Potent and sustained huntingtin lowering via AAV5 encoding miRNA preserves striatal volume and cognitive function in a humanized mouse model of Huntington disease

Abstract

Huntington disease (HD) is a fatal neurodegenerative disease caused by a pathogenic expansion of a CAG repeat in the huntingtin (HTT) gene. There are no disease-modifying therapies for HD. Artificial microRNAs targeting HTT transcripts for degradation have shown preclinical promise and will soon enter human clinical trials. Here, we examine the tolerability and efficacy of non-selective HTT lowering with an AAV5 encoded miRNA targeting human HTT (AAV5-miHTT) in the humanized Hu128/21 mouse model of HD. We show that intrastriatal administration of AAV5-miHTT results in potent and sustained HTT suppression for at least 7 months post-injection. Importantly, non-selective suppression of huntingtin was generally tolerated, however high dose AAV5-miHTT did induce astrogliosis. We observed an improvement of select behavioural and modest neuropathological HD-like phenotypes in Hu128/21 mice, suggesting a potential therapeutic benefit of miRNA-mediated non-selective HTT lowering. Finally, we also observed that potent reduction of wild type HTT (wtHTT) in Hu21 control mice was tolerated up to 7 months post-injection but may induce impairment of motor coordination and striatal atrophy. Taken together, our data suggests that in the context of HD, the therapeutic benefits of mHTT reduction may outweigh the potentially detrimental effects of wtHTT loss following non-selective HTT lowering.

Impaired response of cerebral oxygen metabolism to visual stimulation in Huntington’s disease

“…Antisense oligonucleotides are being administered into the cerebrospinal fluid, 82 which will superfuse the cortex well, and need to diffuse to the striatum. By contrast, adeno-associated virus ribonucleic acid interference reagents shown to be effective in mice 83 will be injected into deep brain structures especially the striatum in human subjects and will need to be transported to the cortex. The fMRI method described here may provide a means to determine metabolic and microvascular abnormalities in the brain regions differentially targeted by these strategies.…”

Mutant Huntingtin Is Cleared from the Brain via Active Mechanisms in Huntington Disease

“…The resulting mutant huntingtin (mHTT) protein disrupts many cellular processes, ultimately leading to neurodegeneration (reviewed in 2 ). Numerous preclinical studies have demonstrated that lowering HTT in the brain can prevent or even reverse HD-like behavioral and neuropathological phenotypes in rodent models of HD [3][4][5][6][7][8][9][10][11][12][13] , leading to advancement of HTT lowering agents into clinical trials for the treatment of HD (NCT03761849, NCT03225833, NCT03225846, NCT04120493). Clinical translation of HTT lowering therapies has necessitated the identification of biomarkers to assess HTT target engagement in the central nervous system (CNS).…”

Downregulation of glial genes involved in synaptic function mitigates Huntington's disease pathogenesis

“…We were curious to identify modifiers that concordantly affect mHTT-induced pathogenesis in both neurons and glia as these might be particularly attractive therapeutic targets for HD. We were particularly interested to discover whether any such shared modifiers exert their effect by reducing mHTT levels, which is considered a promising approach to therapy ( Al-Ramahi et al, 2018 ; Barker et al, 2020 ; Caron et al, 2020 ; Li et al, 2019 ; Tabrizi et al, 2019 ; Wang et al, 2014 ; Wood et al, 2018 ; Yamamoto et al, 2000 ; Yao et al, 2015 ). We therefore again integrated network analysis with high-throughput experimentation.…”