Boston-area Startup Sets Its Sights on ALS by Targeting RNA Splicing

A new Boston-area startup is setting its sights on neurodegenerative diseases including ALS and frontotemporal dementia (FTD). The early-stage biotech company, known as Skyhawk Therapeutics, aims to treat ALS and FTD by correcting RNA splicing defects that may underlie at least some forms of the disease (for example, see March 2011 news; Polymenidou et al., 2011).

Target: RNA. Scientists at Skyhawk Therapeutics are developing potential therapies for ALS and FTD that aim to reduce neurotoxicity by facilitating the processing of RNAs. [Image: RNA mis-splicing in disease. Courtesy of Scotti and Swanson, 2016, Nature Reviews Genetics.]

The approach, being developed in collaboration with Celgene in Summit, New Jersey, uses RNA-targeted small molecules to reduce exon skipping during the splicing process. Skyhawk Therapeutics is currently using this strategy to develop therapies for certain forms of cancer including tumors in the brain and the pancreas.

The partnership, announced on June 26, enables Celgene to license up to 5 potential therapies for ALS, Huntington’s disease and other neurological disorders. The $60M USD licensing deal comes at the heels of a recent study, led by Pietro Fratta at the University College London in England, which found that ALS-linked changes in TDP-43 leads to exon skipping during the splicing of transcripts of at least some genes (see May 2018 news; Fratta et al., 2018).


To learn more about the emerging role of RNA mis-splicing in ALS, check out TDP-43 Skips Out On Some Exons in ALS.


Fratta P, Sivakumar P, Humphrey J, Lo K, Ricketts T, Oliveira H, Brito-Armas JM, Kalmar B, Ule A, Yu Y, Birsa N, Bodo C, Collins T, Conicella AE, Mejia Maza A, Marrero-Gagliardi A, Stewart M, Mianne J, Corrochano S, Emmett W, Codner G, Groves M, Fukumura R, Gondo Y, Lythgoe M, Pauws E, Peskett E, Stanier P, Teboul L, Hallegger M, Calvo A, Chiò A, Isaacs AM, Fawzi NL, Wang E, Housman DE, Baralle F, Greensmith L, Buratti E, Plagnol V, Fisher EM, Acevedo-Arozena A. Mice with endogenous TDP-43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis. EMBO J. 2018 Jun 1;37(11). pii: e98684. [PubMed].

Polymenidou M, Lagier-Tourenne C, Hutt KR, Huelga SC, Moran J, Liang TY, Ling SC, Sun E, Wancewicz E, Mazur C, Kordasiewicz H, Sedaghat Y, Donohue JP, Shiue L, Bennett CF, Yeo GW, Cleveland DW. Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat Neurosci. 2011 Apr;14(4):459-68. [PubMed].

Further Reading

Scotti MM, Swanson MS. RNA mis-splicing in disease. Nat Rev Genet. 2016 Jan;17(1):19-32. [PubMed].

Ling JP, Pletnikova O, Troncoso JC, Wong PC. TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD. Science. 2015 Aug 7;349(6248):650-5. [PubMed].


disease-als disease-ftd exon exclusion exon skipping RNA processing RNA splicing Skyhawk Therapeutics tdp-43 topic-preclinical
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