Scientific American - USA (2020-03)

March 2020, ScientificAmerican.com 53

Nusinersen, Antisense’s Dramatic Success Story

Antisense oligonucleotides, or ASOs, are short segments of DNA or RNA designed to bind to messenger RNA and alter the transcription

of DNA into proteins. After decades of struggle, researchers have achieved spectacular results with nusinersen, which arrests the progression

of spinal muscular atrophy, a lethal neurodegenerative disease, by prompting a nearly inactive gene to efficiently make a vital protein.

In Healthy People ...

Normally a person has two versions of the gene for producing SMN.

The first gene, called SMN1, produces a stable version of the protein

SMN, whereas the second, SMN2, generates an unstable version.

In People with SMA ...

Patients with spinal muscular atrophy are

missing the gene SMN1. They do have SMN2,

but it produces far too little usable protein.

Treatment with Nusinersen

Nusinersen, injected into spinal fluid via lumbar puncture,

homes in on the RNA strands produced by SMN2 and

binds to a section following exon 7. It pre vents the splicing

machinery from cutting crucial instructions from the RNA

strand. In consequence, the RNA ends up being translated

into stable SMN protein.

The nearly identical

genes differ significantly

only in the seventh

exon, or coding block.

DNA

SMN1 messenger

RNA (mRNA) is

complete, resulting

in a stable version of

the SMN protein.

SMN2 has a variation

that causes exon 7 to

be ignored during the

splicing, or cutting and

pasting, of RNA during

transcription. The re ­

sulting mRNA is missing

a segment and is trans­

lated into un stable

SMN protein.

SMN protein

SMN1 mRNA

Both versions of the protein are present

SMN1 gene is

not present

Only the unstable protein version is present

SMN1 gene is

not present

Antisense oligonucleotide

SMN protein

SMN2 mRNA

Exon 6

Exon 7 Exon 8

Splicing

regulator

Illustration by Mesa Schumacher

SMN1 gene SMN2 gene

Unstable

SMN protein

SMN2 mRNA,

lacking exon 7

SMN2 gene

Unstable

SMN protein

SMN2 mRNA,

lacking exon 7

SMN2 gene

Transcription

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