Pfizer and Sangamo Point Fingers at C9orf72 ALS and FTD

Sticky zinc fingers? Scientists at Sangamo Therapeutics in Richmond, California are developing zinc finger repressor proteins (see panel f above), targeted to the C9orf72 repeat expansion, in hopes to reduce levels of repeat-rich C9orf72 RNAs. [Courtesy of Jamieson et al., 2003. Nature Reviews Drug Discovery. ]

Researchers unveiled a new strategy this week to tackle the most common form of ALS. The potential gene therapy, to be developed by Sangamo Therapeutics in partnership with Pfizer, aims to reduce motor neuron toxicity. The strategy is also being developed as a potential treatment for C9orf72-FTD.

The approach, which involves the use of genetically-engineered zinc finger proteins (ZFPs), is one of a growing number of strategies that aims to protect motor neurons against ALS and FTD by reducing levels of potentially toxic C9orf72 repeat-rich RNAs (see December 2017 news; Batra et al., 2017; Pinto et al., 2017).

Scientists are using a similar approach to develop potential treatments for Huntington’s disease (Agustín-Pavón et al., 2016; Garriga-Canut et al., 2012; Zhang et al., 2012; for review, see Wild and Tabrizi, 2017). The strategies are at the preclinical stage.


To learn more about emerging treatments for C9orf72 ALS, check out A New CRISPR Technique Fries C9orf72 RNAs.


Batra R, Nelles DA, Pirie E, Blue SM, Marina RJ, Wang H, Chaim IA, Thomas JD, Zhang N, Nguyen V, Aigner S, Markmiller S, Xia G, Corbett KD, Swanson MS, Yeo GW. Elimination of Toxic Microsatellite Repeat Expansion RNA by RNA-Targeting Cas9. [PubMed]

Pinto BS, Saxena T, Oliveira R, Méndez-Gómez HR, Cleary JD, Denes LT, McConnell O, Arboleda J, Xia G, Swanson MS, Wang ET. Impeding Transcription of Expanded Microsatellite Repeats by Deactivated Cas9. Mol Cell. 2017 Nov 2;68(3):479-490.e5. [PubMed]

Agustín-Pavón C, Mielcarek M, Garriga-Canut M, Isalan M. Deimmunization for gene therapy: host matching of synthetic zinc finger constructs enables long-term mutant Huntingtin repression in mice. Mol Neurodegener. 2016 Sep 6;11(1):64. [PubMed]

Garriga-Canut M, Agustín-Pavón C, Herrmann F, Sánchez A, Dierssen M, Fillat C, Isalan M. Synthetic zinc finger repressors reduce mutant huntingtin expression in the brain of R6/2 mice. Proc Natl Acad Sci U S A. 2012 Nov 6;109(45):E3136-45. [PubMed]

Jamieson AC, Miller JC, Pabo CO. Drug discovery with engineered zinc-finger proteins. Nat Rev Drug Discov. 2003 May;2(5):361-8. [PubMed]

Further Reading

Nelson CE, Robinson-Hamm JN, Gersbach CA. Genome engineering: a new approach to gene therapy for neuromuscular disorders. Nat Rev Neurol. 2017 Nov;13(11):647-661. [PubMed]

Wild EJ, Tabrizi SJ. Therapies targeting DNA and RNA in Huntington’s disease. Lancet Neurol. 2017 Oct;16(10):837-847. [PubMed]

Image on home page: zinc finger, Thomas Splettstoesser under a CC BY 4.0 license.

c9orf72 disease-als disease-ftd topic-randd ZFP zinc finger protein
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