Adrian R. Krainer

Adrian R. Krainer

St. Giles Foundation Professor
Cancer Center Deputy Director of Research

Ph.D., Harvard University, 1986

krainer@cshl.edu | 516-367-8417

Faculty Profile

Our DNA carries the instructions to manufacture all the molecules needed by a cell. After each gene is copied from DNA into RNA, the RNA message is "spliced" - an editing process involving precise cutting and pasting. I am interested in how splicing normally works, how it is altered in genetic diseases and cancer, and how we can correct these defects for therapy.

Adrian Krainer’s lab studies the mechanisms of RNA splicing, ways in which they go awry in cancer and genetic diseases, and the means by which faulty splicing can be corrected. For example, they study splicing in spinal muscular atrophy (SMA), a neuromuscular disease that is the leading genetic cause of death in infants. In SMA, a gene called SMN2 is spliced incorrectly, making it only partially functional. The Krainer lab found a way to correct this defect using a powerful therapeutic approach. It is possible to stimulate SMN protein production by altering mRNA splicing through the introduction into cells of chemically modified pieces of RNA called antisense oligonucleotides (ASOs). Following extensive work with ASOs in mouse models of SMA, one such molecule, known as nusinersen or Spinraza, was taken to the clinic, and at the end of 2016 it became the first FDA-approved drug to treat SMA, by injection into the fluid surrounding the spinal cord. The Krainer lab is currently using antisense technology to develop therapies for other diseases caused by splicing defects, including familial dysautonomia, and to target a cancer-specific alternative-splicing event that controls the Warburg effect. In addition, they are applying antisense technology to stabilize mRNAs that are destroyed by a process called nonsense-mediated mRNA decay (NMD), both to learn about the underlying mechanisms and to develop new therapies, e.g., for a nonsense allele in cystic fibrosis. The Krainer lab has also worked to shed light on how splicing factors and alternative splicing promote cancer progression in the context of breast, liver, brain, pancreatic, and blood malignancies. Finally, the lab continues to study fundamental mechanisms of splicing and its regulation, focusing on the precise recognition of highly diverse intronic and exonic pre-mRNA features by various spliceosome components.

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Selected Publications

Recurrent SRSF2 mutations in MDS affect both splicing and NMD

1 Mar 2020 | Genes and Development | 34(5-6):413-427
Rahman, M, Lin, K, Bradley, R, Abdel-Wahab, O, Krainer, A

PSI-Sigma: a comprehensive splicing-detection method for short-read and long-read RNA-seq analysis

28 May 2019 | Bioinformatics | 35(23):5048-5054
Lin, K, Krainer, A

Quantitative Activity Profile and Context Dependence of All Human 5' Splice Sites

16 Aug 2018 | Molecular Cell | 71(6):1012-1026.e3
Wong, M, Kinney, J, Krainer, A

Antisense oligonucleotides correct the familial dysautonomia splicing defect in IKBKAP transgenic mice

1 Jun 2018 | Nucleic Acids Research | 46(10):4833-4844
Sinha, R, Kim, Y, Nomakuchi, T, Sahashi, K, Hua, Y, Rigo, F, Bennett, C, Krainer, A

Antisense oligonucleotide-directed inhibition of nonsense-mediated mRNA decay

Feb 2016 | Nature Biotechnology | 34(2):164-166
Nomakuchi, T, Rigo, F, Aznarez, I, Krainer, A

All Publications

Higher-order epistasis and phenotypic prediction

27 Sep 2022 | Proceedings of the National Academy of Sciences of USA | 119(39):e2204233119
Zhou, Juannan, Wong, Mandy, Chen, Wei-Chia, Krainer, Adrian, Kinney, Justin, McCandlish, David

Counteracting chromatin effects of a splicing-correcting antisense oligonucleotide improves its therapeutic efficacy in spinal muscular atrophy

9 Jun 2022 | Cell | 185(12):2057-2070.e15
Marasco, Luciano, Dujardin, Gwendal, Sousa-Luís, Rui, Liu, Ying, Stigliano, Jose, Nomakuchi, Tomoki, Proudfoot, Nick, Krainer, Adrian, Kornblihtt, Alberto

Gene-specific nonsense-mediated mRNA decay targeting for cystic fibrosis therapy

27 May 2022 | Nature Communications | 13(1):2978
Kim, Young, Nomakuchi, Tomoki, Papaleonidopoulou, Foteini, Yang, Lucia, Zhang, Qian, Krainer, Adrian

Exon-skipping antisense oligonucleotides for cystic fibrosis therapy

18 Jan 2022 | Proceedings of the National Academy of Sciences of USA | 119(3):e2114858118
Kim, Young, Sivetz, Nicole, Layne, Jessica, Voss, Dillon, Yang, Lucia, Zhang, Qian, Krainer, Adrian

Systematic characterization of short intronic splicing-regulatory elements in SMN2 pre-mRNA.

8 Jan 2022 | Nucleic Acids Research
Gao, Yuan, Lin, Kuan-Ting, Jiang, Tao, Yang, Yang, Rahman, Mohammad, Gong, Shuaishuai, Bai, Jialin, Wang, Li, Sun, Junjie, Sheng, Lei, Krainer, Adrian, Hua, Yimin

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