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

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.

Rahman, M. A. and Lin, K. T. and Bradley, R. K. and Abdel-Wahab, O. and Krainer, A. R. (2020) Recurrent SRSF2 mutations in MDS affect both splicing and NMD. Genes Dev, 34(5-6) pp. 413-427.

Lin, K. T. and Krainer, A. R. (2019) PSI-Sigma: a comprehensive splicing-detection method for short-read and long-read RNA-seq analysis. Bioinformatics, 35(23) pp. 5048-5054.

Wong, M. S. and Kinney, J. B. and Krainer, A. R. (2018) Quantitative Activity Profile and Context Dependence of All Human 5' Splice Sites. Mol Cell, 71(6) pp. 1012-1026.e3.

Sinha, R. and Kim, Y. J. and Nomakuchi, T. and Sahashi, K. and Hua, Y. and Rigo, F. and Bennett, C. F. and Krainer, A. R. (2018) Antisense oligonucleotides correct the familial dysautonomia splicing defect in IKBKAP transgenic mice. Nucleic Acids Res, 46(10) pp. 4833-4844.

Nomakuchi, T. T. and Rigo, F. and Aznarez, I. and Krainer, A. R. (2016) Antisense oligonucleotide-directed inhibition of nonsense-mediated mRNA decay. Nat Biotechnol, 34(2) pp. 164-166.

Additional materials of the author at
CSHL Institutional Repository