Question

Which FDA-approved drug for spinal muscular atrophy (SMA) is administered intrathecally?

• A. Rilotinib
• B. Nusinersen
• C. Ivacaftor
• D. Ditunimumab

Hint:

SMA Therapeutics Comparison:
$\bullet$ Nusinersen (Spinraza): Intrathecal ASO modifier of SMN2 splicing.
$\bullet$ Risdiplam (Evrysdi): Oral small-molecule SMN2 splicing modifier.
$\bullet$ Onasemnogene abeparvovec (Zolgensma): Single IV dose AAV9 gene therapy.

Answer 1

The Correct Option is B

Concept:
Spinal Muscular Atrophy (SMA) is an autosomal recessive neuromuscular disease caused by homozygous deletions or loss-of-function mutations in the SMN1 (Survival Motor Neuron 1) gene on chromosome 5q.
This leads to progressive degeneration of anterior horn alpha motor neurons in the spinal cord, causing proximal muscle weakness, hypotonia, and motor disability.
Explanation:
• Humans possess a nearly identical centromeric paralog gene, SMN2, which contains a single nucleotide transition ($C\rightarrow T$) in exon 7 that causes alternative splicing, producing primarily an unstable, truncated protein ($\text{SMN}\Delta 7$) with only $10$--$20\%$ fully functional SMN protein.

• Nusinersen (Spinraza) is an antisense oligonucleotide (ASO) specifically designed to bind to the intronic splice-silencing site (ISS-N1) of the SMN2 pre-mRNA, promoting exon 7 inclusion and drastically increasing the production of full-length, functional SMN protein.

• Because antisense oligonucleotides do not cross the blood-brain barrier, nusinersen must be administered directly into the cerebrospinal fluid via intrathecal injection (administered in 4 loading doses over 2 months, followed by maintenance injections every 4 months).

• Onasemnogene abeparvovec (Zolgensma) is an AAV9 vector-mediated gene replacement therapy administered as a single intravenous infusion.

• Risdiplam (Evrysdi) is a small molecule SMN2 splicing modifier administered as a daily oral liquid.

• Ivacaftor is a CFTR potentiator used in cystic fibrosis, not SMA.
Final Answer:
Nusinersen is the FDA-approved antisense oligonucleotide therapy for SMA that is administered intrathecally.