Adrian Krainer and the splicing mechanism that became Spinraza

Adrian Krainer's lab at Cold Spring Harbor Laboratory spent twenty-five years studying the basic biology of how human cells choose which exons to include in messenger RNA. The lab worked out the splicing factor codes, the regulatory elements, and the cellular machinery that makes the choice. The work was foundational basic science with no immediate therapeutic intent.

In the mid-2000s, Krainer's group identified an intronic splicing silencer in the SMN2 gene that biased the cell toward producing a truncated, nonfunctional version of the survival motor neuron protein. The same lab then designed antisense oligonucleotides to mask the silencer and shift the cell toward producing functional protein. The lead candidate, manufactured at Ionis Pharmaceuticals under Frank Bennett, became nusinersen. The FDA approved it as Spinraza in December 2016. It was the first drug ever approved for spinal muscular atrophy and the first splice-modulating antisense oligonucleotide approved for any indication.

The arc from basic-science splicing factor mapping to a drug for the leading genetic cause of infant death is the arc most rare-disease ASO programs are now retracing on shorter timelines, with Krainer's mechanistic work as the precedent.

Training

Krainer was born and raised in Montevideo, Uruguay. He came to the United States in 1977 to attend college, completing a B.A. in biochemistry at Columbia College, New York, in 1981. His Ph.D., also in biochemistry, came from Harvard University in 1986, working with Tom Maniatis on the in vitro reconstitution of the spliceosome. He completed his independent postdoctoral fellowship at Cold Spring Harbor and joined the CSHL faculty in 1989.

He is currently the St. Giles Foundation Professor at CSHL and Deputy Director of Research of the CSHL Cancer Center. He is a member of the National Academy of Sciences, the National Academy of Medicine, the American Academy of Arts and Sciences, and the National Academy of Inventors.

What the lab studied

The Krainer lab works on RNA splicing: the cellular process by which pre-messenger RNA is cut at intron-exon boundaries and the exons are joined into a final mRNA that the ribosome translates into protein. Splicing is regulated by sequence elements within the pre-mRNA (splicing enhancers and silencers, both intronic and exonic) and by trans-acting splicing factors (SR proteins, hnRNPs, and the small nuclear ribonucleoproteins that make up the spliceosome).

For most of the lab's history, the work was basic biochemistry. Krainer's group purified splicing factors, identified their binding sites, established the rules by which alternative exons get included or excluded, and characterized how the choices vary across cell types and disease states. The group's contributions to splicing-factor biology, including foundational work on the SR protein family, established the conceptual framework the field still uses.

The translational angle came when the group recognized that splicing-factor-binding sites could be drugged. If a splicing silencer is biasing a gene toward a non-functional isoform, masking the silencer with an antisense oligonucleotide would allow the cell to produce the functional isoform instead. The mechanism is platform-style: the same chemistry that masks one splicing element can mask any other splicing element, with sequence design as the only program-specific work.

SMN2 and nusinersen

Spinal muscular atrophy is caused by loss-of-function mutations in SMN1. Humans carry a paralogous gene, SMN2, with one critical difference: a single nucleotide change in exon 7 disrupts a splicing enhancer, causing the cell to skip exon 7 in approximately 90 percent of SMN2 transcripts. The skipped transcripts produce a truncated SMN protein that is rapidly degraded. SMN2 alone produces too little functional SMN to compensate for SMN1 loss in most tissues, which is why SMA exists.

Krainer's lab and Frank Bennett's group at Ionis Pharmaceuticals collaborated on a series of papers between approximately 2008 and 2014 that worked out how to shift SMN2 splicing toward exon 7 inclusion. The lab identified an intronic splicing silencer in SMN2 intron 7 that suppressed exon 7 inclusion. They designed antisense oligonucleotides complementary to the silencer; when bound to the silencer, the ASO blocked the splicing factors that were suppressing exon 7. The cell then included exon 7 and produced functional, full-length SMN protein.

The 2010 paper in Genes and Development by Hua, Sahashi, Hung, Rigo, Passini, Bennett, and Krainer demonstrated systemic correction of SMA in mice. Nusinersen, the lead candidate, entered clinical trials in 2011 and was approved by the FDA in December 2016 for all types of SMA across all ages. The pivotal phase 3 trial, ENDEAR, was stopped early for benefit; treated infants showed substantial gains in motor function and survival relative to sham-treated controls.

By 2024, nusinersen had been administered to more than 14,000 children and adults globally. It is the most successful nucleic-acid drug ever launched.

Why nusinersen mattered beyond SMA

Nusinersen's significance for the n-of-1 ASO field is not the SMA outcomes alone, although those are substantial. The significance is platform validation. The drug established three things at scale that the broader field had hypothesized but not demonstrated.

First, splice-modulating antisense oligonucleotides are clinically effective. The mechanism Krainer's lab worked out at the molecular level produces measurable disease modification in patients dosed intrathecally on a manageable schedule (loading doses, then maintenance every four months).

Second, the safety profile of intrathecal 2'-MOE phosphorothioate ASOs in pediatric patients is characterizable. The class has known adverse events (CSF pleocytosis, transient transaminase elevations, route-related complications including rare hydrocephalus), and the events are tractable for monitoring protocols. The FDA's 2021 to 2022 guidance series for individualized antisense oligonucleotides leans on this safety database.

Third, the chemistry generalizes. The same 2'-MOE phosphorothioate chemistry, the same intrathecal route, and a similar dosing schedule have since been adapted to milasen for CLN7 Batten disease, atipeksen for ataxia-telangiectasia, valeriasen for KCNT1 epilepsy, jacifusen for FUS-mutated ALS, tofersen for SOD1-mutated ALS, and several other programs. Each of these programs treats nusinersen's chemistry-and-route precedent as the starting point for its own toxicology and safety packages. None of them would have been feasible on their actual timelines without nusinersen's data.

Recognition

Krainer's recognition for the work has come at multiple scales. He shared the 2019 Life Sciences Breakthrough Prize with Frank Bennett for the SMA program. He has received the 2021 Wolf Prize in Medicine, the 2021 Jacob and Louise Gabbay Award in Biotechnology and Medicine, the 2022 August M. Watanabe Prize in Translational Research, the 2024 Albany Prize in Medicine and Biomedical Research, and the 2025 Heinrich Wieland Prize. He was elected to the National Academy of Medicine in 2024.

The recognition pattern is the standard one for translational basic science that produces a transformative drug, and the timing reflects the slow progression: the basic-science papers from the 1990s and 2000s that mapped SMN2 splicing came many years before the first clinical trials, and the awards followed clinical impact rather than mechanistic discovery.

What the lab is doing now

The Krainer lab at CSHL continues to work on splicing in cancer and in genetic disease. Active programs include splicing-targeted therapies for myelodysplastic syndromes, dystrophic conditions caused by exon-skipping-amenable mutations, and other rare-disease indications where splice modulation could correct the molecular defect. The lab also collaborates with rare-disease foundations on candidate ASO design for conditions outside the n-Lorem and Yu-lab pipelines.

The basic science continues, in the same way that produced the SMN2 mechanism in the first place. The lab's published track record suggests that the next platform-changing therapeutic insight is more likely to come from the splicing biology the group is still mapping than from a directed translational program. That is how Spinraza happened.