protein production – Transduced cells continuously synthesize SMN protein, replenishing the deficit caused by *SMN1* loss and *SMN2* mis‑splicing.
• Improved neuromuscular function – Normal SMN levels stabilize motor neurons, enhance axonal transport, and reduce muscle wasting.

*Key terms*: AAV9, SMN1, SMN protein.

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Pharmacokinetics

• Administration: Single, weight‑based intravenous infusion.
• Vector distribution: AAV9 penetrates the blood‑brain barrier efficiently, transducing cortical motor neurons and spinal cord cells.
• Expression kinetics: Peak SMN expression occurs ~1 week post‑infusion and persists for ≥5 years due to long‑lived episomal vector DNA.
• Clearance: Viral capsids are cleared by the reticuloendothelial system; no significant metabolite formation.
• Special populations: No dose adjustments for renal or hepatic impairment are recommended; however, caution is advised in severe liver dysfunction.

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Indications

• Spinal muscular atrophy (SMA) type 1, 2, and 3 in infants, children, and adults with confirmed *SMN1* mutation and low *SMN2* copy number.
• Early or presymptomatic disease – Initiation before overt motor deficits yields superior motor milestones.
• Contraindicated in patients with known hypersensitivity to any component of the product.

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Contraindications

• Absolute contraindications
• Hypersensitivity to AAV9 vector or the human serum albumin (HSA) used as a carrier.
• Relative warnings
• Acute liver injury – Rare but serious; prompt monitoring of ALT/AST.
• Thrombocytopenia – May develop after infusion; manage with platelet transfusion if >30 % drop.
• Immune‑mediated adverse events – Cytokine release and systemic inflammation can occur; pre‑medicate with steroids in high‑risk patients.
• Potential for viral replication – Monitor for breakthrough infections in immunocompromised patients.

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Dosing

• Premedication: Consider acetaminophen 10 mg/kg and IV dexamethasone 0.5 mg/kg in patients with a history of infusion reactions.
• Infusion support: Monitor vitals every 15 min for the first 2 h, then hourly.
• Post‑infusion: Observe for 6 h for delayed hepatic or hematologic signs.

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Monitoring

• Baseline: CBC, CMP (ALT/AST, bilirubin, albumin), coagulation profile, viral serology (HBV/HCV/HIV).
• Post‑infusion schedule:
• Day 7–14: CBC, CMP, liver‑panel.
• Month 1, 3, 6, 12: CBC, CMP, neurofunctional assessment.
• Every 6 months thereafter: CBC, liver function, SMN protein levels.
• Neurologic: Regular motor milestone evaluations (HINE, CHOP INTEND).

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Clinical Pearls

1. Early is better – Administer Elevidys as soon as SMA is confirmed, ideally before motor neuron loss occurs.

2. One‑time therapy – Because of durable SMN expression, repeat dosing is unnecessary; focus on long‑term follow‑up rather than re‑infusion.

3. Differentiate from nusinersen – Elevidys targets the root cause, whereas nusinersen (Spinraza) modifies SMN2 splicing; combination is not routinely recommended.

4. Liver monitoring is critical – Even mild elevations in aminotransferases warrant a thorough evaluation; severe elevations may necessitate dexamethasone or an immunosuppressive regimen.

5. Patient selection matters – Adults with >10 SMN2 copies may derive less benefit; consider genetic counseling and prognosis when discussing therapy.

6. Vaccination – Immunogenicity of AAV9 is low; however, vaccinate patients pre‑therapy to avoid live attenuated vaccines that could compromise vector efficacy.

7. Data transparency – Encourage participation in registries (e.g., AAV‑SMA Registry) to contribute real‑world outcomes and refine safety profiles.

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• *Key takeaways*: Elevidys offers a single, weight‑based IV infusion for SMA patients, restoring SMN protein levels through AAV9‑mediated gene transfer. Prompt initiation, vigilant monitoring of liver enzymes and platelet counts, and clear distinctions from other SMA therapies are essential for optimal patient outcomes.