Adrian R. Krainer

Adrian Krainer is the world's leading authority on therapeutic RNA splicing manipulation and the principal academic architect of nusinersen (Spinraza), the first antisense oligonucleotide drug approved by the FDA for the treatment of spinal muscular atrophy (SMA). His career at Cold Spring Harbor Laboratory has spanned more than three decades, during which he has fundamentally advanced both the basic biochemistry of pre-mRNA splicing and its direct therapeutic applications. Krainer's foundational work in the 1980s and 1990s characterized the biochemical activities of serine/arginine-rich (SR) proteins — a family of essential splicing factors that promote exon recognition and spliceosome assembly. His rigorous in vitro reconstitution of the splicing reaction with defined components established the mechanistic rules governing exon inclusion and skipping, providing the mechanistic bedrock upon which rational splice-switching therapy was later built. The clinical centerpiece of Krainer's career is nusinersen. SMA is caused by insufficient levels of the survival motor neuron (SMN) protein due to deletions or mutations in the SMN1 gene. Humans carry a near-identical paralog, SMN2, but a critical C-to-T transition in exon 7 causes the exon to be predominantly skipped, producing a truncated, unstable protein. Krainer's laboratory designed antisense oligonucleotides (ASOs) that block an intronic splicing silencer downstream of SMN2 exon 7, forcing the spliceosome to include the exon and produce full-length, functional SMN protein. Developed in collaboration with Ionis Pharmaceuticals and Biogen, nusinersen received FDA approval in December 2016 and has transformed the lives of thousands of infants and children with the most severe form of SMA. Beyond SMA, Krainer's group has applied splice-switching ASO technology to cancer. His laboratory demonstrated that aberrant splicing of cancer-relevant pre-mRNAs — including BRCA1, MDM2, and oncogenic kinases — can be corrected or exploited using sequence-specific ASOs, opening avenues for precision splice-switching therapy in oncology. He has characterized how mutations in splicing factor genes (SF3B1, U2AF1, SRSF2) commonly found in myeloid malignancies alter splicing programs to drive cancer progression, and has explored ASO-based restoration of normal splicing as a therapeutic strategy. Krainer is a member of the National Academy of Sciences and the National Academy of Medicine, and has received numerous prizes including the Breakthrough Prize in Life Sciences (2019) and the Lasker~DeBakey Clinical Medical Research Award (2023).

Adrian Krainer 是治疗性RNA剪接操控领域的世界顶尖权威，也是 nusinersen（Spinraza）的主要学术设计者——这是FDA批准的首个用于治疗脊髓性肌萎缩症（SMA）的反义寡核苷酸药物。他在冷泉港实验室三十余年的职业生涯中，从根本上推进了前体mRNA剪接的基本生化机制及其直接治疗应用。 Krainer 对富含丝氨酸/精氨酸的SR蛋白进行了系统的生化表征，为理性剪接转换治疗奠定了机制基础。其临床巅峰之作是 nusinersen：SMA 由 SMN1 基因缺失导致 SMN 蛋白不足引起，他的实验室设计了能够阻断 SMN2 内含子剪接沉默子的 ASO，强制剪接体纳入外显子7，产生全长功能性 SMN 蛋白。nusinersen 于2016年12月获得 FDA 批准，已改变数千名严重 SMA 患儿的命运。 在癌症领域，他将剪接转换 ASO 技术应用于 BRCA1、MDM2 等癌症相关前体 mRNA 的异常剪接校正，并深入研究了 SF3B1、U2AF1 等剪接因子基因突变在骨髓恶性肿瘤中的致癌机制。