Publications by authors named "Anne Rosser"

122 Publications

Do foetal transplant studies continue to be justified in Huntington's disease?

Neuronal Signal 2021 Dec 13;5(4):NS20210019. Epub 2021 Dec 13.

Cardiff University Brain Repair Group, School of Biosciences, Life Sciences Building, Cardiff CF10 3AX, U.K.

Early CNS transplantation studies used foetal derived cell products to provide a foundation of evidence for functional recovery in preclinical studies and early clinical trials. However, it was soon recognised that the practical limitations of foetal tissue make it unsuitable for widespread clinical use. Considerable effort has since been directed towards producing target cell phenotypes from pluripotent stem cells (PSCs) instead, and there now exist several publications detailing the differentiation and characterisation of PSC-derived products relevant for transplantation in Huntington's disease (HD). In light of this progress, we ask if foetal tissue transplantation continues to be justified in HD research. We argue that (i) the extent to which accurately differentiated target cells can presently be produced from PSCs is still unclear, currently making them undesirable for studying wider CNS transplantation issues; (ii) foetal derived cells remain a valuable tool in preclinical research for advancing our understanding of which products produce functional striatal grafts and as a reference to further improve PSC-derived products; and (iii) until PSC-derived products are ready for human trials, it is important to continue using foetal cells to gather clinical evidence that transplantation is a viable option in HD and to use this opportunity to optimise practical parameters (such as trial design, clinical practices, and delivery strategies) to pave the way for future PSC-derived products.
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http://dx.doi.org/10.1042/NS20210019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8674623PMC
December 2021

A MDS Evidence-Based Review on Treatments for Huntington's Disease.

Mov Disord 2021 Nov 29. Epub 2021 Nov 29.

Instituto de Medicina Molecular João Lobo Antunes, Lisbon, Portugal.

Background: Huntington's disease (HD) is a rare neurodegenerative disorder with protean clinical manifestations. Its management is challenging, consisting mainly of off-label treatments.

Objectives: The International Parkinson and Movement Disorder Society commissioned a task force to review and evaluate the evidence of available therapies for HD gene expansion carriers.

Methods: We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Eligible randomized controlled trials were identified via an electronic search of the CENTRAL, MEDLINE, and EMBASE databases. All eligible trials that evaluated one or more of 33 predetermined clinical questions were included. Risk of bias was evaluated using the Cochrane Risk of Bias tool. A framework was adapted to allow for efficacy and safety conclusions to be drawn from the balance between the GRADE level of evidence and the importance of the benefit/harm of the intervention.

Results: Twenty-two eligible studies involving 17 interventions were included, providing data to address 8 clinical questions. These data supported a likely effect of deutetrabenazine on motor impairment, chorea, and dystonia and of tetrabenazine on chorea. The data did not support a disease-modifying effect for premanifest and manifest HD. There was no eligible evidence to support the use of specific treatments for depression, psychosis, irritability, apathy, or suicidality. Similarly, no evidence was eligible to support the use of physiotherapy, occupational therapy, exercise, dietary, or surgical treatments.

Conclusions: Data for therapeutic interventions in HD are limited and support only the use of VMAT2 inhibitors for specific motor symptoms. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28855DOI Listing
November 2021

Enroll-HD: An Integrated Clinical Research Platform and Worldwide Observational Study for Huntington's Disease.

Front Neurol 2021 18;12:667420. Epub 2021 Aug 18.

CHDI Management/CHDI Foundation, Princeton, NJ, United States.

Established in July 2012, Enroll-HD is both an integrated clinical research platform and a worldwide observational study designed to meet the clinical research requirements necessary to develop therapeutics for Huntington's disease (HD). The platform offers participants a low-burden entry into HD research, providing a large, well-characterized, research-engaged cohort with associated clinical data and biosamples that facilitates recruitment into interventional trials and other research studies. Additional studies that use Enroll-HD data and/or biosamples are built into the platform to further research on biomarkers and outcome measures. Enroll-HD is now operating worldwide in 21 countries at 159 clinical sites across four continents-Europe, North America, Latin America, and Australasia-and has recruited almost 25,000 participants, generating a large, rich clinical database with associated biosamples to expedite HD research; any researcher at a verifiable research organization can access the clinical datasets and biosamples from Enroll-HD and nested studies. Important operational features of Enroll-HD include a strong emphasis on standardization, data quality, and protecting participant identity, a single worldwide study protocol, a flexible EDC system capable of integrating multiple studies, a comprehensive monitoring infrastructure, an online portal to train and certify site personnel, and standardized study documents including informed consent forms and contractual agreements.
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http://dx.doi.org/10.3389/fneur.2021.667420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416308PMC
August 2021

Cognitive decline in Huntington's disease in the Digitalized Arithmetic Task (DAT).

PLoS One 2021 23;16(8):e0253064. Epub 2021 Aug 23.

Département d'Etudes Cognitives, École normale supérieure, PSL University, Paris, France.

Background: Efficient cognitive tasks sensitive to longitudinal deterioration in small cohorts of Huntington's disease (HD) patients are lacking in HD research. We thus developed and assessed the digitized arithmetic task (DAT), which combines inner language and executive functions in approximately 4 minutes.

Methods: We assessed the psychometric properties of DAT in three languages, across four European sites, in 77 early-stage HD patients (age: 52 ± 11 years; 27 females), and 57 controls (age: 50 ± 10, 31 females). Forty-eight HD patients and 34 controls were followed up to one year with 96 participants who underwent MRI brain imaging (HD patients = 46) at baseline and 50 participants (HD patients = 22) at one year. Linear mixed models and Pearson correlations were used to assess associations with clinical assessment.

Results: At baseline, HD patients were less accurate (p = 0.0002) with increased response time (p<0.0001) when compared to DAT in controls. Test-retest reliability in HD patients ranged from good to excellent for response time (range: 0.63-0.79) and from questionable to acceptable for accuracy (range: r = 0.52-0.69). Only DAT, the Mattis Dementia Rating Scale, the Symbol Digit Modalities Test, and Total Functional Capacity scores were able to detect a decline within a one-year follow-up in HD patients (all p< 0.05). In contrast with all the other cognitive tasks, DAT correlated with striatal atrophy over time (p = 0.037) but not with motor impairment.

Conclusions: DAT is fast, reliable, motor-free, applicable in several languages, and able to unmask cognitive decline correlated with striatal atrophy in small cohorts of HD patients. This likely makes it a useful endpoint in future trials for HD and other neurodegenerative diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253064PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382187PMC
November 2021

Oxygen-glucose deprivation in neurons: implications for cell transplantation therapies.

Prog Neurobiol 2021 10 30;205:102126. Epub 2021 Jul 30.

School of Pharmacy and Pharmaceutical Sciences, Cardiff University, CF10 3NB, Wales, UK; Leibniz Institute for Polymer Research Dresden (IPF), Hohe Straße 6, 01069, Dresden, Germany. Electronic address:

Cell replacement therapies hold the potential to restore neuronal networks compromised by neurodegenerative diseases (such as Parkinson's disease or Huntington's disease), or focal tissue damage (via a stroke or spinal cord injury). Despite some promising results achieved to date, transplanted cells typically exhibit poor survival in the central nervous system, thus limiting therapeutic efficacy of the graft. Although cell death post-transplantation is likely to be multifactorial in causality, growing evidence suggests that the lack of vascularisation at the graft site, and the resulting ischemic host environment, may play a fundamental role in the fate of grafted cells. Herein, we summarise data showing how the deprivation of either oxygen, glucose, or both in combination, impacts the survival of neurons and review strategies which may improve graft survival in the central nervous system.
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http://dx.doi.org/10.1016/j.pneurobio.2021.102126DOI Listing
October 2021

Multi-compartment analysis of the complex gradient-echo signal quantifies myelin breakdown in premanifest Huntington's disease.

Neuroimage Clin 2021 5;30:102658. Epub 2021 Apr 5.

Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, Maindy Road, Cardiff, CF 24 4HQ, UK.

White matter (WM) alterations have been identified as a relevant pathological feature of Huntington's disease (HD). Increasing evidence suggests that WM changes in this disorder are due to alterations in myelin-associated biological processes. Multi-compartmental analysis of the complex gradient-echo MRI signal evolution in WM has been shown to quantify myelin in vivo, therefore pointing to the potential of this technique for the study of WM myelin changes in health and disease. This study first characterized the reproducibility of metrics derived from the complex multi-echo gradient-recalled echo (mGRE) signal across the corpus callosum in healthy participants, finding highest reproducibility in the posterior callosal segment. Subsequently, the same analysis pipeline was applied in this callosal region in a sample of premanifest HD patients (n = 19) and age, sex and education matched healthy controls (n = 21). In particular, we focused on two myelin-associated derivatives: i. the myelin water signal fraction (f), a parameter dependent on myelin content; and ii. The difference in frequency between myelin and intra-axonal water pools (Δω), a parameter dependent on the ratio between the inner and the outer axonal radii. f was found to be lower in HD patients (β = -0.13, p = 0.03), while Δω did not show a group effect. Performance in tests of working memory, executive function, social cognition and movement was also assessed, and a greater age-related decline in executive function was detected in HD patients (β = -0.06, p = 0.006), replicating previous evidence of executive dysfunction in HD. Finally, the correlation between f, executive function, and proximity to disease onset was explored in patients, and a positive correlation between executive function and f was detected (r = 0.542; p = 0.02). This study emphasises the potential of complex mGRE signal analysis for aiding understanding of HD pathogenesis and progression. Moreover, expanding on evidence from pathology and animal studies, it provides novel in vivo evidence supporting myelin breakdown as an early feature of HD.
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http://dx.doi.org/10.1016/j.nicl.2021.102658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079666PMC
July 2021

Timing and Impact of Psychiatric, Cognitive, and Motor Abnormalities in Huntington Disease.

Neurology 2021 05 25;96(19):e2395-e2406. Epub 2021 Mar 25.

From the Division of Psychological Medicine and Clinical Neurosciences (B.M., N.M.W., P.H., L.J., T.H.M.), Brain Repair Group (A.E.R.), Schools of Medicine and Biosciences, and Neuroscience and Mental Health Research Institute (A.E.R.), Cardiff University, UK; Molecular Neurogenetic Unit (J.F.G., J.-M.L., M.E.M.), Center for Genomic Medicine, Massachusetts General Hospital; Department of Genetics (J.F.G., J.-M.L., M.E.M.), Harvard Medical School, Boston, MA; Department of Neurology (G.B.L.), University of Ulm, Germany; and Swiss Huntington's Disease Centre (M.O.), Siloah, Bern, Switzerland.

Objective: To assess the prevalence, timing, and functional impact of psychiatric, cognitive, and motor abnormalities in Huntington disease (HD) gene carriers, we analyzed retrospective clinical data from individuals with manifest HD.

Methods: Clinical features of patients with HD were analyzed for 6,316 individuals in an observational study of the European Huntington's Disease Network (REGISTRY) from 161 sites across 17 countries. Data came from clinical history and the patient-completed Clinical Characteristics Questionnaire that assessed 8 symptoms: motor, cognitive, apathy, depression, perseverative/obsessive behavior, irritability, violent/aggressive behavior, and psychosis. Multiple logistic regression was used to analyze relationships between symptoms and functional outcomes.

Results: The initial manifestation of HD is increasingly likely to be motor and less likely to be psychiatric as age at presentation increases and is independent of pathogenic CAG repeat length. The Clinical Characteristics Questionnaire captures data on nonmotor symptom prevalence that correlate specifically with validated clinical measures. Psychiatric and cognitive symptoms are common in HD gene carriers, with earlier onsets associated with longer CAG repeats. Of patients with HD, 42.4% reported at least 1 psychiatric or cognitive symptom before motor symptoms, with depression most common. Each nonmotor symptom was associated with significantly reduced total functional capacity scores.

Conclusions: Psychiatric and cognitive symptoms are common and functionally debilitating in HD gene carriers. They require recognition and targeting with clinical outcome measures and treatments. However, because it is impossible to distinguish confidently between nonmotor symptoms arising from HD and primary psychiatric disorders, particularly in younger premanifest patients, nonmotor symptoms should not be used to make a clinical diagnosis of HD.

Trial Registration Information: ClinicalTrials.gov Identifier: NCT01590589.
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http://dx.doi.org/10.1212/WNL.0000000000011893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166441PMC
May 2021

Neural modeling of antisaccade performance of healthy controls and early Huntington's disease patients.

Chaos 2021 Jan;31(1):013121

School of Optometry and Vision Sciences, Cardiff University, Cardiff CF24 4HQ, United Kingdom.

Huntington's disease (HD), a genetically determined neurodegenerative disease, is positively correlated with eye movement abnormalities in decision making. The antisaccade conflict paradigm has been widely used to study response inhibition in eye movements, and reliable performance deficits in HD subjects have been observed, including a greater number and timing of direction errors. We recorded the error rates and response latencies of early HD patients and healthy age-matched controls performing the mirror antisaccade task. HD participants displayed slower and more variable antisaccade latencies and increased error rates relative to healthy controls. A competitive accumulator-to-threshold neural model was then employed to quantitatively simulate the controls' and patients' reaction latencies and error rates and uncover the mechanisms giving rise to the observed HD antisaccade deficits. Our simulations showed that (1) a more gradual and noisy rate of accumulation of evidence by HD patients is responsible for the observed prolonged and more variable antisaccade latencies in early HD; (2) the confidence level of early HD patients making a decision is unaffected by the disease; and (3) the antisaccade performance of healthy controls and early HD patients is the end product of a neural lateral competition (inhibition) between a correct and an erroneous decision process, and not the end product of a third top-down stop signal suppressing the erroneous decision process as many have speculated.
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http://dx.doi.org/10.1063/5.0021584DOI Listing
January 2021

Injectable Glycosaminoglycan-Based Cryogels from Well-Defined Microscale Templates for Local Growth Factor Delivery.

ACS Chem Neurosci 2021 04 23;12(7):1178-1188. Epub 2021 Mar 23.

Leibniz-Institut für Polymerforschung Dresden e.V., Max Bergmann Center of Biomaterials Dresden, Hohe Straße 6, D-01069 Dresden, Germany.

Glycosaminoglycan-based hydrogels hold great potential for applications in tissue engineering and regenerative medicine. By mimicking the natural extracellular matrix processes of growth factor binding and release, such hydrogels can be used as a sustained delivery device for growth factors. Since neural networks commonly follow well-defined, high-aspect-ratio paths through the central and peripheral nervous system, we sought to create a fiber-like, elongated growth factor delivery system. Cryogels, with networks formed at subzero temperatures, are well-suited for the creation of high-aspect-ratio biomaterials, because they have a macroporous structure making them mechanically robust (for ease of handling) yet soft and highly compressible (for interfacing with brain tissue). Unlike hydrogels, cryogels can be synthesized in advance of their use, stored with ease, and rehydrated quickly to their original shape. Herein, we use solvent-assisted microcontact molding to form sacrificial templates, in which we produced highly porous cryogel microscale scaffolds with a well-defined elongated shape via the photopolymerization of poly(ethylene glycol) diacrylate and maleimide-functionalized heparin. Dissolution of the template yielded cryogels that could load nerve growth factor (NGF) and release it over a period of 2 weeks, causing neurite outgrowth in PC12 cell cultures. This microscale template-assisted synthesis technique allows tight control over the cryogel scaffold dimensions for high reproducibility and ease of injection through fine gauge needles.
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http://dx.doi.org/10.1021/acschemneuro.1c00005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033563PMC
April 2021

Cell Therapy for Huntington's Disease: Learning from Failure.

Mov Disord 2021 03;36(3):787-788

Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York, USA.

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http://dx.doi.org/10.1002/mds.28503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8506258PMC
March 2021

Objectively characterizing Huntington's disease using a novel upper limb dexterity test.

J Neurol 2021 Jul 8;268(7):2550-2559. Epub 2021 Feb 8.

Centre for Trials Research, Cardiff University, 4th Floor, Neuadd Meirionnydd, Heath Park, Cardiff, CF14 4YS, United Kingdom.

Background: The Clinch Token Transfer Test (C3t) is a bi-manual coin transfer task that incorporates cognitive tasks to add complexity. This study explored the concurrent and convergent validity of the C3t as a simple, objective assessment of impairment that is reflective of disease severity in Huntington's, that is not reliant on clinical expertise for administration.

Methods: One-hundred-and-five participants presenting with pre-manifest (n = 16) or manifest (TFC-Stage-1 n = 39; TFC-Stage-2 n = 43; TFC-Stage-3 n = 7) Huntington's disease completed the Unified Huntington's Disease Rating Scale and the C3t at baseline. Of these, thirty-three were followed up after 12 months. Regression was used to estimate baseline individual and composite clinical scores (including cognitive, motor, and functional ability) using baseline C3t scores. Correlations between C3t and clinical scores were assessed using Spearman's R and visually inspected in relation to disease severity using scatterplots. Effect size over 12 months provided an indication of longitudinal behaviour of the C3t in relation to clinical measures.

Results: Baseline C3t scores predicted baseline clinical scores to within 9-13% accuracy, being associated with individual and composite clinical scores. Changes in C3t scores over 12 months were small ([Formula: see text] ≤ 0.15) and mirrored the change in clinical scores.

Conclusion: The C3t demonstrates promise as a simple, easy to administer, objective outcome measure capable of predicting impairment that is reflective of Huntington's disease severity and offers a viable solution to support remote clinical monitoring. It may also offer utility as a screening tool for recruitment to clinical trials given preliminary indications of association with the prognostic index normed for Huntington's disease.
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http://dx.doi.org/10.1007/s00415-020-10375-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868671PMC
July 2021

Protocol for an open label: phase I trial within a cohort of foetal cell transplants in people with Huntington's disease.

Brain Commun 2021 19;3(1):fcaa230. Epub 2021 Jan 19.

Brain Repair and Intracranial Neurotherapeutics (BRAIN) Unit, Cardiff University, Cardiff, CF24 4HQ, UK.

Huntington's disease is a progressive neurodegenerative disorder characterized by motor, cognitive and psychiatric symptoms. Currently, no disease-modifying therapies are available to slow or halt disease progression. Huntington's disease is characterized by relatively focal and specific loss of striatal medium spiny neurons, which makes it suitable for cell-replacement therapy, a process involving the transplantation of donor cells to replace those lost due to disease. TRIal DEsigns for delivery of Novel Therapies in neurodegeneration is a phase I Trial Within a Cohort designed to assess safety and feasibility of transplanting human foetal striatal cells into the striatum of people with Huntington's disease. A minimum of 18 participants will be enrolled in the study cohort, and up to five eligible participants will be randomly selected to undergo transplantation of 12-22 million foetal cells in a dose escalation paradigm. Independent reviewers will assess safety outcomes (lack of significant infection, bleeding or new neurological deficit) 4 weeks after surgery, and ongoing safety will be established before conducting each subsequent surgery. All participants will undergo detailed clinical and functional assessment at baseline (6 and 12 months). Surgery will be performed 1 month after baseline, and transplant participants will undergo regular clinical follow-up for at least 12 months. Evaluation of trial processes will also be undertaken. Transplant participants and their carers will be interviewed ∼1 month before and after surgery. Interviews will also be conducted with non-transplanted participants and healthcare staff delivering the intervention and involved in the clinical care of participants. Evaluation of clinical and functional efficacy outcomes and intervention costs will be carried out to explore plausible trial designs for subsequent randomized controlled trials aimed at evaluating efficacy and cost-effectiveness of cell-replacement therapy. TRIal DEsigns for delivery of Novel Therapies in neurodegeneration will enable the assessment of the safety, feasibility, acceptability and cost of foetal cell transplants in people with Huntington's disease. The data collected will inform trial designs for complex intra-cranial interventions in a range of neurodegenerative conditions and facilitate the development of stable surgical pipelines for delivery of future stem cell trials. ISRCTN52651778.
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http://dx.doi.org/10.1093/braincomms/fcaa230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850012PMC
January 2021

Delayed diagnosis of spinal cord injuries in Huntington's disease.

Pract Neurol 2021 Jun 4;21(3):231-234. Epub 2021 Feb 4.

Division of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, UK.

Huntington's disease is a neurodegenerative disorder, characterised by progressive cognitive, motor and psychiatric symptoms. Patients with advanced disease presenting to emergency medical services can pose a diagnostic and management challenge for physicians unfamiliar with the condition. We describe two patients with Huntington's disease in whom the diagnosis of traumatic spinal cord injury was delayed, discuss the role that cognitive bias and other factors played in this delay, and the lessons we can learn.
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http://dx.doi.org/10.1136/practneurol-2020-002854DOI Listing
June 2021

Induced pluripotent stem cells derived from the developing striatum as a potential donor source for cell replacement therapy for Huntington disease.

Cytotherapy 2021 02 25;23(2):111-118. Epub 2020 Nov 25.

Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, UK; MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK; Wales Brain Repair and Intracranial Neurotherapeutics Unit, School of Medicine, Cardiff University, Cardiff, UK. Electronic address:

Background: Cell replacement therapy (CRT) for Huntington disease (HD) requires a source of striatal (STR) progenitors capable of restoring the function lost due to STR degeneration. Authentic STR progenitors can be collected from the fetal putative striatum, or whole ganglionic eminence (WGE), but these tissues remain impractical for widespread clinical application, and alternative donor sources are required. Here we begin exploring the possibility that induced pluripotent stem cells (iPSC) derived from WGE may retain an epigenetic memory of their tissue of origin, which could enhance their ability to differentiate into STR cells.

Results: We generate four iPSC lines from human WGE (hWGE) and establish that they have a capacity similar to human embryonic stem cells with regard to their ability to differentiate toward an STR phenotype, as measured by expression and demethylation of key STR genes, while maintaining an overall different methylome. Finally, we demonstrate that these STR-differentiated hWGE iPSCs share characteristics with hWGE (i.e., authentic STR tissues) both in vitro and following transplantation into an HD model. Overall, iPSCs derived from human WGE show promise as a donor source for CRT for HD.
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http://dx.doi.org/10.1016/j.jcyt.2020.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822401PMC
February 2021

Cell therapy in Huntington's disease: Taking stock of past studies to move the field forward.

Stem Cells 2021 02 25;39(2):144-155. Epub 2020 Nov 25.

Centre for Trials Research, Cardiff University, Cardiff, UK.

Huntington's disease (HD) is a rare inherited neurodegenerative disease that manifests mostly in adulthood with progressive cognitive, behavioral, and motor dysfunction. Neuronal loss occurs predominantly in the striatum but also extends to other brain regions, notably the cortex. Most patients die around 20 years after motor onset, although there is variability in the rate of progression and some phenotypic heterogeneity. The most advanced experimental therapies currently are huntingtin-lowering strategies, some of which are in stage 3 clinical trials. However, even if these approaches are successful, it is unlikely that they will be applicable to all patients or will completely halt continued loss of neural cells in all cases. On the other hand, cellular therapies have the potential to restore atrophied tissues and may therefore provide an important complementary therapeutic avenue. Pilot studies of fetal cell grafts in the 2000s reported the most dramatic clinical improvements yet achieved for this disease, but subsequent studies have so far failed to identify methodology to reliably reproduce these results. Moving forward, a major challenge will be to generate suitable donor cells from (nonfetal) cell sources, but in parallel there are a host of procedural and trial design issues that will be important for improving reliability of transplants and so urgently need attention. Here, we consider findings that have emerged from clinical transplant studies in HD to date, in particular new findings emerging from the recent multicenter intracerebral transplant HD study, and consider how these data may be used to inform future cell therapy trials.
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http://dx.doi.org/10.1002/stem.3300DOI Listing
February 2021

Heparin-based, injectable microcarriers for controlled delivery of interleukin-13 to the brain.

Biomater Sci 2020 Sep;8(18):4997-5004

Leibniz-Institut für Polymerforschung Dresden e.V., Hohe Str. 6, 01069 Dresden, Germany. and School of Pharmacy and Pharmaceutical Sciences, Cardiff University, CF10 3NB, Cardiff, UK.

Interleukin-13 (IL-13) drives cells of myeloid origin towards a more anti-inflammatory phenotype, but delivery to the brain remains problematic. Herein, we show that heparin-based cryogel microcarriers load high amounts of IL-13, releasing it slowly. Intra-striatal injection of loaded microcarriers caused local up-regulation of ARG1 in myeloid cells for pro-regenerative immunomodulation in the brain.
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http://dx.doi.org/10.1039/d0bm01249aDOI Listing
September 2020

Drumming Motor Sequence Training Induces Apparent Myelin Remodelling in Huntington's Disease: A Longitudinal Diffusion MRI and Quantitative Magnetization Transfer Study.

J Huntingtons Dis 2020 ;9(3):303-320

Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, Maindy Road, Cardiff, UK.

Background: Impaired myelination may contribute to Huntington's disease (HD) pathogenesis.

Objective: This study assessed differences in white matter (WM) microstructure between HD patients and controls, and tested whether drumming training stimulates WM remodelling in HD. Furthermore, it examined whether training-induced microstructural changes are related to improvements in motor and cognitive function.

Methods: Participants undertook two months of drumming exercises. Working memory and executive function were assessed before and post-training. Changes in WM microstructure were investigated with diffusion tensor magnetic resonance imaging (DT-MRI)-based metrics, the restricted diffusion signal fraction (Fr) from the composite hindered and restricted model of diffusion (CHARMED) and the macromolecular proton fraction (MPF) from quantitative magnetization transfer (qMT) imaging. WM pathways linking putamen and supplementary motor areas (SMA-Putamen), and three segments of the corpus callosum (CCI, CCII, CCIII) were studied using deterministic tractography. Baseline MPF differences between patients and controls were assessed with tract-based spatial statistics.

Results: MPF was reduced in the mid-section of the CC in HD subjects at baseline, while a significantly greater change in MPF was detected in HD patients relative to controls in the CCII, CCIII, and the right SMA-putamen post-training. Further, although patients improved their drumming and executive function performance, such improvements did not correlate with microstructural changes. Increased MPF suggests training-induced myelin changes in HD.

Conclusion: Though only preliminary and based on a small sample size, these results suggest that tailored behavioural stimulation may lead to neural benefits in early HD, that could be exploited for delaying disease progression.
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http://dx.doi.org/10.3233/JHD-200424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836062PMC
August 2021

Is the Immunological Response a Bottleneck for Cell Therapy in Neurodegenerative Diseases?

Front Cell Neurosci 2020 11;14:250. Epub 2020 Aug 11.

Laboratory of Stem Cells and Regenerative Medicine, Department of Biomedicine, University of Barcelona, Barcelona, Spain.

Neurodegenerative disorders such as Parkinson's (PD) and Huntington's disease (HD) are characterized by a selective detrimental impact on neurons in a specific brain area. Currently, these diseases have no cures, although some promising trials of therapies that may be able to slow the loss of brain cells are underway. Cell therapy is distinguished by its potential to replace cells to compensate for those lost to the degenerative process and has shown a great potential to replace degenerated neurons in animal models and in clinical trials in PD and HD patients. Fetal-derived neural progenitor cells, embryonic stem cells or induced pluripotent stem cells are the main cell sources that have been tested in cell therapy approaches. Furthermore, new strategies are emerging, such as the use of adult stem cells, encapsulated cell lines releasing trophic factors or cell-free products, containing an enriched secretome, which have shown beneficial preclinical outcomes. One of the major challenges for these potential new treatments is to overcome the host immune response to the transplanted cells. Immune rejection can cause significant alterations in transplanted and endogenous tissue and requires immunosuppressive drugs that may produce adverse effects. T-, B-lymphocytes and microglia have been recognized as the main effectors in striatal graft rejection. This review aims to summarize the preclinical and clinical studies of cell therapies in PD and HD. In addition, the precautions and strategies to ensure the highest quality of cell grafts, the lowest risk during transplantation and the reduction of a possible immune rejection will be outlined. Altogether, the wide-ranging possibilities of advanced therapy medicinal products (ATMPs) could make therapeutic treatment of these incurable diseases possible in the near future.
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http://dx.doi.org/10.3389/fncel.2020.00250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433375PMC
August 2020

A randomised feasibility study of computerised cognitive training as a therapeutic intervention for people with Huntington's disease (CogTrainHD).

Pilot Feasibility Stud 2020 19;6:88. Epub 2020 Jun 19.

Centre for Trials Research (CTR), Cardiff University, Neuadd Meironnydd, Heath Park, Cardiff, CF14 4YS UK.

Background: Huntington's disease (HD) is associated with a range of cognitive deficits including problems with executive function. In the absence of a disease modifying treatment, cognitive training has been proposed as a means of slowing cognitive decline; however, the impact of cognitive training in HD patient populations remains unclear. The CogTrainHD study assessed the feasibility and acceptability of home-based computerised executive function training, for people impacted by HD.

Methods: Thirty HD gene carriers were recruited and randomised to either executive function training or non-intervention control groups. Participants allocated to the intervention group were asked to complete executive function training three times a week for 30 min for 12 weeks in their own homes. Semi-structured interviews were conducted with participants and friends, family or carers, to determine their views on the study.

Results: 26 out of 30 participants completed the baseline assessments and were subsequently randomised: 13 to the control group and 13 to the intervention group. 23 of the 30 participants were retained until study completion: 10/13 in the intervention group and 13/13 in the control group. 4/10 participants fully adhered to the executive function training. All participants in the control group 13/13 completed the study as intended. Interview data suggested several key facilitators including participant determination, motivation, incorporation of the intervention into routine and support from friends and family members. Practical limitations, including lack of time, difficulty and frustration in completing the intervention, were identified as barriers to study completion.

Conclusions: The CogTrainHD feasibility study provides important evidence regarding the feasibility and acceptability of a home-based cognitive training intervention for people with HD. Variable adherence to the cognitive training implies that the intervention is not feasible to all participants in its current form. The study has highlighted important aspects in relation to both the study and intervention design that require consideration, and these include the design of games in the executive function training software, logistical considerations such as lack of time, the limited time participants had to complete the intervention and the number of study visits required. Further studies are necessary before computerised executive function training can be recommended routinely for people with HD.

Trial Registration: ClinicalTrials.gov, Registry number NCT02990676.
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http://dx.doi.org/10.1186/s40814-020-00623-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304172PMC
June 2020

Altered cerebrovascular response to acute exercise in patients with Huntington's disease.

Brain Commun 2020 16;2(1):fcaa044. Epub 2020 Apr 16.

Cardiff University Brain Research Imaging Centre, School of Physics and Astronomy, Cardiff University, Cardiff CF24 4HQ, UK.

The objective of this study was to determine whether a single session of exercise was sufficient to induce cerebral adaptations in individuals with Huntington's disease and to explore the time dynamics of any acute cerebrovascular response. In this case-control study, we employed arterial-spin labelling MRI in 19 Huntington's disease gene-positive participants (32-65 years, 13 males) and 19 controls (29-63 years, 10 males) matched for age, gender, body mass index and self-reported activity levels, to measure global and regional perfusion in response to 20 min of moderate-intensity cycling. Cerebral perfusion was measured at baseline and 15, 40 and 60 min after exercise cessation. Relative to baseline, we found that cerebral perfusion increased in patients with Huntington's disease yet was unchanged in control participants in the precentral gyrus ( = 0.016), middle frontal gyrus ( = 0.046) and hippocampus ( = 0.048) 40 min after exercise cessation (+15 to +32.5% change in Huntington's disease participants, -7.7 to 0.8% change in controls). The length of the disease-causing trinucleotide repeat expansion in the huntingtin gene predicted the change in the precentral gyrus ( = 0.03) and the intensity of the exercise intervention predicted hippocampal perfusion change in Huntington's disease participants ( < 0.001). In both groups, exercise increased hippocampal blood flow 60 min after exercise cessation ( = 0.039). These findings demonstrate the utility of acute exercise as a clinically sensitive experimental paradigm to modulate the cerebrovasculature. Twenty minutes of aerobic exercise induced transient cerebrovascular adaptations in the hippocampus and cortex selectively in Huntington's disease participants and likely represents latent neuropathology not evident at rest.
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http://dx.doi.org/10.1093/braincomms/fcaa044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293798PMC
April 2020

A Critical Review of White Matter Changes in Huntington's Disease.

Mov Disord 2020 08 15;35(8):1302-1311. Epub 2020 Jun 15.

Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, Cardiff, United Kingdom.

Huntington's disease is a genetic neurodegenerative disorder. White matter alterations have recently been identified as a relevant pathophysiological feature of Huntington's disease, but their etiology and role in disease pathogenesis and progression remain unclear. Increasing evidence suggests that white matter changes in this disorder are attributed to alterations in myelin-associated biological processes. This review first discusses evidence from neurochemical studies lending support to the demyelination hypothesis of Huntington's disease, demonstrating aberrant myelination and changes in oligodendrocytes in the Huntington's brain. Next, evidence from neuroimaging studies is reviewed, the limitations of the described methodologies are discussed, and suggested interpretations of findings from published studies are challenged. Although our understanding of Huntington's associated pathological changes in the brain will increasingly rely on neuroimaging techniques, the shortcomings of these methodologies must not be forgotten. Advances in magnetic resonance imaging techniques and tissue modeling will enable a better in vivo, longitudinal characterization of the biological properties of white matter microstructure. This in turn will facilitate identification of disease-related biomarkers and the specification of outcome measures in clinical trials. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28109DOI Listing
August 2020

Dopaminergic Progenitors Derived From Epiblast Stem Cells Function Similarly to Primary VM-Derived Progenitors When Transplanted Into a Parkinson's Disease Model.

Front Neurosci 2020 7;14:312. Epub 2020 Apr 7.

Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, United Kingdom.

Neural transplantation in neurodegenerative diseases such as Parkinson's disease (PD) offers to replace cells lost during the progression of the disease process. Primary fetal ventral mesencephalon (VM), the origin of midbrain dopaminergic (DAergic) precursors, is currently the gold standard source of cells for transplantation in PD. However, the use of tissue from this source raises ethical and logistical constraints necessitating the need for alternative supplies of donor cells. The requirement of any alternative donor cell source is to have the capability to generate authentic mature DAergic neurons, which could be utilized in cell-replacement strategies. Mouse pluripotent stem cells can efficiently generate electrochemically mature midbrain DAergic precursors using a stepwise control of FGF signaling. Here, we have compared DAergic transplants derived from two progenitor cell sources in an allograft system: mouse epiblast stem cells (EpiSC) and primary fetal mouse VM tissue. Cells were transplanted into the striatum of 6-OHDA lesioned mice pre-treated with L-DOPA. Drug-induced rotations, a number of motor tests and drug-induced abnormal involuntary movements (AIMs) were assessed. Functional improvements were demonstrated post-transplantation in some behavioral tests, with no difference in graft volume or the number of TH immuno-positive cells in the grafts of the two transplant groups. L-DOPA-induced AIMs and amphetamine-induced AIMs were observed in both transplant groups, with no differences in rate or severity between the two groups. Collectively, in this mouse-to-mouse allograft system, we report no significant differences in the functional ability between the gold standard primary VM derived and pluripotent stem cell-derived DAergic transplants.
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http://dx.doi.org/10.3389/fnins.2020.00312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154167PMC
April 2020

Hypertension, Antihypertensive Use and the Delayed-Onset of Huntington's Disease.

Mov Disord 2020 06 4;35(6):937-946. Epub 2020 Feb 4.

Cardiff University Brain Research Imaging Centre (CUBRIC), School of Physics and Astronomy, Maindy Road, Cardiff University, Cardiff, Wales, UK.

Background: Hypertension is a modifiable cardiovascular risk factor implicated in neurodegeneration and dementia risk. In Huntington's disease, a monogenic neurodegenerative disease, autonomic and vascular abnormalities have been reported. This study's objective was to examine the relationship between hypertension and disease severity and progression in Huntington's disease.

Methods: Using longitudinal data from the largest worldwide observational study of Huntington's disease (n = 14,534), we assessed the relationship between hypertension, disease severity, and rate of clinical progression in Huntington's disease mutation carriers. Propensity score matching was used to statistically match normotensive and hypertensive participants for age, sex, body mass index, ethnicity, and CAG length.

Results: Huntington's disease patients had a lower prevalence of hypertension compared with age-matched gene-negative controls. Huntington's disease patients with hypertension had worse cognitive function, a higher depression score, and more marked motor progression over time compared with Huntington's disease patients without hypertension. However, hypertensive patients taking antihypertensive medication had less motor, cognitive, and functional impairment than Huntington's disease patients with untreated hypertension and a later age of clinical onset compared with untreated hypertensive patients and normotensive individuals with Huntington's disease.

Conclusions: We report the novel finding that hypertension and antihypertensive medication use are associated with altered disease severity, progression, and clinical onset in patients with Huntington's disease. These findings have implications for the management of hypertension in Huntington's disease and suggest that prospective studies of the symptomatic or disease-modifying potential of antihypertensives in neurodegenerative diseases are warranted. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317197PMC
June 2020

Insensitivity to loss predicts apathy in huntington's disease.

Mov Disord 2019 09 30;34(9):1381-1391. Epub 2019 Jul 30.

Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.

Background: Apathy is a deficit in goal-directed behavior that significantly affects quality of life and function. It is common in Huntington's disease and other disorders affecting corticostriatal pathways. Deficits in processing of reward, altered effort, and executive dysfunction are associated with apathy in other disorders, but the cognitive processes leading to apathy in Huntington's disease remain largely unknown. A previously reported deficit in learning from losses in Huntington's disease raises the possibility of a hitherto unrecognized mechanism leading to apathy. This study's objective was to delineate the cognitive processes associated with apathy in HD.

Methods: We tested 51 Huntington's disease participants and 26 controls on a battery of novel and established measures to assess the contribution to apathy in Huntington's disease of executive function, reward value, reward-effort calculations, instrumental learning, and response to reward and loss.

Results: Huntington's disase participants had deficits in instrumental learning with impaired response to loss, but no evidence to suggest altered reward-related behavior or effort. We also saw an executive dysfunction contribution to apathy in Huntington's disease.

Discussion: We report the novel finding that apathy in Huntington's disease is associated with blunted responses to losses and impaired instrumental learning. This association is consistent with the known early degeneration of the indirect pathway and amygdala involvement in apathy in Huntington's disease, but is previously unreported in any disorder. In keeping with the comparative preservation of the ventral striatum and orbitofrontal cortex in Huntington's disease, reward valuation and reward-effort calculations did not contribute to apathy. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27787DOI Listing
September 2019

International Guidelines for the Treatment of Huntington's Disease.

Front Neurol 2019 3;10:710. Epub 2019 Jul 3.

NeuroZentrumSiloah and Department of Neurology, Swiss HD Center, University of Bern, Bern, Switzerland.

The European Huntington's Disease Network (EHDN) commissioned an international task force to provide global evidence-based recommendations for everyday clinical practice for treatment of Huntington's disease (HD). The objectives of such guidelines are to standardize pharmacological, surgical and non-pharmacological treatment regimen and improve care and quality of life of patients. A formalized consensus method, adapted from the French Health Authority recommendations was used. First, national committees (French and English Experts) reviewed all studies published between 1965 and 2015 included dealing with HD symptoms classified in motor, cognitive, psychiatric, and somatic categories. Quality grades were attributed to these studies based on levels of scientific evidence. Provisional recommendations were formulated based on the strength and the accumulation of scientific evidence available. When evidence was not available, recommendations were framed based on professional agreement. A European Steering committee supervised the writing of the final recommendations through a consensus process involving two rounds of online questionnaire completion with international multidisciplinary HD health professionals. Patients' associations were invited to review the guidelines including the HD symptoms. Two hundred and nineteen statements were retained in the final guidelines. We suggest to use this adapted method associating evidence base-medicine and expert consensus to other rare diseases.
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http://dx.doi.org/10.3389/fneur.2019.00710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618900PMC
July 2019

Physical Activity and Exercise Outcomes in Huntington Disease (PACE-HD): Protocol for a 12-Month Trial Within Cohort Evaluation of a Physical Activity Intervention in People With Huntington Disease.

Phys Ther 2019 09;99(9):1201-1210

Centre for Trials Research, Cardiff University, 4th Floor, Neuadd Meirionydd Health Park, Cardiff, South Glamorgan CF14 7YS, United Kingdom.

Background: Exercise is emerging as an important aspect in the management of disease-related symptoms and functional decline in people with Huntington disease (HD). Long-term evaluation of physical activity and exercise participation in HD has yet to be undertaken.

Objective: The objective is to investigate the feasibility of a nested randomized controlled trial (RCT) alongside a longitudinal observational study of physical activity and exercise outcomes in people with HD.

Design: This will be a 12-month longitudinal observational study (n = 120) with a nested evaluation of a physical activity intervention (n = 30) compared with usual activity (n = 30) using a "trial within a cohort" design.

Setting: The study will take place in HD specialist clinics in Germany, Spain, and the United States, with intervention delivery in community settings.

Participants: The participants will have early-mid-stage HD and be participating in the Enroll-HD study.

Intervention: This will be a 12-month physical activity behavioral change intervention, delivered by physical therapists in 18 sessions, targeting uptake of aerobic exercise and increased physical activity.

Measurements: All participants (n = 120) will complete Enroll-HD assessments (motor, cognitive, behavioral, and quality of life) at baseline and at 12 months. Additional Physical ACtivity and Exercise Outcomes in Huntington Disease (PACE-HD) assessments include fitness (predicted maximal oxygen uptake [V  o2max]), self-reported and quantitative measures of physical activity, disease-specific symptoms, and walking endurance. RCT participants (n = 60) will complete an additional battery of quantitative motor assessments and a 6-month interim assessment. Enroll-HD data will be linked to PACE-HD physical activity and fitness data.

Limitations: The limitations include that the embedded RCT is open, and assessors at RCT sites are not blinded to participant allocation.

Conclusion: PACE-HD will enable determination of the feasibility of long-term physical activity interventions in people with HD. The novel "trial within a cohort" design and incorporation of data linkage have potential to reduce participant burden. This design could be applied to other neurological diseases and movement disorders where recruitment and retention are challenging.
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http://dx.doi.org/10.1093/ptj/pzz075DOI Listing
September 2019

Targeting Huntingtin Expression in Patients with Huntington's Disease.

N Engl J Med 2019 06 6;380(24):2307-2316. Epub 2019 May 6.

From University College London (UCL) Huntington's Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, and the U.K. Dementia Research Institute at UCL, London (S.J.T., E.J.W.), the Department of Clinical Neuroscience, Addenbrooke's Hospital, University of Cambridge, Cambridge (R.A.B., N.F.B.), Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester University NHS Foundation Trust, and the Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester (D.C.), the University of Edinburgh and the U.K. Dementia Research Institute, Edinburgh (J.P.), the Institute of Clinical Sciences, College of Medical and Dental Sciences, University Hospital Birmingham, Birmingham (H.R.), and the Cardiff University Brain Repair Group, Brain Repair and Intracranial Neurotherapeutics Unit, Neuroscience and Mental Health Research Institute and School of Biosciences, Cardiff (A.R.) - all in the United Kingdom; the Centre for Huntington's Disease, Department of Medical Genetics, and the Division of Neurology, Department of Medicine, University of British Columbia, and the Centre for Molecular Medicine and Therapeutics, B.C. Children's Hospital, Vancouver, Canada (B.R.L.); the Department of Neurology, Ulm University, Huntington's Disease Centre, Ulm (G.B.L.), the Department of Neurology, Huntington Center North Rhine-Westphalia, Ruhr University Bochum, St. Josef-Hospital, Bochum (C.S.), and the Department of Neuropsychiatry, Charité-Universitätsmedizin Berlin, Deutsches Zentrum für Neurodegenerative Erkrankungen, Berlin (J.P.) - all in Germany; Ionis Pharmaceuticals, Carlsbad, CA (H.B.K., E.E.S., D.A.N., T.B., E.P., A.V.S., C.F.B., R.M.L.); and F. Hoffmann-La Roche, Basel, Switzerland (C.C., I.G., S.A.S.).

Background: Huntington's disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in , resulting in a mutant huntingtin protein. IONIS-HTT (hereafter, HTT) is an antisense oligonucleotide designed to inhibit messenger RNA and thereby reduce concentrations of mutant huntingtin.

Methods: We conducted a randomized, double-blind, multiple-ascending-dose, phase 1-2a trial involving adults with early Huntington's disease. Patients were randomly assigned in a 3:1 ratio to receive HTT or placebo as a bolus intrathecal administration every 4 weeks for four doses. Dose selection was guided by a preclinical model in mice and nonhuman primates that related dose level to reduction in the concentration of huntingtin. The primary end point was safety. The secondary end point was HTT pharmacokinetics in cerebrospinal fluid (CSF). Prespecified exploratory end points included the concentration of mutant huntingtin in CSF.

Results: Of the 46 patients who were enrolled in the trial, 34 were randomly assigned to receive HTT (at ascending dose levels of 10 to 120 mg) and 12 were randomly assigned to receive placebo. Each patient received all four doses and completed the trial. Adverse events, all of grade 1 or 2, were reported in 98% of the patients. No serious adverse events were seen in HTT-treated patients. There were no clinically relevant adverse changes in laboratory variables. Predose (trough) concentrations of HTT in CSF showed dose dependence up to doses of 60 mg. HTT treatment resulted in a dose-dependent reduction in the concentration of mutant huntingtin in CSF (mean percentage change from baseline, 10% in the placebo group and -20%, -25%, -28%, -42%, and -38% in the HTT 10-mg, 30-mg, 60-mg, 90-mg, and 120-mg dose groups, respectively).

Conclusions: Intrathecal administration of HTT to patients with early Huntington's disease was not accompanied by serious adverse events. We observed dose-dependent reductions in concentrations of mutant huntingtin. (Funded by Ionis Pharmaceuticals and F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02519036.).
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http://dx.doi.org/10.1056/NEJMoa1900907DOI Listing
June 2019

Clinical Presentation and Features of Juvenile-Onset Huntington's Disease: A Systematic Review.

J Huntingtons Dis 2019 ;8(2):171-179

MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.

Background: Juvenile-onset Huntington's disease (JHD) is defined by onset at the age of 20 or younger and represents approximately 5% of all HD cases. Patients with JHD present with a broad range of symptoms and signs that only overlap partially with adult-onset HD. A greater awareness and understanding of the presentation of JHD would improve the diagnosis and treatment of this condition.

Objective: To undertake a systematic review of the literature relating to the clinical features at first presentation of JHD.

Methods: We searched MEDLINE and EMBASE for all studies describing presenting features of JHD patients, performed quality control, and collated and analysed the data.

Results: We screened 2917 records for eligibility, and included 79 studies (n = 285 individuals) in the analysis. All were case reports and case series, synthesising data from 25 different countries. Thirty-four different clinical features at presentation were identified. Four groups of symptoms or signs were present in more than 15% of cases: behavioural disturbance, falls/gait disturbance, cognitive impairment and parkinsonian features. Where data were available, the median age of onset was 9 years, 52% were female, the mutant HTT allele was transmitted paternally in 80% of cases, and the median CAG repeat length was 64.

Conclusions: JHD can present with a wide variety of symptoms and signs, with non-motor characteristics being observed most frequently. Greater recognition of these presentations will facilitate early diagnosis and management. Tailored rating scales to score motor, non-motor, and functional impairments specifically in JHD are required to standardise research studies, and are under development.
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http://dx.doi.org/10.3233/JHD-180339DOI Listing
April 2020

Outcome of cell suspension allografts in a patient with Huntington's disease.

Ann Neurol 2018 12 25;84(6):950-956. Epub 2018 Oct 25.

Centre de Recherche du CHU de Québec (CHUQ), Axe Neurosciences, Québec, QC, Canada.

For patients with incurable neurodegenerative disorders such as Huntington's (HD) and Parkinson's disease, cell transplantation has been explored as a potential treatment option. Here, we present the first clinicopathological study of a patient with HD in receipt of cell-suspension striatal allografts who took part in the NEST-UK multicenter clinical transplantation trial. Using various immunohistochemical techniques, we found a discrepancy in the survival of grafted projection neurons with respect to grafted interneurons as well as major ongoing inflammatory and immune responses to the grafted tissue with evidence of mutant huntingtin aggregates within the transplant area. Our results indicate that grafts can survive more than a decade post-transplantation, but show compromised survival with inflammation and mutant protein being observed within the transplant site. Ann Neurol 2018;84:950-956.
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http://dx.doi.org/10.1002/ana.25354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587549PMC
December 2018

Oxygen producing microscale spheres affect cell survival in conditions of oxygen-glucose deprivation in a cell specific manner: implications for cell transplantation.

Biomater Sci 2018 Sep;6(10):2571-2577

Leibniz Institute of Polymer Research Dresden (IPF), Hohe Strasse 6, 01069 Dresden, Germany.

This study outlines the synthesis of microscale oxygen producing spheres, which, when used in conjunction with catalase, can raise the dissolved oxygen content of cell culture media for 16-20 hours. In conditions of oxygen and glucose deprivation, designed to mimic the graft environment in vivo, the spheres rescue SH-SY5Y cells and meschymal stem cells, showing that oxygen producing biomaterials may hold potential to improve the survival of cells post-transplantation.
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http://dx.doi.org/10.1039/c8bm00490kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157640PMC
September 2018
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