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Cited by 261Genetic Neurodegenerative DiseasesRNA Interference and Gene DeliveryAmyotrophic Lateral Sclerosis Research

Five siRNAs Targeting Three SNPs May Provide Therapy for Three-Quarters of Huntington's Disease Patients

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Pfister, Edith L., Kennington, Lori, Straubhaar, Juerg, Wagh, Sujata, Liu, Wanzhou, DiFiglia, Marian, Landwehrmeyer, Bernhard, Vonsattel, Jean-Paul +2 more·2009·Current Biology
DOI 10.1016/j.cub.2009.03.030PMC PMC2746439
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Abstract

Among dominant neurodegenerative disorders, Huntington's disease (HD) is perhaps the best candidate for treatment with small interfering RNAs (siRNAs) [1-9]. Invariably fatal, HD is caused by expansion of a CAG repeat in the Huntingtin gene, creating an extended polyglutamine tract that makes the Huntingtin protein toxic [10]. Silencing mutant Huntingtin messenger RNA (mRNA) should provide therapeutic benefit, but normal Huntingtin likely contributes to neuronal function [11-13]. No siRNA strategy can yet distinguish among the normal and disease Huntingtin alleles and other mRNAs containing CAG repeats [14]. siRNAs targeting the disease isoform of a heterozygous single-nucleotide polymorphism (SNP) in Huntingtin provide an alternative [15-19]. We sequenced 22 predicted SNP sites in 225 human samples corresponding to HD and control subjects. We find that 48% of our patient population is heterozygous at a single SNP site; one isoform of this SNP is associated with HD. Several other SNP sites are frequently heterozygous. Consequently, five allele-specific siRNAs, corresponding to just three SNP sites, could be used to treat three-quarters of the United States and European HD patient populations. We have designed and validated selective siRNAs for the three SNP sites, laying the foundation for allele-specific RNA interference (RNAi) therapy for HD.

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  • A non-selective strategy would allow for treatment of all HD patients with a single entity.

    “a non-selective strategy would allow for treatment of all HD patients with a single entity49”

    From A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system (2019) · cites this paper as [49]

    The Discussion (page unavailable) addresses allele-selective siRNAs: one could target nearly half the studied patients, while five could cover about three-quarters. A search for a non-selective, single-entity strategy found no passage assessing whether it could treat all HD patients. The paper's limited coverage estimates for selective siRNAs do not settle that different proposal. (LLM, conf=0.74)

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References 26 · Cited by 261

Research works printed but not linked: 24

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Authors
Pfister, E. L., Kennington, L., Straubhaar, J., Wagh, S., Liu, W., DiFiglia, M., Landwehrmeyer, B., Vonsattel, J.-P., Zamore, P. D., & Aronin, N.
Affiliations
  • Howard Hughes Medical Institute (US)
  • Massachusetts General Hospital (US)
  • Columbia University (US)
Corresponding author
Zamore, Phillip D.
ORCID
Venue
Current Biology
Publisher
Elsevier BV
Published
2009-05
Volume
19
Issue
9
Pages
774-778
ISSN
0960-9822 (ISSN-L)
DOI
10.1016/j.cub.2009.03.030
PMC
PMC2746439
OpenAlex
W2051587165
Cited by
261
References
26
Citations by year
2026: 3 · 2025: 4 · 2024: 10 · 2023: 15 · 2022: 9 · 2021: 11 · 2020: 12 · 2019: 12 · 2018: 13 · 2017: 15 · 2016: 8 · 2015: 18 · 2014: 22 · 2013: 22 · 2012: 28
FWCI
11.36
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship@UMassChan (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Institute on Aging (P50AG008702)
  • National Institute of General Medical Sciences (R01GM065236)
  • National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007302, P30DK032520)
  • National Institute of Neurological Disorders and Stroke (NS38194, R01NS038194)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
Huntington's disease, siRNA therapeutics, single nucleotide polymorphisms, huntingtin gene, CAG repeat expansion, polyglutamine, heterozygous SNPs, siRNA design
MeSH terms
Huntingtin Protein, Genetic Carrier Screening, Humans, Huntington Disease, Nerve Tissue Proteins, Nuclear Proteins, Genetic Therapy, Sequence Analysis, DNA, Polymorphism, Single Nucleotide, RNA Interference, RNA, Small Interfering

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