Today this review paper from @BrunhildeWirth in Trends in Neuroscience on SMA. I like how the abstract states that young researchers should not give up when things are difficult. In science they usually are, but uncovering them can lead to great discoveries and even therapy

Why was/is research for SMA so difficult? First the gene involved was hard to find due to copy number variation of a pseudogene in the locus (SMN2), the unknown function of SMN1/2 & the presence of NAIP in the locus, a gene encoding a protein that prevents motor neuron apoptosis.

Then variable phenotypes were seen from very severe to milder, see also this very nice Figure. Severity inversely correlates with the number of SMN2 copies, but not perfectly. There are also genetic modifiers such as plastin 3, that can be protective.

While SMN 1 and 2 differ only in 5 positions and all coding variations are silent, SMN2 produces only low amounts of protein because exon 7 is poorly recognized by the splicing machinery. Thus lacking SMN1 genes reduced amounts of SMN protein are produced.

SMN has multiple functions during embryogenesis and postnatally. Especially motor neurons are sensitive to drops in proteins. However also other organs are affected below a certain level in mice.

Three therapies are available for SMA patients now: Zolgensma: a gene therapy that restores SMN protein. This needs to be delivered with AAV gene therapy IV in young babies before the blood-brain barrier becomes impenetrable for AAV.

Risdiplam is a daily taken oral drug that improves recognition of exon 7 of SMN2 resulting in more SMN production. Nusinersen is an antisense oligonucleotide that does the same but this needs intrathecal delivery 5 times in year 1 and 3 times/year after.

All drugs have more effect when given early so newborn screening is crucial in countries that can afford the drugs. Unfortunately setting up NBS takes time. This is a lesson for other rare diseases: governments should prepare rather than starting when the therapy is there.