UC Irvine

Huntington’s disease (HD) is a genetic neurodegenerative disease caused by a polyglutamine (PolyQ) repeat expansion within the Huntingtin (HTT) protein. One of the hallmarks of Huntington’s disease is aberrant accumulation and aggregation of misfolded mutant HTT (mHTT), leading to production of large inclusion bodies within cells. While the precise impact of aggregation in HD is not clear, studies suggest that smaller, soluble forms of mHTT accumulation may confer toxicity. The chaperone protein CCT (chaperonin containing TCP-1/TCP-1 ring) binds and folds proteins during de novo protein synthesis. Previous studies demonstrated that exogenous delivery of the substrate-binding apical domain of subunit 1 of CCT (ApiCCT1) is sufficient to decrease mHTT aggregation and rescue mHTT-mediated toxicity in multiple cell models of HD, making ApiCCT1 a promising therapeutic for HD. The goal of this dissertation is to evaluate delivery methods of a novel modifier of mHTT accumulation in mouse models of Huntington’s disease (HD).

Here, we compare local, striatal viral delivery with global, systemic viral delivery and provide a proof of concept for mouse neural stem cells (mNSCs) as a delivery vehicle. Striatal in vivo delivery of ApiCCT1 with a secretion signal (sAiCCT1) targets multiple cell types, likely due to its ability to penetrate the cell membrane in multiple cell types. We find that viral delivery of sApiCCT1 to striatum provides robust expression and can modulate mHTT accumulation and motor phenotypes; however, the in vivo studies reported here were complicated by confounding factors. Further, systemic delivery of ApiCCT1 did not appear to ameliorate behavioral or biochemical outcomes in HD mice under the conditions tested. Data from viral studies suggests that ApiCCT1 is not sufficient to overcome disease phenotypes in the presence of additional stressors. Finally, we provide evidence suggesting the mNSCs engineered to secrete ApiCCT1 modulate mHTT accumulation after striatal transplantation, supporting the ability of ApiCCT1 to impact protein accumulation and aggregation. Data presented here provides support for mNSC-mediated delivery of sApiCCT1 as a therapeutic approach for Huntington’s disease and elicits important caveats and considerations for future study design involving viral delivery.