HTTsilencing delays onset and slows progression of Huntington’s disease like phenotype: Monitoring with a novel neurovascular biomarker

Abstract

Huntington’s disease (HD) is a dominantly inherited, fatal neurodegenerative disorder caused by a CAG expansion in the Huntingtin (HTT) gene, coding for pathologic mutant HTT protein (mHTT). Because of its gain-of-function mechanism and monogenic etiology, strategies to lower HTT are being actively investigated as disease-modifying therapies. Most approaches are currently targeted at the manifest HD stage, when clinical outcomes are used to evaluate the effectiveness of therapy. However, as almost 50% of striatal volume has been lost at the time of onset of manifest HD it would be preferable to begin therapy in the premanifest period. An unmet challenge is how to evaluate therapeutic efficacy before the presence of clinical symptoms as outcome measures. To address this, we have been developing more sensitive biomarkers such as functional neuroimaging with the goal of identifying noninvasive biomarkers that provide insight into the best time to introduce HTT-lowering treatment. In this study, we mapped the temporal trajectories of arteriolar cerebral blood volumes (CBVa) using inflow-based vascular-space-occupancy (iVASO) MRI technique in an HD mouse model. Significantly elevated CBVa was evident in premanifest zQ175 HD mice prior to motor deficits and striatal atrophy, recapitulating altered CBVa in human premanifest HD. CRISPR/Cas9-mediated non-allele-specific HTT silencing in striatal neurons restored altered CBVa in premanifest zQ175 mice, delayed onset of striatal atrophy, and slowed the progression of motor phenotype and brain pathology. This study showed the potential of CBVa as a noninvasive fMRI biomarker for premanifest HD clinical trials and demonstrates long-term benefits of introducing an HTT lowering treatment in the premanifest HD.

From Neurodevelopmental to Neurodegenerative Disorders: The Vascular Continuum

“…Several studies have reported elevated CBV in preHD patients (Hua et al, 2014;Liu et al, 2020). In addition, there is evidence of increased CBV in cortical gray matter after HD onset (Drouin-Ouellet et al, 2015), suggesting that arteriolar CBV may be a sensitive biomarker for premanifest HD (Hua et al, 2014;Liu et al, 2020). From these studies it was suggest that imaging of CBF may be used to detect widespread functional abnormalities in HD, and possibly predict HD symptoms onset during premanifest stages.…”

“…While CBF is starting to emerge as a biomarker for HD, mounting evidence supports the utilization of CBV as an additional metric. Several studies have reported elevated CBV in preHD patients (Hua et al, 2014;Liu et al, 2020). In addition, there is evidence of increased CBV in cortical gray matter after HD onset (Drouin-Ouellet et al, 2015), suggesting that arteriolar CBV may be a sensitive biomarker for premanifest HD (Hua et al, 2014;Liu et al, 2020).…”