SMA is an autosomal recessive motor neuron disease caused by loss of the SMN1 gene, leaving only the low-output backup gene SMN2. Nusinersen is an antisense oligonucleotide that corrects SMN2 splicing to raise SMN protein. This phase 3 CHERISH trial asked whether intrathecal nusinersen improves motor function in children with later-onset SMA (types 2 and 3) compared with a sham procedure.
SMA is the archetype disease for connecting a genetic defect to a targeted therapy, and it is high-yield for pediatric neuromuscular questions. Know the mechanism cold: SMN1 deletion causes disease, SMN2 makes mostly truncated protein because exon 7 is skipped, and nusinersen is an antisense oligonucleotide that forces exon 7 inclusion to raise functional SMN protein.
Remember the type definitions by onset and milestone: type 1 (onset by 6 months, never sits), type 2 (onset 6 to 18 months, never walks), type 3 (onset after 18 months, walks at some point). Higher SMN2 copy number means milder disease.
The practical lesson is timing. Younger children and those treated earlier gained the most, and the improvement barely met significance for milestones, so earlier intervention before neuron loss is the goal. One appraisal caveat worth carrying: because the milestone endpoint missed significance, endpoints below it in the testing hierarchy are only exploratory.
SMA is an autosomal recessive motor neuron disease caused by loss of the SMN1 gene, leaving only the low-output backup gene SMN2. Nusinersen is an antisense oligonucleotide that corrects SMN2 splicing to raise SMN protein. This phase 3 CHERISH trial asked whether intrathecal nusinersen improves motor function in children with later-onset SMA (types 2 and 3) compared with a sham procedure.
SMA is the archetype disease for connecting a genetic defect to a targeted therapy, and it is high-yield for pediatric neuromuscular questions. Know the mechanism cold: SMN1 deletion causes disease, SMN2 makes mostly truncated protein because exon 7 is skipped, and nusinersen is an antisense oligonucleotide that forces exon 7 inclusion to raise functional SMN protein.
Remember the type definitions by onset and milestone: type 1 (onset by 6 months, never sits), type 2 (onset 6 to 18 months, never walks), type 3 (onset after 18 months, walks at some point). Higher SMN2 copy number means milder disease.
The practical lesson is timing. Younger children and those treated earlier gained the most, and the improvement barely met significance for milestones, so earlier intervention before neuron loss is the goal. One appraisal caveat worth carrying: because the milestone endpoint missed significance, endpoints below it in the testing hierarchy are only exploratory.