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Molecular features of a Huntington's disease knock-in minipig.

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος: Molecular features of a Huntington's disease knock-in minipig.
Συγγραφείς: Kolesnikova A; Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov 27721, Czech Republic.; Department of Cell Biology, Faculty of Science, Charles University in Prague, Prague 12800, Czech Republic., Sathasivam K; Huntington's Disease Centre and Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK., Tusi SK; Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.; Department of Neurology, Massachusetts Hospital and Harvard Medical School, Boston, MA 02114, USA., Landles C; Huntington's Disease Centre and Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK., Osborne GF; Huntington's Disease Centre and Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK., Kovalenko M; Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA., Gillis T; Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA., Kamenná E; Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov 27721, Czech Republic.; Department of Cell Biology, Faculty of Science, Charles University in Prague, Prague 12800, Czech Republic., Sekáč D; Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov 27721, Czech Republic.; Department of Cell Biology, Faculty of Science, Charles University in Prague, Prague 12800, Czech Republic., Nguyen DT; Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov 27721, Czech Republic.; Department of Cell Biology, Faculty of Science, Charles University in Prague, Prague 12800, Czech Republic., Valeková I; Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov 27721, Czech Republic., Juhás Š; Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov 27721, Czech Republic., Juhásová J; Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov 27721, Czech Republic., Levinská B; Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov 27721, Czech Republic., Baxa M; Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov 27721, Czech Republic., Motlík J; Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov 27721, Czech Republic., Klíma J; Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov 27721, Czech Republic., Howland D; CHDI Management, Inc., the company that manages the scientific activities of CHDI Foundation Inc., Princeton, NJ 08540, USA., Wheeler VC; Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.; Department of Neurology, Massachusetts Hospital and Harvard Medical School, Boston, MA 02114, USA., Bates GP; Huntington's Disease Centre and Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK., Ellederova Z; Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov 27721, Czech Republic.
Πηγή: Disease models & mechanisms [Dis Model Mech] 2026 May 01; Vol. 19 (5). Date of Electronic Publication: 2026 May 26.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Company of Biologists Ltd Country of Publication: England NLM ID: 101483332 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1754-8411 (Electronic) Linking ISSN: 17548403 NLM ISO Abbreviation: Dis Model Mech Subsets: MEDLINE
Imprint Name(s): Original Publication: Cambridge : Company of Biologists Ltd., c2008-
Ιατρικοί όροι (MeSH): Huntington Disease*/genetics , Huntington Disease*/pathology , Swine, Miniature*/genetics , Gene Knock-In Techniques*, Huntingtin Protein/genetics ; RNA, Messenger/metabolism ; RNA, Messenger/genetics ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Brain/metabolism ; Brain/pathology ; Protein Isoforms/metabolism ; Protein Isoforms/genetics ; Mutant Proteins/metabolism ; Animals ; Swine ; Organ Specificity ; Humans
Περίληψη: Huntington's disease is caused by a CAG expansion in the HTT gene, leading to somatic repeat instability, alternative processing of HTT pre-mRNA, and mutant huntingtin protein production. To model these features, we generated a knock-in minipig (KI-85Q-HD) carrying a (CAG)82CAA(CAG)2 repeat in the endogenous HTT locus. To evaluate this, we quantified somatic expansion in various tissues using small pool- and bulk-PCR; detected HTT1a, an aberrantly spliced HTT transcript, using 3' rapid amplification of cDNA ends and quantitative PCR; and assessed mutant huntingtin protein isoforms using homogeneous time-resolved fluorescence assays. Moderate levels of tissue-specific and age-dependent somatic expansion were observed, highest in the caudate nucleus, kidney and spleen, and detectable in blood cells. We confirmed the presence of HTT1a transcripts terminating at a cryptic polyadenylation site in HTT intron 1, and detected soluble full-length mutant HTT and HTT1a proteins across brain regions and peripheral tissues, while aggregated HTT1a was only detected in the cortex. These results indicate that KI-85Q-HD minipigs exhibit molecular features of Huntington's disease at a pre-symptomatic stage and may serve as a platform for assessing therapeutic distribution and potency.
(© 2026. Published by The Company of Biologists.)
Competing Interests: Competing interests V.C.W. is a scientific advisory board member of LoQus23 Therapeutics Ltd and has provided paid consulting services to Acadia Pharmaceuticals Inc., Alnylam Inc., Biogen Inc., Passage Bio and Rgenta Therapeutics. The other authors declare no competing or financial interests.
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Grant Information: CHDI Foundation; Akademie Věd České Republiky; CZ.02.01.01/00/22_008/0004562 Ministerstvo Školství, Mládeže a Tělovýchovy; 101165643 Innovative Health Initiative; Ústav živocišné fyziologie a genetiky AV CR
Contributed Indexing: Keywords: HTT transcripts; HTT1a protein; Huntington's disease; Knock-in minipig model; Somatic instability
Substance Nomenclature: 0 (Huntingtin Protein)
0 (RNA, Messenger)
0 (Nerve Tissue Proteins)
0 (Protein Isoforms)
0 (Mutant Proteins)
Entry Date(s): Date Created: 20260526 Date Completed: 20260717 Latest Revision: 20260813
Update Code: 20260813
PubMed Central ID: PMC13267775
DOI: 10.1242/dmm.052803
PMID: 42186428
Βάση Δεδομένων: MEDLINE
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  Data: Molecular features of a Huntington's disease knock-in minipig.
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  Data: <searchLink fieldCode="AU" term="%22Kolesnikova+A%22">Kolesnikova A</searchLink>; Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov 27721, Czech Republic.; Department of Cell Biology, Faculty of Science, Charles University in Prague, Prague 12800, Czech Republic.<br /><searchLink fieldCode="AU" term="%22Sathasivam+K%22">Sathasivam K</searchLink>; Huntington's Disease Centre and Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.<br /><searchLink fieldCode="AU" term="%22Tusi+SK%22">Tusi SK</searchLink>; Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.; Department of Neurology, Massachusetts Hospital and Harvard Medical School, Boston, MA 02114, USA.<br /><searchLink fieldCode="AU" term="%22Landles+C%22">Landles C</searchLink>; Huntington's Disease Centre and Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.<br /><searchLink fieldCode="AU" term="%22Osborne+GF%22">Osborne GF</searchLink>; Huntington's Disease Centre and Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.<br /><searchLink fieldCode="AU" term="%22Kovalenko+M%22">Kovalenko M</searchLink>; Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.<br /><searchLink fieldCode="AU" term="%22Gillis+T%22">Gillis T</searchLink>; Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.<br /><searchLink fieldCode="AU" term="%22Kamenná+E%22">Kamenná E</searchLink>; Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov 27721, Czech Republic.; Department of Cell Biology, Faculty of Science, Charles University in Prague, Prague 12800, Czech Republic.<br /><searchLink fieldCode="AU" term="%22Sekáč+D%22">Sekáč D</searchLink>; Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov 27721, Czech Republic.; Department of Cell Biology, Faculty of Science, Charles University in Prague, Prague 12800, Czech Republic.<br /><searchLink fieldCode="AU" term="%22Nguyen+DT%22">Nguyen DT</searchLink>; Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov 27721, Czech Republic.; Department of Cell Biology, Faculty of Science, Charles University in Prague, Prague 12800, Czech Republic.<br /><searchLink fieldCode="AU" term="%22Valeková+I%22">Valeková I</searchLink>; Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov 27721, Czech Republic.<br /><searchLink fieldCode="AU" term="%22Juhás+Š%22">Juhás Š</searchLink>; Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov 27721, Czech Republic.<br /><searchLink fieldCode="AU" term="%22Juhásová+J%22">Juhásová J</searchLink>; Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov 27721, Czech Republic.<br /><searchLink fieldCode="AU" term="%22Levinská+B%22">Levinská B</searchLink>; Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov 27721, Czech Republic.<br /><searchLink fieldCode="AU" term="%22Baxa+M%22">Baxa M</searchLink>; Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov 27721, Czech Republic.<br /><searchLink fieldCode="AU" term="%22Motlík+J%22">Motlík J</searchLink>; Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov 27721, Czech Republic.<br /><searchLink fieldCode="AU" term="%22Klíma+J%22">Klíma J</searchLink>; Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov 27721, Czech Republic.<br /><searchLink fieldCode="AU" term="%22Howland+D%22">Howland D</searchLink>; CHDI Management, Inc., the company that manages the scientific activities of CHDI Foundation Inc., Princeton, NJ 08540, USA.<br /><searchLink fieldCode="AU" term="%22Wheeler+VC%22">Wheeler VC</searchLink>; Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.; Department of Neurology, Massachusetts Hospital and Harvard Medical School, Boston, MA 02114, USA.<br /><searchLink fieldCode="AU" term="%22Bates+GP%22">Bates GP</searchLink>; Huntington's Disease Centre and Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.<br /><searchLink fieldCode="AU" term="%22Ellederova+Z%22">Ellederova Z</searchLink>; Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov 27721, Czech Republic.
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  Data: <i>Publisher: </i><searchLink fieldCode="PB" term="%22Company+of+Biologists+Ltd%22">Company of Biologists Ltd </searchLink><i>Country of Publication: </i>England <i>NLM ID: </i>101483332 <i>Publication Model: </i>Print-Electronic <i>Cited Medium: </i>Internet <i>ISSN: </i>1754-8411 (Electronic) <i>Linking ISSN: </i><searchLink fieldCode="IS" term="%2217548403%22">17548403 </searchLink><i>NLM ISO Abbreviation: </i>Dis Model Mech <i>Subsets: </i>MEDLINE
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  Data: <i>Original Publication</i>: Cambridge : Company of Biologists Ltd., c2008-
– Name: SubjectMESH
  Label: MeSH Terms
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  Data: <searchLink fieldCode="MM" term="%22Huntington+Disease%22">Huntington Disease*</searchLink>/<searchLink fieldCode="MM" term="%22Huntington+Disease+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22Huntington+Disease%22">Huntington Disease*</searchLink>/<searchLink fieldCode="MM" term="%22Huntington+Disease+pathology%22">pathology</searchLink> <br /><searchLink fieldCode="MM" term="%22Swine%2C+Miniature%22">Swine, Miniature*</searchLink>/<searchLink fieldCode="MM" term="%22Swine%2C+Miniature+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22Gene+Knock-In+Techniques%22">Gene Knock-In Techniques*</searchLink><br /><searchLink fieldCode="MH" term="%22Huntingtin+Protein%22">Huntingtin Protein</searchLink>/<searchLink fieldCode="MH" term="%22Huntingtin+Protein+genetics%22">genetics</searchLink> ; <searchLink fieldCode="MH" term="%22RNA%2C+Messenger%22">RNA, Messenger</searchLink>/<searchLink fieldCode="MH" term="%22RNA%2C+Messenger+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22RNA%2C+Messenger%22">RNA, Messenger</searchLink>/<searchLink fieldCode="MH" term="%22RNA%2C+Messenger+genetics%22">genetics</searchLink> ; <searchLink fieldCode="MH" term="%22Nerve+Tissue+Proteins%22">Nerve Tissue Proteins</searchLink>/<searchLink fieldCode="MH" term="%22Nerve+Tissue+Proteins+genetics%22">genetics</searchLink> ; <searchLink fieldCode="MH" term="%22Nerve+Tissue+Proteins%22">Nerve Tissue Proteins</searchLink>/<searchLink fieldCode="MH" term="%22Nerve+Tissue+Proteins+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22Brain%22">Brain</searchLink>/<searchLink fieldCode="MH" term="%22Brain+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22Brain%22">Brain</searchLink>/<searchLink fieldCode="MH" term="%22Brain+pathology%22">pathology</searchLink> ; <searchLink fieldCode="MH" term="%22Protein+Isoforms%22">Protein Isoforms</searchLink>/<searchLink fieldCode="MH" term="%22Protein+Isoforms+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22Protein+Isoforms%22">Protein Isoforms</searchLink>/<searchLink fieldCode="MH" term="%22Protein+Isoforms+genetics%22">genetics</searchLink> ; <searchLink fieldCode="MH" term="%22Mutant+Proteins%22">Mutant Proteins</searchLink>/<searchLink fieldCode="MH" term="%22Mutant+Proteins+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22Animals%22">Animals</searchLink> ; <searchLink fieldCode="MH" term="%22Swine%22">Swine</searchLink> ; <searchLink fieldCode="MH" term="%22Organ+Specificity%22">Organ Specificity</searchLink> ; <searchLink fieldCode="MH" term="%22Humans%22">Humans</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Huntington's disease is caused by a CAG expansion in the HTT gene, leading to somatic repeat instability, alternative processing of HTT pre-mRNA, and mutant huntingtin protein production. To model these features, we generated a knock-in minipig (KI-85Q-HD) carrying a (CAG)82CAA(CAG)2 repeat in the endogenous HTT locus. To evaluate this, we quantified somatic expansion in various tissues using small pool- and bulk-PCR; detected HTT1a, an aberrantly spliced HTT transcript, using 3' rapid amplification of cDNA ends and quantitative PCR; and assessed mutant huntingtin protein isoforms using homogeneous time-resolved fluorescence assays. Moderate levels of tissue-specific and age-dependent somatic expansion were observed, highest in the caudate nucleus, kidney and spleen, and detectable in blood cells. We confirmed the presence of HTT1a transcripts terminating at a cryptic polyadenylation site in HTT intron 1, and detected soluble full-length mutant HTT and HTT1a proteins across brain regions and peripheral tissues, while aggregated HTT1a was only detected in the cortex. These results indicate that KI-85Q-HD minipigs exhibit molecular features of Huntington's disease at a pre-symptomatic stage and may serve as a platform for assessing therapeutic distribution and potency.<br /> (© 2026. Published by The Company of Biologists.)
– Name: Abstract
  Label: Competing Interests
  Group: Ab
  Data: Competing interests V.C.W. is a scientific advisory board member of LoQus23 Therapeutics Ltd and has provided paid consulting services to Acadia Pharmaceuticals Inc., Alnylam Inc., Biogen Inc., Passage Bio and Rgenta Therapeutics. The other authors declare no competing or financial interests.
– Name: Ref
  Label: References
  Group: RefInfo
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– Name: GrantInfo
  Label: Grant Information
  Group: Grant
  Data: CHDI Foundation; Akademie Věd České Republiky; CZ.02.01.01/00/22_008/0004562 Ministerstvo Školství, Mládeže a Tělovýchovy; 101165643 Innovative Health Initiative; Ústav živocišné fyziologie a genetiky AV CR
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  Data: <i>Keywords: </i>HTT transcripts; HTT1a protein; Huntington's disease; Knock-in minipig model; Somatic instability
– Name: NumberCAS
  Label: Substance Nomenclature
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  Data: 0 (Huntingtin Protein)<br />0 (RNA, Messenger)<br />0 (Nerve Tissue Proteins)<br />0 (Protein Isoforms)<br />0 (Mutant Proteins)
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  Data: <i>Date Created: </i>20260526 <i>Date Completed: </i>20260717 <i>Latest Revision: </i>20260813
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  Data: 10.1242/dmm.052803
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PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=cmedm&AN=42186428
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        Value: 10.1242/dmm.052803
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      – Code: eng
        Text: English
    Subjects:
      – SubjectFull: Huntingtin Protein genetics
        Type: general
      – SubjectFull: RNA, Messenger metabolism
        Type: general
      – SubjectFull: RNA, Messenger genetics
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      – SubjectFull: Nerve Tissue Proteins genetics
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      – SubjectFull: Humans
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      – SubjectFull: Huntington Disease genetics
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      – SubjectFull: Huntington Disease pathology
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      – SubjectFull: Swine, Miniature genetics
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      – SubjectFull: Gene Knock-In Techniques
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      – TitleFull: Molecular features of a Huntington's disease knock-in minipig.
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              Text: 2026 May 01
              Type: published
              Y: 2026
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