We created a new nonhuman primate model of the genetic neurodegenerative disorder Huntington’s disease (HD) by injecting a mixture of recombinant adeno-associated viral vectors, serotypes AAV2 and AAV2.retro, each expressing a fragment of human mutant HTT (mHTT) into the caudate and putamen of adult rhesus macaques. This modeling strategy results in expression of mutant huntingtin protein (mHTT) and aggregate formation in the injected brain regions, as well as dozens of other cortical and subcortical brain regions affected in human HD patients. We queried the disruption of cortico-basal ganglia circuitry for 30 months post-surgery using a variety of behavioral and imaging readouts. Compared to controls, mHTT-treated macaques developed working memory decline and progressive motor impairment. Multimodal imaging revealed circuit-wide white and gray matter degenerative processes in several key brain regions affected in HD. Taken together, we have developed a novel macaque model of HD that may be used to develop disease biomarkers and screen promising therapeutics.
We created a new nonhuman primate model of the genetic neurodegenerative disorder, Huntington's disease (HD), by injecting a mixture of recombinant adeno-associated viral vectors, serotypes AAV2 and AAV2.retro, each expressing a fragment of human mutant HTT (mHTT) into the caudate and putamen of adult rhesus macaques. This novel modeling strategy results in robust expression of mutant huntingtin protein (mHTT) in the injected brain regions, as well as dozens of other cortical and subcortical brain regions that are also affected in human HD patients. We queried the disruption of cortico-basal ganglia circuitry for 20-months post-surgery using a variety of behavioral and imaging readouts. Compared to controls, mHTT-treated macaques developed progressive working memory decline and motor impairment. Multimodal imaging revealed circuit-wide white and gray matter degenerative processes in several key brain regions affected in HD. This novel model will aid in the development of disease biomarkers and therapeutic strategies for this devastating disorder.
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