Brain Alterations in Aged OVT73 Sheep Model of Huntington's Disease: An MRI Based Approach.
Huntington’s disease
clinical translation
diffusion tensor imaging
large animal model
magnetic resonance spectroscopy
transgenic OVT73 sheep model of Huntington’s disease
Journal
Journal of Huntington's disease
ISSN: 1879-6400
Titre abrégé: J Huntingtons Dis
Pays: Netherlands
ID NLM: 101589965
Informations de publication
Date de publication:
2022
2022
Historique:
pubmed:
4
10
2022
medline:
21
12
2022
entrez:
3
10
2022
Statut:
ppublish
Résumé
Huntington's disease (HD) is a fatal neurodegenerative autosomal dominant disorder with prevalence of 1 : 20000 that has no effective treatment to date. Translatability of candidate therapeutics could be enhanced by additional testing in large animal models because of similarities in brain anatomy, size, and immunophysiology. These features enable realistic pre-clinical studies of biodistribution, efficacy, and toxicity. Here we non-invasively characterized alterations in brain white matter microstructure, neurochemistry, neurological status, and mutant Huntingtin protein (mHTT) levels in cerebrospinal fluid (CSF) of aged OVT73 HD sheep. Similar to HD patients, CSF mHTT differentiates HD from normal sheep. Our results are indicative of a decline in neurological status, and alterations in brain white matter diffusion and spectroscopy metric that are more severe in aged female HD sheep. Longitudinal analysis of aged female HD sheep suggests that the decline is detectable over the course of a year. In line with reports of HD human studies, white matter alterations in corpus callosum correlates with a decline in gait of HD sheep. Moreover, alterations in the occipital cortex white matter correlates with a decline in clinical rating score. In addition, the marker of energy metabolism in striatum of aged HD sheep, shows a correlation with decline of clinical rating score and eye coordination. This data suggests that OVT73 HD sheep can serve as a pre-manifest large animal model of HD providing a platform for pre-clinical testing of HD therapeutics and non-invasive tracking of the efficacy of the therapy.
Sections du résumé
BACKGROUND
Huntington's disease (HD) is a fatal neurodegenerative autosomal dominant disorder with prevalence of 1 : 20000 that has no effective treatment to date. Translatability of candidate therapeutics could be enhanced by additional testing in large animal models because of similarities in brain anatomy, size, and immunophysiology. These features enable realistic pre-clinical studies of biodistribution, efficacy, and toxicity.
OBJECTIVE AND METHODS
Here we non-invasively characterized alterations in brain white matter microstructure, neurochemistry, neurological status, and mutant Huntingtin protein (mHTT) levels in cerebrospinal fluid (CSF) of aged OVT73 HD sheep.
RESULTS
Similar to HD patients, CSF mHTT differentiates HD from normal sheep. Our results are indicative of a decline in neurological status, and alterations in brain white matter diffusion and spectroscopy metric that are more severe in aged female HD sheep. Longitudinal analysis of aged female HD sheep suggests that the decline is detectable over the course of a year. In line with reports of HD human studies, white matter alterations in corpus callosum correlates with a decline in gait of HD sheep. Moreover, alterations in the occipital cortex white matter correlates with a decline in clinical rating score. In addition, the marker of energy metabolism in striatum of aged HD sheep, shows a correlation with decline of clinical rating score and eye coordination.
CONCLUSION
This data suggests that OVT73 HD sheep can serve as a pre-manifest large animal model of HD providing a platform for pre-clinical testing of HD therapeutics and non-invasive tracking of the efficacy of the therapy.
Identifiants
pubmed: 36189602
pii: JHD220526
doi: 10.3233/JHD-220526
pmc: PMC9837686
doi:
Substances chimiques
Mutant Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
391-406Références
Neuropsychologia. 2011 Jan;49(2):264-70
pubmed: 21094653
PLoS Genet. 2007 May 11;3(5):e82
pubmed: 17500595
J Neurosci. 2019 Mar 6;39(10):1892-1909
pubmed: 30626701
J Neuropathol Exp Neurol. 1985 Nov;44(6):559-77
pubmed: 2932539
Neuropsychologia. 2015 Dec;79(Pt A):138-46
pubmed: 26519555
NMR Biomed. 2018 Mar;31(3):
pubmed: 29315899
Parkinsonism Relat Disord. 2013 Feb;19(2):192-7
pubmed: 23102616
Nat Rev Drug Discov. 2021 Jun;20(6):412-413
pubmed: 34012000
Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2366-70
pubmed: 23341618
Mov Disord. 2015 Mar;30(3):393-401
pubmed: 25690257
Nature. 1983 Nov 17-23;306(5940):234-8
pubmed: 6316146
Mov Disord. 2021 May;36(5):1259-1264
pubmed: 33471951
Eur J Neurosci. 2014 Jul;40(2):2417-26
pubmed: 24698429
Hum Mol Genet. 2014 Jul 1;23(13):3375-83
pubmed: 24488771
Trends Genet. 2004 Mar;20(3):146-54
pubmed: 15036808
PLoS One. 2014 Oct 23;9(10):e109676
pubmed: 25340651
Proc Natl Acad Sci U S A. 1988 Aug;85(15):5733-7
pubmed: 2456581
J Clin Mov Disord. 2019 Jul 24;6:3
pubmed: 31367459
CNS Neurosci Ther. 2018 Apr;24(4):250-280
pubmed: 29582587
Sci Rep. 2015 Jul 15;5:12166
pubmed: 26174131
Mov Disord. 2007 Sep 15;22(12):1783-9
pubmed: 17579363
Hum Brain Mapp. 2018 Dec;39(12):4776-4786
pubmed: 30144208
Sci Rep. 2016 Feb 11;6:20681
pubmed: 26864449
J Neurosci. 2000 May 15;20(10):3705-13
pubmed: 10804212
Hum Mol Genet. 2005 Oct 1;14(19):2871-80
pubmed: 16115812
EBioMedicine. 2021 Mar;65:103266
pubmed: 33706250
Lancet Neurol. 2013 Jul;12(7):637-49
pubmed: 23664844
Sci Rep. 2017 Mar 23;7(1):379
pubmed: 28336929
Neurology. 2010 Apr 13;74(15):1208-16
pubmed: 20385893
Exp Neurol. 2009 Dec;220(2):226-9
pubmed: 19786020
Neuroimage Clin. 2018 Feb 19;20:236-242
pubmed: 30090698
Am J Hum Genet. 2001 Feb;68(2):313-24
pubmed: 11133364
MAGMA. 2019 Aug;32(4):461-471
pubmed: 30771034
Neuroscience. 2019 Apr 1;403:79-92
pubmed: 28579146
Lancet Neurol. 2014 Dec;13(12):1193-201
pubmed: 25453459
Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4604-9
pubmed: 10200309
Lancet Neurol. 2012 Jan;11(1):42-53
pubmed: 22137354
Nature. 2021 May;593(7858):180
pubmed: 33963316
Brain Imaging Behav. 2011 Sep;5(3):171-80
pubmed: 21437574
Hum Mol Genet. 2010 May 15;19(10):1873-82
pubmed: 20154343
Sci Rep. 2020 Apr 24;10(1):6970
pubmed: 32332773
J Biol Chem. 2001 May 4;276(18):14545-8
pubmed: 11278258
Brain. 2006 Apr;129(Pt 4):877-86
pubmed: 16464959
Biochim Biophys Acta. 2016 Sep;1862(9):1650-62
pubmed: 27267344
Mov Disord. 1996 Mar;11(2):136-42
pubmed: 8684382
J Huntingtons Dis. 2020;9(3):201-216
pubmed: 32925082
J Huntingtons Dis. 2013;2(3):279-95
pubmed: 25062676
Brain Pathol. 2015 Nov;25(6):701-11
pubmed: 25495445
Trends Cell Biol. 2009 Apr;19(4):147-55
pubmed: 19269181
Parkinsonism Relat Disord. 2009 Mar;15(3):213-9
pubmed: 18632301
J Neurol. 2011 Dec;258(12):2230-9
pubmed: 21614431
J Clin Invest. 2015 May;125(5):1979-86
pubmed: 25844897
J Huntingtons Dis. 2015;4(4):333-46
pubmed: 26756590
Trends Biochem Sci. 2003 Aug;28(8):425-33
pubmed: 12932731
J Med Genet. 2016 Mar;53(3):190-9
pubmed: 26740508
Brain. 2008 Apr;131(Pt 4):1057-68
pubmed: 18337273
Lancet Neurol. 2009 Sep;8(9):791-801
pubmed: 19646924
Arch Neurol. 2011 Feb;68(2):265-7
pubmed: 21320997
Neurology. 2010 Nov 9;75(19):1702-10
pubmed: 21060093
Sci Transl Med. 2018 Sep 12;10(458):
pubmed: 30209243
J Neuropathol Exp Neurol. 1988 Sep;47(5):516-25
pubmed: 2971785
PLoS One. 2007 Jul 25;2(7):e647
pubmed: 17653274
Front Neurosci. 2016 May 23;10:197
pubmed: 27242403
Sci Rep. 2016 Sep 01;6:32423
pubmed: 27581950
Hum Brain Mapp. 2012 Jan;33(1):203-12
pubmed: 21264990
Dialogues Clin Neurosci. 2007;9(2):191-7
pubmed: 17726917
Biochim Biophys Acta. 2016 Sep;1862(9):1675-84
pubmed: 27288730
Brain Pathol. 2013 Mar;23(2):165-77
pubmed: 22925167
Brain. 1996 Dec;119 ( Pt 6):2085-95
pubmed: 9010012
Cereb Cortex. 2012 Dec;22(12):2858-66
pubmed: 22223853
IUBMB Life. 2008 Nov;60(11):724-8
pubmed: 18756529
J Med Genet. 2001 Jul;38(7):450-2
pubmed: 11432963
Ann Clin Transl Neurol. 2018 Apr 02;5(5):570-582
pubmed: 29761120
Handb Clin Neurol. 2011;100:83-100
pubmed: 21496571
Eur J Hum Genet. 2016 Dec;24(12):1826-1827
pubmed: 27329733
Front Neurol. 2020 Jul 07;11:571
pubmed: 32733356
Lancet Neurol. 2020 Nov;19(11):930-939
pubmed: 33098802
Mol Ther. 2018 Apr 4;26(4):947-962
pubmed: 29503201
Science. 1997 Sep 26;277(5334):1990-3
pubmed: 9302293
Hum Mol Genet. 2000 Nov 22;9(19):2789-97
pubmed: 11092755
Neurobiol Dis. 2015 Feb;74:406-12
pubmed: 25497085
Hum Brain Mapp. 2017 Oct;38(10):5035-5050
pubmed: 28657159
Sci Transl Med. 2020 Dec 16;12(574):
pubmed: 33328328
Curr Top Behav Neurosci. 2015;22:33-80
pubmed: 25300927
PLoS Genet. 2017 Jul 17;13(7):e1006846
pubmed: 28715425
Proc Natl Acad Sci U S A. 2017 Dec 26;114(52):E11293-E11302
pubmed: 29229845