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opencc-zeroFeb 2022View details →

Genetic modifiers of Huntington's disease differentially influence motor and cognitive domains

Genome-wide association studies (GWAS) of Huntington's disease (HD) have identified six DNA maintenance gene loci (among others) as modifiers and implicated a two step-mechanism of pathogenesis: somatic instability of the causative HTT CAG repeat with subsequent triggering of neuronal damage. The largest studies have been limited to HD individuals with a rater-estimated age at motor onset. To capitalize on the wealth of phenotypic data in several large HD natural history studies, we have performed algorithmic prediction using common motor and cognitive measures to predict age at other disease landmarks as additional phenotypes for GWAS. Combined with imputation using the Trans-Omics for Precision Medicine reference panel, predictions using integrated measures provided objective landmark phenotypes with greater power to detect most modifier loci. Importantly, substantial differences in the relative modifier signal across loci, highlighted by comparing common modifiers at MSH3 and FAN1, revealed that individual modifier effects can act preferentially in the motor or cognitive domains. Individual components of the DNA maintenance modifier mechanisms may therefore act differentially on the neuronal circuits underlying the corresponding clinical measures. In addition, we identified new modifier effects at the PMS1 and PMS2 loci and implicated a potential new locus on chromosome 7. These findings indicate that broadened discovery and characterization of HD genetic modifiers based on additional quantitative or qualitative phenotypes offers not only the promise of in-human validated therapeutic targets, but also a route to dissecting the mechanisms and cell types involved in both the somatic instability and toxicity components of HD pathogenesis.

opencc-zeroAug 2022View details →

PAM-altering SNP-based allele-specific CRISPR-Cas9 therapeutic strategies for Huntington's disease

Huntington's disease (HD) is caused by an expanded CAG repeat in huntingtin (HTT). Since HD is dominant, and loss of HTT leads to neurological abnormalities, safe therapeutic strategies require selective inactivation of mutant HTT. Previously, we proposed a concept of CRISPR-Cas9 using mutant-specific PAM sites generated by SNPs to selectively inactivate mutant HTT. Aiming at revealing suitable targets for clinical development, we analyzed the largest HD genotype dataset to reveal target PAM-altering SNPs (PAS) and subsequently evaluated their allele specificities. The gRNAs based on the PAM sites generated by rs2857935, rs16843804, and rs16843836 showed high levels of allele specificity in patient-derived cells. Simultaneous use of two gRNAs based on rs2857935-rs16843804 or rs2857935-rs16843836 produced selective genomic deletions in mutant HTT and prevented the transcription of mutant HTT mRNA without impacting the expression of normal counterpart or re-integration of the excised fragment elsewhere in the genome. RNAseq and off-target analysis confirmed high levels of allele specificity and the lack of recurrent off-targeting. Approximately 60% of HD subjects are eligible for mutant-specific CRISPR-Cas9 strategies of targeting one of these 3 PAS in conjunction with one non-allele-specific site, supporting high applicability of PAS-based allele-specific CRISPR approaches in the HD patient population.

opencc-zeroAug 2022View details →

Complete allele-specific silencing of the gain-of-function mutation of Huntington's disease

Dominant gain-of-function mechanism in Huntington's disease (HD) suggests selective inactivation of mutant HTT produces the biggest therapeutic benefit. Here, we developed a complete allele-specific CRISPR/Cas9 strategy to permanently silence mutant HTT through nonsense-mediated decay (NMD), capitalizing on an exonic PAM (protospacer adjacent motif)-Altering SNP (PAS). Comprehensive sequence/haplotype analysis identified PAS-generated NGG PAM sites on exons of common HTT haplotypes in HD patients, revealing a single clinically meaningful PAS-based mutant-specific NMD-CRISPR/Cas9 strategy. The alternative allele of rs363099 eliminates NGG PAM site on the most frequent normal HTT haplotype in HD, permitting mutant HTT-specific CRISPR/Cas9 therapeutics in ~20% of HD patients with European ancestry. Our rs363099-based CRISPR/Cas9 showed perfect allele specificity and good targeting efficiencies in cells derived from HD patients. Dramatically reduced mutant HTT mRNA and complete loss of mutant HTT protein indicate that our allele-specific CRISPR/Cas9 strategy completely inactivates mutant HTT through NMD. RNAseq analysis also supported high levels of on-target gene specificity because no other genes except HTT were altered in clonal lines developed through our NMD-CRISPR/Cas9 strategy. Together, our data demonstrating significant target population, selective inactivation of mutant HTT, good targeting efficiency, and lack of recurrent off-targeting establish its therapeutic value of novel rs363099-based mutant HTT-specific NMD-CRISPR/Cas9 strategy in HD.

opencc-zeroMay 2024View details →

Base editing strategies to convert CAG to CAA diminish the disease-causing mutation in Huntington's disease

An expanded CAG repeat in the huntingtin gene (HTT) causes Huntington's disease (HD). Since the length of uninterrupted CAG repeat, not polyglutamine, determines the age-at-onset in HD, base editing strategies to convert CAG to CAA are anticipated to delay onset by shortening the uninterrupted CAG repeat. Here, we developed base editing strategies to convert CAG in the repeat to CAA and determined their molecular outcomes and effects on relevant disease phenotypes. Base editing strategies employing combinations of cytosine base editors and gRNAs efficiently converted CAG to CAA at various sites in the CAG repeat without generating significant indels, off-target edits, or transcriptome alterations, demonstrating their feasibility and specificity. Candidate BE strategies converted CAG to CAA on both expanded and non-expanded CAG repeats without altering HTT mRNA and protein levels. In addition, somatic CAG repeat expansion, which is the major disease driver in HD, was significantly decreased in the liver by a candidate BE strategy treatment in HD knock-in mice carrying canonical CAG repeats. Notably, CAG repeat expansion was abolished entirely in HD knock-in mice carrying CAA-interrupted repeats, supporting the therapeutic potential of CAG-to-CAA conversion strategies in HD and potentially other repeat expansion disorders.

opencc-zeroMar 2023View details →

Ex vivo 100 μm isotropic diffusion MRI‐based tractography of connectivity changes in the end‐stage R6/2 mouse model of Huntington's disease

<div> <div> <div> <div> Background: Huntington's disease is a progressive neurodegenerative disorder. Brain atrophy, as measured by volumetric magnetic resonance imaging (MRI), is a downstream consequence of neurodegeneration, but microstructural changes within brain tissue are expected to precede this volumetric decline. The tissue microstructure can be assayed non-invasively using diffusion MRI, which also allows a tractographic analysis of brain connectivity. Methods: We here used ex vivo diffusion MRI (11.7T) to measure microstructural changes in different brain regions of end‐stage (14 weeks of age) wild type and R6/2 mice (male and female) modeling Huntington's disease. To probe the microstructure of different brain regions, reduce partial volume effects and measure connectivity between different regions, a 100 μm isotropic voxel resolution was acquired. Results: Although fractional anisotropy did not reveal any difference between wild‐type controls and R6/2 mice, mean, axial, and radial diffusivity were increased in female R6/2 mice and decreased in male R6/2 mice. Whole brain streamlines were only reduced in male R6/2 mice, but streamline density was increased. Region‐to‐region tractography indicated reductions in connectivity between the cortex, hippocampus, and thalamus with the striatum, as well as within the basal ganglia (striatum—globus pallidus—subthalamic nucleus—substantia nigra—thalamus). Conclusions: Biological sex and left/right hemisphere affected tractographic results, potentially reflecting different stages of disease progression. This proof‐of‐principle study indicates that diffusion MRI and tractography potentially provide novel biomarkers that connect volumetric changes across different brain regions. In a translation setting, these measurements constitute a novel tool to assess the therapeutic impact of interventions such as neuroprotective agents in transgenic models, as well as patients with Huntington's disease. </div> </div> </div> </div>

closedIPD-NOFeb 2026View details →

PRidopidine's Outcome On Function in Huntington Disease, PROOF- HD

ClinicalTrials.gov study NCT04556656. IPD Sharing: NO. Countries: 11. Publications: 1.

Atomoxetine and Huntington's Disease

ClinicalTrials.gov study NCT00368849. IPD Sharing: Not stated. Countries: 1. Publications: 13.

A Study to Evaluate the Efficacy and Safety of Intrathecally Administered RO7234292 (RG6042) in Participants With Manifest Huntington's Disease

ClinicalTrials.gov study NCT03761849. IPD Sharing: Not stated. Countries: 18. Publications: 2.

A Study of Treatment With Pridopidine (ACR16) in Participants With Huntington's Disease

ClinicalTrials.gov study NCT00665223. IPD Sharing: Not stated. Countries: 8. Publications: 2.

Safety and Tolerability of WVE-120102 in Patients With Huntington's Disease

ClinicalTrials.gov study NCT03225846. IPD Sharing: Not stated. Countries: 8. Publications: 2.

closedIPD-NOFeb 2026View details →

A Study Evaluating if Pridopidine is Safe, Efficacious, and Tolerable in Patients With Huntington's Disease

ClinicalTrials.gov study NCT02494778. IPD Sharing: NO. Countries: 11. Publications: 1.

A Study to Evaluate the Safety and Efficacy of PTC518 in Participants With Huntington's Disease (HD)

ClinicalTrials.gov study NCT05358717. IPD Sharing: Not stated. Countries: 11. Publications: 2.

closedIPD-NOFeb 2026View details →

Study of WVE-003 in Patients With Huntington's Disease

ClinicalTrials.gov study NCT05032196. IPD Sharing: NO. Countries: 10. Publications: 2.

Effect of PBT2 in Patients With Early to Mid Stage Huntington Disease

ClinicalTrials.gov study NCT01590888. IPD Sharing: Not stated. Countries: 2. Publications: 4.

First Time Use of SD-809 in Huntington Disease

ClinicalTrials.gov study NCT01795859. IPD Sharing: Not stated. Countries: 3. Publications: 5.

Safety and Tolerability of WVE-120101 in Patients With Huntington's Disease

ClinicalTrials.gov study NCT03225833. IPD Sharing: Not stated. Countries: 7. Publications: 2.

Study to Measure Cerebrospinal Fluid Mutant Huntingtin Protein in Participants With Early Manifest Stage I or Stage II Huntington's Disease

ClinicalTrials.gov study NCT03664804. IPD Sharing: Not stated. Countries: 4. Publications: 0.

A Study to Evaluate Sigma-1 and Dopamine-2 Receptor Occupancy by Pridopidine in the Human Brain of Healthy Volunteers and in Patients With Huntington's Disease

ClinicalTrials.gov study NCT03019289. IPD Sharing: Not stated. Countries: 1. Publications: 1.