A novel humanized mouse model of Huntington disease for preclinical development of therapeutics targeting mutant huntingtin alleles

Amber L Southwell; Niels H Skotte; Erika B Villanueva; Michael E Østergaard; Xiaofeng Gu; Holly B Kordasiewicz; Chris Kay; Daphne Cheung; Yuanyun Xie; Sabine Waltl; Louisa Dal Cengio; Hailey Findlay-Black; Crystal N Doty; Eugenia Petoukhov; Diepiriye Iworima; Ramy Slama; Jolene Ooi; Mahmoud A Pouladi; X William Yang; Eric E Swayze; Punit P Seth; Michael R Hayden

doi:10.1093/hmg/ddx021

A novel humanized mouse model of Huntington disease for preclinical development of therapeutics targeting mutant huntingtin alleles

Amber L Southwell, Niels H Skotte, Erika B Villanueva, Michael E Østergaard, Xiaofeng Gu, Holly B Kordasiewicz, Chris Kay, Daphne Cheung, Yuanyun Xie, Sabine Waltl, Louisa Dal Cengio, Hailey Findlay-Black, Crystal N Doty, Eugenia Petoukhov, Diepiriye Iworima, Ramy Slama, Jolene Ooi, Mahmoud A Pouladi, X William Yang, Eric E SwayzePunit P Seth, Michael R Hayden

11 Citationer (Scopus)

Abstract

Huntington disease (HD) is a neurodegenerative disease caused by a mutation in the huntingtin (HTT) gene. HTT is a large protein, interacts with many partners and is involved in many cellular pathways, which are perturbed in HD. Therapies targeting HTT directly are likely to provide the most global benefit. Thus there is a need for preclinical models of HD recapitulating human HTT genetics. We previously generated a humanized mouse model of HD, Hu97/18, by intercrossing BACHD and YAC18 mice with knockout of the endogenous mouse HD homolog (Hdh). Hu97/18 mice recapitulate the genetics of HD, having two full-length, genomic human HTT transgenes heterozygous for the HD mutation and polymorphisms associated with HD in populations of Caucasian descent. We have now generated a companion model, Hu128/21, by intercrossing YAC128 and BAC21 mice on the Hdh-/- background. Hu128/21 mice have two full-length, genomic human HTT transgenes heterozygous for the HD mutation and polymorphisms associated with HD in populations of East Asian descent and in a minority of patients from other ethnic groups. Hu128/21 mice display a wide variety of HD-like phenotypes that are similar to YAC128 mice. Additionally, both transgenes in Hu128/21 mice match the human HTT exon 1 reference sequence. Conversely, the BACHD transgene carries a floxed, synthetic exon 1 sequence. Hu128/21 mice will be useful for investigations of human HTT that cannot be addressed in Hu97/18 mice, for developing therapies targeted to exon 1, and for preclinical screening of personalized HTT lowering therapies in HD patients of East Asian descent.

Originalsprog	Engelsk
Tidsskrift	Human Molecular Genetics
Vol/bind	26
Udgave nummer	6
Sider (fra-til)	1115-1132
Antal sider	18
ISSN	0964-6906
DOI	https://doi.org/10.1093/hmg/ddx021
Status	Udgivet - 15 mar. 2017

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10.1093/hmg/ddx021

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https://academic.oup.com/hmg/article-pdf/26/6/1115/24338814/ddx021.pdf

Citationsformater

Southwell, A. L., Skotte, N. H., Villanueva, E. B., Østergaard, M. E., Gu, X., Kordasiewicz, H. B., Kay, C., Cheung, D., Xie, Y., Waltl, S., Dal Cengio, L., Findlay-Black, H., Doty, C. N., Petoukhov, E., Iworima, D., Slama, R., Ooi, J., Pouladi, M. A., Yang, X. W., ... Hayden, M. R. (2017). A novel humanized mouse model of Huntington disease for preclinical development of therapeutics targeting mutant huntingtin alleles. Human Molecular Genetics, 26(6), 1115-1132. https://doi.org/10.1093/hmg/ddx021

Southwell, AL, Skotte, NH , Villanueva, EB, Østergaard, ME, Gu, X, Kordasiewicz, HB, Kay, C, Cheung, D, Xie, Y, Waltl, S, Dal Cengio, L, Findlay-Black, H, Doty, CN, Petoukhov, E, Iworima, D, Slama, R, Ooi, J, Pouladi, MA, Yang, XW, Swayze, EE, Seth, PP & Hayden, MR 2017, 'A novel humanized mouse model of Huntington disease for preclinical development of therapeutics targeting mutant huntingtin alleles', Human Molecular Genetics, bind 26, nr. 6, s. 1115-1132. https://doi.org/10.1093/hmg/ddx021

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title = "A novel humanized mouse model of Huntington disease for preclinical development of therapeutics targeting mutant huntingtin alleles",

abstract = "Huntington disease (HD) is a neurodegenerative disease caused by a mutation in the huntingtin (HTT) gene. HTT is a large protein, interacts with many partners and is involved in many cellular pathways, which are perturbed in HD. Therapies targeting HTT directly are likely to provide the most global benefit. Thus there is a need for preclinical models of HD recapitulating human HTT genetics. We previously generated a humanized mouse model of HD, Hu97/18, by intercrossing BACHD and YAC18 mice with knockout of the endogenous mouse HD homolog (Hdh). Hu97/18 mice recapitulate the genetics of HD, having two full-length, genomic human HTT transgenes heterozygous for the HD mutation and polymorphisms associated with HD in populations of Caucasian descent. We have now generated a companion model, Hu128/21, by intercrossing YAC128 and BAC21 mice on the Hdh-/- background. Hu128/21 mice have two full-length, genomic human HTT transgenes heterozygous for the HD mutation and polymorphisms associated with HD in populations of East Asian descent and in a minority of patients from other ethnic groups. Hu128/21 mice display a wide variety of HD-like phenotypes that are similar to YAC128 mice. Additionally, both transgenes in Hu128/21 mice match the human HTT exon 1 reference sequence. Conversely, the BACHD transgene carries a floxed, synthetic exon 1 sequence. Hu128/21 mice will be useful for investigations of human HTT that cannot be addressed in Hu97/18 mice, for developing therapies targeted to exon 1, and for preclinical screening of personalized HTT lowering therapies in HD patients of East Asian descent.",

keywords = "Alleles, Animals, Disease Models, Animal, Exons, Heterozygote, Humans, Huntingtin Protein, Huntington Disease, Mice, Mice, Transgenic, Mutation, Phenotype, Journal Article, Research Support, Non-U.S. Gov't",

author = "Southwell, {Amber L} and Skotte, {Niels H} and Villanueva, {Erika B} and {\O}stergaard, {Michael E} and Xiaofeng Gu and Kordasiewicz, {Holly B} and Chris Kay and Daphne Cheung and Yuanyun Xie and Sabine Waltl and {Dal Cengio}, Louisa and Hailey Findlay-Black and Doty, {Crystal N} and Eugenia Petoukhov and Diepiriye Iworima and Ramy Slama and Jolene Ooi and Pouladi, {Mahmoud A} and Yang, {X William} and Swayze, {Eric E} and Seth, {Punit P} and Hayden, {Michael R}",

year = "2017",

month = mar,

day = "15",

doi = "10.1093/hmg/ddx021",

language = "English",

volume = "26",

pages = "1115--1132",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "6",

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TY - JOUR

T1 - A novel humanized mouse model of Huntington disease for preclinical development of therapeutics targeting mutant huntingtin alleles

AU - Southwell, Amber L

AU - Skotte, Niels H

AU - Villanueva, Erika B

AU - Østergaard, Michael E

AU - Gu, Xiaofeng

AU - Kordasiewicz, Holly B

AU - Kay, Chris

AU - Cheung, Daphne

AU - Xie, Yuanyun

AU - Waltl, Sabine

AU - Dal Cengio, Louisa

AU - Findlay-Black, Hailey

AU - Doty, Crystal N

AU - Petoukhov, Eugenia

AU - Iworima, Diepiriye

AU - Slama, Ramy

AU - Ooi, Jolene

AU - Pouladi, Mahmoud A

AU - Yang, X William

AU - Swayze, Eric E

AU - Seth, Punit P

AU - Hayden, Michael R

PY - 2017/3/15

Y1 - 2017/3/15

N2 - Huntington disease (HD) is a neurodegenerative disease caused by a mutation in the huntingtin (HTT) gene. HTT is a large protein, interacts with many partners and is involved in many cellular pathways, which are perturbed in HD. Therapies targeting HTT directly are likely to provide the most global benefit. Thus there is a need for preclinical models of HD recapitulating human HTT genetics. We previously generated a humanized mouse model of HD, Hu97/18, by intercrossing BACHD and YAC18 mice with knockout of the endogenous mouse HD homolog (Hdh). Hu97/18 mice recapitulate the genetics of HD, having two full-length, genomic human HTT transgenes heterozygous for the HD mutation and polymorphisms associated with HD in populations of Caucasian descent. We have now generated a companion model, Hu128/21, by intercrossing YAC128 and BAC21 mice on the Hdh-/- background. Hu128/21 mice have two full-length, genomic human HTT transgenes heterozygous for the HD mutation and polymorphisms associated with HD in populations of East Asian descent and in a minority of patients from other ethnic groups. Hu128/21 mice display a wide variety of HD-like phenotypes that are similar to YAC128 mice. Additionally, both transgenes in Hu128/21 mice match the human HTT exon 1 reference sequence. Conversely, the BACHD transgene carries a floxed, synthetic exon 1 sequence. Hu128/21 mice will be useful for investigations of human HTT that cannot be addressed in Hu97/18 mice, for developing therapies targeted to exon 1, and for preclinical screening of personalized HTT lowering therapies in HD patients of East Asian descent.

AB - Huntington disease (HD) is a neurodegenerative disease caused by a mutation in the huntingtin (HTT) gene. HTT is a large protein, interacts with many partners and is involved in many cellular pathways, which are perturbed in HD. Therapies targeting HTT directly are likely to provide the most global benefit. Thus there is a need for preclinical models of HD recapitulating human HTT genetics. We previously generated a humanized mouse model of HD, Hu97/18, by intercrossing BACHD and YAC18 mice with knockout of the endogenous mouse HD homolog (Hdh). Hu97/18 mice recapitulate the genetics of HD, having two full-length, genomic human HTT transgenes heterozygous for the HD mutation and polymorphisms associated with HD in populations of Caucasian descent. We have now generated a companion model, Hu128/21, by intercrossing YAC128 and BAC21 mice on the Hdh-/- background. Hu128/21 mice have two full-length, genomic human HTT transgenes heterozygous for the HD mutation and polymorphisms associated with HD in populations of East Asian descent and in a minority of patients from other ethnic groups. Hu128/21 mice display a wide variety of HD-like phenotypes that are similar to YAC128 mice. Additionally, both transgenes in Hu128/21 mice match the human HTT exon 1 reference sequence. Conversely, the BACHD transgene carries a floxed, synthetic exon 1 sequence. Hu128/21 mice will be useful for investigations of human HTT that cannot be addressed in Hu97/18 mice, for developing therapies targeted to exon 1, and for preclinical screening of personalized HTT lowering therapies in HD patients of East Asian descent.

KW - Alleles

KW - Animals

KW - Disease Models, Animal

KW - Exons

KW - Heterozygote

KW - Humans

KW - Huntingtin Protein

KW - Huntington Disease

KW - Mice

KW - Mice, Transgenic

KW - Mutation

KW - Phenotype

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1093/hmg/ddx021

DO - 10.1093/hmg/ddx021

M3 - Journal article

C2 - 28104789

SN - 0964-6906

VL - 26

SP - 1115

EP - 1132

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 6

ER -

A novel humanized mouse model of Huntington disease for preclinical development of therapeutics targeting mutant huntingtin alleles

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