Natural History Study in Prodromal and Manifest Huntington Disease(HD)
Research type
Research Study
Full title
Natural History Study in Prodromal and Manifest Huntington Disease (HD) Gene Expansion Carriers (HDGECs) - SHIELD HD
IRAS ID
278819
Contact name
Anne Rosser
Contact email
Sponsor organisation
Triplet Therapeutics
Duration of Study in the UK
2 years, 0 months, 1 days
Research summary
Huntington Disease (HD) is a chronic progressive condition that causes relentless loss of cognitive, emotional, and motor function. Options are available for treating symptoms, but no medical care that can stop or reverse HD exists.
HD is caused by a mutation in DNA (deoxyribonucleic acid). In the case of HD, the mutant (faulty) gene is called Huntingtin (HTT).
In this study researchers want to look at the faulty HTT gene and genes that can influence the faulty HTT gene. The faulty HTT gene is shown to be unstable and continues to expand and become longer as individuals with HD age. This is called somatic expansion. The more expanded and longer the faulty HTT gene becomes, the more it is unstable and prone to further expansion, which leads to increasing toxicity in the brain.
Researchers have shown the instability of the faulty HTT gene is influenced by DNA damage repair (DDR) genes. These genes are important for surveilling and repairing DNA during an individuals’ lifetime. But encountering the elongated faulty HTT gene, proteins encoded by the DDR genes can maladapt, inducing further expansion of the faulty HTT gene and thus increase its toxic effects. This mechanism has been studied in mice and humans carrying the faulty HTT gene. The human data corroborated and expanded preclinical findings illustrating DDR gene variants have significant impact on age of onset and disease progression in HD. Targeting a DDR gene has the potential to prevent or treat HD, and other similar diseases, at its root, namely to stop or slow the continued expansion of the faulty, elongated gene.
The data from this natural history study will be used to guide the design of a future interventional treatment trial in HD that aims at delaying onset and slowing progression of HD by targeting a DDR gene.Lay summary of study results: DISCUSSION AND OVERALL CONCLUSIONS
The SHIELD HD study was a natural history study in PwHD (persons with Huntington’s Disease) for robust longitudinal assessments of HD biomarkers, cognitive and motor function, and neuroimaging markers, for insight into individual disease trajectories and stage-specific progression patterns. SHIELD-HD was conducted at 10 sites across the United States, Canada, Germany, France, and the United Kingdom. Key inclusion included criteria participants with a CAG repeat length of 39 or greater in the HTT gene, age 18 to 63, CAG-age product (CAP) score of at least 290 and a score of 70 or greater on the UHDRS Independence Scale (IS).SHIELD-HD recruited 70 participants. Two participants with CAG less than 40 are excluded from the analysis. Thirty seven females and 31 males were recruited. Average age was 44.9 years (SD 10.8, range 23-63 years). Median CAG length was 42 with range from 40-49 CAG repeats.
Participants were stratified into three cohorts based on CAP scores, reflecting early (Cohort 1), mid-stage (Cohort 2), and advanced (Cohort 3) disease progression stages of Huntington's Disease (HD). The age distribution varied across the cohorts, as expected, with a mean age of 40.5 years in Cohort 1, 46.0 years in Cohort 2, and 48.3 years in Cohort 3. The minimum age of 23 years was observed in Cohort 1, while the maximum age of 63 years was shared by participants in Cohorts 2 and 3.
Overall, Cohort 1 participants demonstrated stable measures in biomarkers, motor function, and cognitive performance, Cohort 2 exhibited moderate changes across efficacy measures and Cohort 3 showed significant declines across motor, cognitive, and biomarker measures, consistent with the accelerated deterioration characteristic of advanced HD.CSF and Plasma Biomarker Analysis
Neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF) and plasma emerged as sensitive markers of neuronal damage and disease progression. Cohort 1 demonstrated stability in both CSF and plasma NfL levels throughout the study, reflecting minimal neuronal damage consistent with early HD. In Cohort 2, moderate increases in NfL were observed, whereas, Cohort 3 exhibited marked elevations in NfL levels, with increases of up to 18% in plasma by Week 96, indicative of significant neuronal degeneration in advanced HD.These findings support NfL as a non-invasive biomarker for tracking HD progression, particularly in mid- and late-stage disease. NfL is a potential predictive tool for monitoring disease trajectory and evaluating therapeutic responses in future interventional trials.
Neuroimaging Findings
MRI analyses revealed minimal volumetric changes in Cohort 1, consistent with early-stage HD. Cohort 2 demonstrated moderate cortical and subcortical atrophy, averaging a 6% reduction in brain volume over 96 weeks. Cohort 3 showed significant structural degeneration, with reductions exceeding 12%, particularly in the caudate, putamen and cerebral cortex, regions known to be impacted by HD.Cognitive and Motor Function
Comprehensive assessments of cognitive and motor function were conducted using the Unified Huntington’s Disease Rating Scale (UHDRS) and the Huntington’s Disease Cognitive Assessment Battery (HD CAB). These measures effectively captured stage-specific changes across the three cohorts, demonstrating distinct trajectories of functional and cognitive decline.In Cohort 1, participants’ maintained independence and stable motor function, with cognitive scores showing minimal changes over time. Cohort 2 exhibited moderate declines in motor and cognitive domains, including a 6% drop in Symbol Digit Modalities Test (SDMT) scores and noticeable increases in UHDRS motor scores. Cohort 3 displayed pronounced impairments, characterized by sharp declines in independence scores and a 20% increase in UHDRS motor scores, reflecting the severe impact of advanced HD.
Cognitive tests such as the HVLT-R, Trail Making Test, and SDMT proved particularly sensitive to changes in mid- and late-stage HD, effectively capturing progressive impairments in executive function, memory, and processing speed. The Z-HD Composite Score exhibited the steepest declines in Cohort 3, underscoring its utility in monitoring cognitive deterioration in advanced HD.
Safety and Tolerability
Consistent with the observational nature of the study, adverse events (AEs) were common but predominantly mild to moderate in severity.
Study Implications and Future Directions
This study provides significant contributions to the understanding of HD's natural history. Key insights include:
• CSF and Plasma Biomarkers: Plasma and CSF NfL levels emerged as reliable indicators of neuronal damage, with distinct stage-specific trends. Their noninvasive nature underscores their potential as tools for monitoring disease trajectory and evaluating therapeutic efficacy in clinical trials.
• Cognitive and Motor Assessments: UHDRS and HD-CAB captured subtle and advanced disease changes, emphasizing their importance in detecting stage-specific impairments and informing therapeutic interventions.
• Neuroimaging as a Biomarker: MRI findings supported clinical observations and highlighted the role of structural changes in HD progression
Overall, the SHIELD HD study underscores the importance of integrating biomarkers, neuroimaging, and cognitive assessments to comprehensively monitor HD progression. The distinct trajectories observed across the three cohorts emphasize the need for stage-specific therapeutic strategies, with a focus on early intervention to preserve functionality and mitigate neuronal damage. The findings serve as a foundation for future trials, offering validated efficacy parameters and biomarkers that reflect the clinical and biological burden of HD progression.REC name
Wales REC 5
REC reference
20/WA/0177
Date of REC Opinion
24 Jun 2020
REC opinion
Favourable Opinion