{
  "abstract": "Huntington's disease (HD) is an inherited and ultimately fatal neurodegenerative disorder caused by an expanded polyglutamine-encoding CAG repeat within exon 1 of the huntingtin (HTT) gene, which produces a mutant protein that destroys striatal and cortical neurons. Importantly, a critical event in the pathogenesis of HD is the proteolytic cleavage of the mutant HTT protein by caspase-6, which generates fragments of the N-terminal domain of the protein that form highly toxic aggregates. Given the role that proteolysis of the mutant HTT protein plays in HD, strategies for preventing this process hold potential for treating the disorder. By screening 141 CRISPR base editor variants targeting splice elements in the HTT gene, we identified platforms capable of producing HTT protein isoforms resistant to caspase-6-mediated proteolysis via editing of the splice acceptor sequence for exon 13. When delivered to the striatum of a rodent HD model, these base editors induced efficient exon skipping and decreased the formation of the N-terminal fragments, which in turn reduced HTT protein aggregation and attenuated striatal and cortical atrophy. Collectively, these results illustrate the potential for CRISPR base editing to decrease the toxicity of the mutant HTT protein for HD.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Bioengineering, The Grainger College of Engineering, University of Illinois Urbana-Champaign, Urbana, IL, USA",
    "Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA",
    "Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL, USA",
    "Department of Physics, University of Illinois Urbana-Champaign, Urbana, IL, USA",
    "Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA. gaj@illinois.edu",
    "Department of Bioengineering, The Grainger College of Engineering, University of Illinois Urbana-Champaign, Urbana, IL, USA. gaj@illinois.edu",
    "Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL, USA. pablo@illinois.edu",
    "Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA. pablo@illinois.edu",
    "Department of Bioengineering, The Grainger College of Engineering, University of Illinois Urbana-Champaign, Urbana, IL, USA. pablo@illinois.edu",
    "Department of Biomedical and Translational Science, The Carle Illinois College of Medicine, University of Illinois Urbana-Champaign, Urbana, IL, USA. pablo@illinois.edu",
    "Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL, USA. pablo@illinois.edu"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 25,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Shraddha Shirguppe"
    },
    {
      "affs": [
        1,
        0
      ],
      "name": "Michael Gapinske"
    },
    {
      "affs": [
        0
      ],
      "name": "Devyani Swami"
    },
    {
      "affs": [
        0
      ],
      "name": "Kyrollos Shenouda"
    },
    {
      "affs": [
        0
      ],
      "name": "Angelo Miskalis",
      "orcid": "0000-0001-5788-4060"
    },
    {
      "affs": [
        1,
        0
      ],
      "name": "Nicholas C. Gosstola",
      "orcid": "0000-0001-6558-0307"
    },
    {
      "affs": [
        0
      ],
      "name": "Daniela Del Bosque Siller",
      "orcid": "0009-0006-7884-3958"
    },
    {
      "affs": [
        0
      ],
      "name": "Isabelle Guerra"
    },
    {
      "affs": [
        0
      ],
      "name": "Pankaj Acharya"
    },
    {
      "affs": [
        0
      ],
      "name": "Dana Joulani"
    },
    {
      "affs": [
        0
      ],
      "name": "Maddie G. Szkwarek"
    },
    {
      "affs": [
        0
      ],
      "name": "Ananthan Nambiar",
      "orcid": "0000-0002-9767-9456"
    },
    {
      "affs": [
        0
      ],
      "name": "Abhishek Bhattacharjee"
    },
    {
      "affs": [
        0
      ],
      "name": "Anagha S. Dangi"
    },
    {
      "affs": [
        0
      ],
      "name": "Norah Odle"
    },
    {
      "affs": [
        0
      ],
      "name": "Gabrielle E. Nathan"
    },
    {
      "affs": [
        0
      ],
      "name": "Gianna Elias"
    },
    {
      "affs": [
        0
      ],
      "name": "Michelle Stilger"
    },
    {
      "affs": [
        0
      ],
      "name": "Jackson Winter"
    },
    {
      "affs": [
        0
      ],
      "name": "Wendy S. Woods",
      "orcid": "0009-0005-6313-510X"
    },
    {
      "affs": [
        2
      ],
      "name": "Daphine Anand"
    },
    {
      "affs": [
        0
      ],
      "name": "Colin K.W. Lim",
      "orcid": "0000-0001-8370-4609"
    },
    {
      "affs": [
        1,
        0,
        3
      ],
      "name": "Sergei Maslov",
      "orcid": "0000-0002-3701-492X"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Thomas Gaj",
      "orcid": "0000-0001-6004-9664"
    },
    {
      "affs": [
        6,
        7,
        8,
        9,
        10
      ],
      "name": "Pablo Pérez‐Piñera",
      "orcid": "0000-0002-9167-0004"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/e836857f340n3.bib",
  "cited_by": 7,
  "doi": "10.1038/s41551-026-01747-y",
  "fulltext_url": null,
  "id": "e836857f340n3",
  "issns": [
    "2157-846X"
  ],
  "landing_url": "https://doi.org/10.1038/s41551-026-01747-y",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2804|Genetic Neurodegenerative Diseases"
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  "openalex": "W4400428152",
  "pdf_url": "https://www.nature.com/articles/s41551-026-01747-y.pdf",
  "pmcid": "PMC11245100",
  "pmid": "39005280",
  "published": "2026-07-29",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/e836857f340n3.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:26:53Z",
      "native_id": "W4400428152",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s41551-026-01747-y"
    }
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  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2804|Genetic Neurodegenerative Diseases",
      "subfield": "neuroscience"
    }
  ],
  "title": "In vivo CRISPR base editing for treatment of Huntington’s disease",
  "title_text": "In vivo CRISPR base editing for treatment of Huntington’s disease",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T13:20:36Z",
  "url": "https://research.draconitic.com/paper/e836857f340n3",
  "venue": "Nature Biomedical Engineering",
  "versions": []
}