Journal of Huntington's Disease - Volume 13, issue 1

Authors: Estevez-Fraga, Carlos | Tabrizi, Sarah J. | Wild, Edward J.

Article Type: Other

Abstract: In this edition of the Huntington’s Disease Clinical Trials Update, we expand on the ongoing program from VICO Therapeutics and on the recently terminated VIBRANT-HD clinical trials. We also discuss updates from uniQure’s AMT-130 program and PTC therapeutics’ trial of PTC518 and list all currently registered and ongoing clinical trials in Huntington’s disease.

Keywords: Huntington disease, clinical trials

DOI: 10.3233/JHD-240017

Citation: Journal of Huntington's Disease, vol. 13, no. 1, pp. 1-14, 2024

Authors: Escudero-Cabarcas, Johana | Pineda-Alhucema, Wilmar | Martinez-Banfi, Martha | Acosta-López, Johan E. | Cervantes-Henriquez, Martha L. | Mejía-Segura, Elsy | Jiménez-Figueroa, Giomar | Sánchez-Barros, Cristian | Puentes-Rozo, Pedro J. | Noguera-Machacón, Luz M. | Ahmad, Mostapha | de la Hoz, Moisés | Vélez, Jorge I. | Arcos-Burgos, Mauricio | Pineda, David A. | Sánchez, Manuel

Article Type: Systematic Review

Abstract: Background: People with Huntington’s disease (HD) exhibit neurocognitive alterations throughout the disease, including deficits in social cognitive processes such as Theory of Mind (ToM). Objective: The aim is to identify methodologies and ToM instruments employed in HD, alongside relevant findings, within the scientific literature of the past two decades. Methods: We conducted a comprehensive search for relevant papers in the SCOPUS, PubMed, APA-PsyArticles, Web of Science, Redalyc, and SciELO databases. In the selection process, we specifically focused on studies that included individuals with a confirmed genetic status of HD and investigated ToM functioning …in patients with and without motor symptoms. The systematic review followed the PRISMA protocol. Results: A total of 27 papers were selected for this systematic review, covering the period from 2003 to 2023. The findings consistently indicate that ToM is globally affected in patients with manifest motor symptoms. In individuals without motor symptoms, impairments are focused on the affective dimensions of ToM. Conclusions: Based on our analysis, affective ToM could be considered a potential biomarker for HD. Therefore, it is recommended that ToM assessment be included as part of neuropsychological evaluation protocols in clinical settings. Suchinclusion could aid in the identification of early stages of the disease and provide new opportunities for treatment, particularly with emerging drugs like antisense oligomers. The Prospero registration number for this review is CRD42020209769. Show more

Keywords: Chorea, Huntington’s disease, theory of mind, social cognition, social functioning, social perception, neuropsychology, assessment

DOI: 10.3233/JHD-230594

Citation: Journal of Huntington's Disease, vol. 13, no. 1, pp. 15-31, 2024

Authors: Handley, Renee R. | Reid, Suzanne J. | Burch, Zoe | Jacobsen, Jessie C. | Gillis, Tammy | Correia, Kevin | Rudiger, Skye R. | McLaughlin, Clive J. | Bawden, C. Simon | MacDonald, Marcy E. | Wheeler, Vanessa C. | Snell, Russell G.

Article Type: Short Communication

Abstract: Somatic instability of the huntingtin (HTT ) CAG repeat mutation modifies age-at-onset of Huntington’s disease (HD). Understanding the mechanism and pathogenic consequences of instability may reveal therapeutic targets. Using small-pool PCR we analyzed CAG instability in the OVT73 sheep model which expresses a full-length human cDNA HTT transgene. Analyses of five- and ten-year old sheep revealed the transgene (CAG)69 repeat was remarkably stable in liver, striatum, and other brain tissues. As OVT73 sheep at ten years old have minimal cell death and behavioral changes, our findings support instability of the HTT expanded-CAG repeat as being required for the …progression of HD. Show more

Keywords: Huntington’s disease, somatic instability, CAG repeat, transgenic sheep, OVT73, animal model, genetic modifier

DOI: 10.3233/JHD-231516

Citation: Journal of Huntington's Disease, vol. 13, no. 1, pp. 33-40, 2024

Authors: Louessard, Morgane | Cailleret, Michel | Jarrige, Margot | Bigarreau, Julie | Lenoir, Sophie | Dufour, Noëlle | Rey, Maria | Saudou, Frédéric | Deglon, Nicole | Perrier, Anselme L.

Article Type: Research Article

Abstract: Background: Mutations in the Huntingtin (HTT ) gene cause Huntington’s disease (HD), a neurodegenerative disorder. As a scaffold protein, HTT is involved in numerous cellular functions, but its normal and pathogenic functions during human forebrain development are poorly understood. Objective: To investigate the developmental component of HD, with a specific emphasis on understanding the functions of wild-type and mutant HTT alleles during forebrain neuron development in individuals carrying HD mutations. Methods: We used CRISPR/Cas9 gene-editing technology to disrupt the ATG region of the HTT gene via non-homologous end joining to produce mono- or biallelic …HTT knock-out human induced pluripotent stem cell (iPSC) clones. Results: We showed that the loss of wild-type, mutant, or both HTT isoforms does not affect the pluripotency of iPSCs or their transition into neural cells. However, we observed that HTT loss causes division impairments in forebrain neuro-epithelial cells and alters maturation of striatal projection neurons (SPNs) particularly in the acquisition of DARPP32 expression, a key functional marker of SPNs. Finally, young post-mitotic neurons derived from HTT-/- human iPSCs display cellular dysfunctions observed in adult HD neurons. Conclusions: We described a novel collection of isogenic clones with mono- and biallelic HTT inactivation that complement existing HD-hiPSC isogenic series to explore HTT functions and test therapeutic strategies in particular HTT-lowering drugs. Characterizing neural and neuronal derivatives from human iPSCs of this collection, we show evidence that HTT loss or mutation has impacts on neuro-epithelial and striatal neurons maturation, and on basal DNA damage and BDNF axonal transport in post-mitotic neurons. Show more

Keywords: Induced pluripotent stem cells, Huntingtin, Huntington’s disease, neurodegenerative disease, BDNF, DNA repair, iPS

DOI: 10.3233/JHD-231509

Citation: Journal of Huntington's Disease, vol. 13, no. 1, pp. 41-53, 2024

Authors: Wells, Russell G. | Azzam, Azzam F. | Hiller, Amie L. | Sardinia, Michael F.

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric dysfunction caused by a mutant huntingtin protein. Compromised metabolic activity resulting from systemic administration of the mitochondrial toxin, 3-nitropropionic acid (3-NP), is known to mimic the pathology of HD and induce HD-like symptoms in rats. N-hexanoic-Tyr-Ile-(6)-amino hexanoic amide (PNB-0408), also known as Dihexa, has been shown to have neuroprotective and procognitive properties in animal models of Alzheimer’s and Parkinson’s diseases. Given the mechanism of action and success in other neurodegenerative diseases, we felt it an appropriate compound to investigate further for HD. Objective: …The present study was designed to test if PNB-0408, an angiotensin IV analog, could attenuate 3-NP-induced HD-like symptoms in rats and serve as a potential therapeutic agent. Methods: Forty male Wistar rats were randomized into three groups consisting of a “vehicle” group, a “3-NP” group, and a “3-NP + PNB-0408” group. PNB-0408 was administered along with chronic exposure to 3-NP. Animal body weight, motor function, and cognitive abilities were measured for five weeks, before euthanasia and histopathological analysis. Results: Exposure to 3-NP decreased the amount of weight rats gained, impaired spatial learning and memory consolidation, and led to marked motor dysfunction. From our observations and analysis, PNB-0408 did not protect rats from the deficits induced by 3-NP neurotoxicity. Conclusions: Our findings suggest that PNB-0408 may not be an efficacious treatment strategy for preventing 3-NP-induced HD-like symptoms in a preclinical model. These data highlight the need for further research of this compound in alternate models and/or alternative approaches to managing this disorder. Show more

Keywords: Huntington’s disease, animal model, 3-nitropropionic acid, N-hexanoic-Tyr-Ile-(6) aminohexanoic amide (Dihexa), experimental therapy

DOI: 10.3233/JHD-231507

Citation: Journal of Huntington's Disease, vol. 13, no. 1, pp. 55-66, 2024

Authors: Li, Haoyu | Desai, Radhika | Quiles, Norberto | Quinn, Lori | Friel, Ciarán

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is an autosomal dominant, neurodegenerative disease that involves dysfunction in the autonomic nervous system (ANS). Heart rate variability (HRV) is a valid and noninvasive measure for ANS dysfunction, yet no study has characterized HRV response to exercise in people with HD. Objective: Characterize HRV response to exercise in individuals with HD and explore its implications for exercise prescription and cardiac dysautonomia mechanisms. Methods: 19 participants with HD were recruited as part of a cohort of individuals enrolled in the Physical Activity and Exercise Outcomes in Huntington ’s Disease (PACE-HD) …study at Teachers College, Columbia University (TC). 13 non-HD age- and gender-matched control participants were also recruited from TC. HRV was recorded with a Polar H10 heart rate (HR) monitor before, during, and after a ramp cycle-ergometer exercise test. Results: Participants with HD showed reduced HR peak (p  < 0.01) and HR reserve (p  < 0.001) compared with controls. Participants with HD demonstrated reduced root mean square of successive differences between normal-to-normal intervals (RMSSD) and successive differences of normal-to-normal intervals (SDSD) at rest (p  < 0.001). Participants with HD also showed differences for low frequency (LF) power (p  < 0.01), high frequency (HF) normalized units (nu) (p  < 0.05), LF (nu) (p  < 0.001), and HF/LF ratio (p  < 0.05) compared with controls. Conclusions: We found reduced aerobic exercise capacity and sympathovagal dysautonomia both at rest and during post-exercise recovery in people with HD, suggesting modified exercise prescription may be required for people with HD. Further investigations focusing on cardiac dysautonomia and underlying mechanisms of sympathovagal dysautonomia in people with HD are warranted. Show more

Keywords: Autonomic nervous system, heart rate variability, Huntington’s disease, maximal exercise testing

DOI: 10.3233/JHD-230593

Citation: Journal of Huntington's Disease, vol. 13, no. 1, pp. 67-76, 2024

Authors: Knights, Harry | Coleman, Annabelle | Hobbs, Nicola Z. | Tabrizi, Sarah J. | Scahill, Rachael I.

Article Type: Research Article

Abstract: Background: The Huntington’s Disease Integrated Staging System (HD-ISS) defined disease onset using volumetric cut-offs for caudate and putamen derived from FreeSurfer 6 (FS6). The impact of the latest software update (FS7) on volumes remains unknown. The Huntington’s Disease Young Adult Study (HD-YAS) is appropriately positioned to explore differences in FS bias when detecting early atrophy. Objective: Explore the relationships and differences between raw caudate and putamen volumes, calculated total intracranial volumes (cTICV), and adjusted caudate and putamen volumes, derived from FS6 and FS7, in HD-YAS. Methods: Images from 123 participants were segmented and …quality controlled. Relationships and differences between volumes were explored using intraclass correlation (ICC) and Bland-Altman analysis. Results: Across the whole cohort, ICC for raw caudate and putamen was 0.99, cTICV 0.93, adjusted caudate 0.87, and adjusted putamen 0.86 (all p  < 0.0005). Compared to FS6, FS7 calculated: i) larger raw caudate (+0.8%, p  < 0.00005) and putamen (+1.9%, p  < 0.00005), with greater difference for larger volumes; and ii) smaller cTICV (–5.1%, p  < 0.00005), with greater difference for smaller volumes. The systematic and proportional difference in cTICV was greater than raw volumes. When raw volumes were adjusted for cTICV, these effects compounded (adjusted caudate +7.0%, p  < 0.00005; adjusted putamen +8.2%, p  < 0.00005), with greater difference for larger volumes. Conclusions: As new software is released, it is critical that biases are explored since differences have the potential to significantly alter the findings of HD trials. Until conversion factors are defined, the HD-ISS must be applied using FS6. This should be incorporated into the HD-ISS online calculator. Show more

Keywords: Huntington’s Disease, FreeSurfer, MRI, segmentation, caudate, putamen, HD-ISS

DOI: 10.3233/JHD-231512

Citation: Journal of Huntington's Disease, vol. 13, no. 1, pp. 77-90, 2024

Authors: Coleman, Annabelle | Langan, Mackenzie T. | Verma, Gaurav | Knights, Harry | Sturrock, Aaron | Leavitt, Blair R. | Tabrizi, Sarah J. | Scahill, Rachael I. | Hobbs, Nicola Z.

Article Type: Research Article

Abstract: Background: Perivascular spaces (PVS) are fluid-filled cavities surrounding small cerebral blood vessels. There are limited reports of enlarged PVS across the grey matter in manifest Huntington’s disease (HD). Little is known about how PVS morphometry in the white matter may contribute to HD. Enlarged PVS have the potential to both contribute to HD pathology and affect the distribution and success of intraparenchymal and intrathecally administered huntingtin-lowering therapies. Objective: To investigate PVS morphometry in the global white matter across the spectrum of HD. Relationships between PVS morphometry and disease burden and severity measures were examined. …Methods: White matter PVS were segmented on 3T T2 W MRI brain scans of 33 healthy controls, 30 premanifest HD (pre-HD), and 32 early manifest HD (early-HD) participants from the Vancouver site of the TRACK-HD study. PVS count and total PVS volume were measured. Results: PVS total count slightly increased in pre-HD (p  = 0.004), and early-HD groups (p  = 0.005), compared to healthy controls. PVS volume, as a percentage of white matter volume, increased subtly in pre-HD compared to healthy controls (p  = 0.044), but not in early-HD. No associations between PVS measures and HD disease burden or severity were found. Conclusions: This study reveals relatively preserved PVS morphometry across the global white matter of pre-HD and early-HD. Subtle morphometric abnormalities are implied but require confirmation in a larger cohort. However, in conjunction with previous publications, further investigation of PVS in HD and its potential impact on future treatments, with a focus on subcortical grey matter, is warranted. Show more

Keywords: Huntington’s disease, magnetic resonance imaging, perivascular spaces, PVSSAS

DOI: 10.3233/JHD-231508

Citation: Journal of Huntington's Disease, vol. 13, no. 1, pp. 91-101, 2024

Authors: Pfalzer, Anna C. | Shiino, Shuhei | Silverman, James | Codreanu, Simona G. | Sherrod, Stacy D. | McLean, John A. | Claassen, Daniel O.

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is a neurodegenerative disorder caused by expanded cytosine-adenine-guanine (CAG) repeats in the Huntingtin gene, resulting in the production of mutant huntingtin proteins (mHTT). Previous research has identified urea as a key metabolite elevated in HD animal models and postmortem tissues of HD patients. However, the relationship between disease course and urea elevations, along with the molecular mechanisms responsible for these disturbances remain unknown. Objective: To better understand the molecular disturbances and timing of urea cycle metabolism across different stages in HD. Methods: We completed a global metabolomic profile of cerebrospinal …fluid (CSF) from individuals who were at several stages of disease: pre-manifest (PRE), manifest (MAN), and late manifest (LATE) HD participants, and compared to controls. Results: Approximately 500 metabolites were significantly altered in PRE participants compared to controls, although no significant differences in CSF urea or urea metabolites were observed. CSF urea was significantly elevated in LATE participants only. There were no changes in the urea metabolites citrulline, ornithine, and arginine. Conclusions: Overall, our study confirms that CSF elevations occur late in the HD course, and these changes may reflect accumulating deficits in cellular energy metabolism. Show more

Keywords: Huntington’s disease, urea, neurodegeneration, metabolism, cerebrospinal fluid

DOI: 10.3233/JHD-231511

Citation: Journal of Huntington's Disease, vol. 13, no. 1, pp. 103-111, 2024

Article Type: Meeting Report

DOI: 10.3233/JHD-249000

Citation: Journal of Huntington's Disease, vol. 13, no. 1, pp. 113-113, 2024