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Proposals - Announcements - Treatment -
Ghrelin, potential treatment of Huntington's disease pathology
In addition to classical neurological symptoms, Huntington's disease (HD) is complicated by peripheral pathology, including weight loss, altered metabolism and muscle atrophy. In this project we will evaluate a treatment strategy using ghrelin administration in a HD mouse model. Ghrelin, is a peptide hormone that has multi-tissue effects. Ghrelin has for example been shown to improve muscle wasting and prevent weight loss. In addition, ghrelin analogues (ie ghrelin similar compounds), have been shown to have beneficial effects on cognition. We believe that by targeting multiple tissues, we will both get increased understanding of the complex HD pathology as well as possibly find new treatment strategies.
Investigating the therapeutic potential of manipulating DNA repair in Huntington's disease
New evidence from genetics highlights DNA repair as a mechanism underlying HD and in this project we are exploring the changes in the DNA repair machinery. Intact DNA is vital in cells so all cells have machinery to fix DNA damage. To repair DNA the machinery needs to cut out the incorrect segment and replace it with the correct one. If it cuts in the CAG repeat, when the gap in the DNA is filled the machinery may loose count and inserts too many CAGs, leading to further expansion of the repeat. We know this expansion happens in HD and we are developing an assay to investigate this in many samples at once, in order to develop potential drugs to prevent CAG expansion.
Analysis and recovery of neuronal microcircuit activity in Huntington’s disease using two-photon microscopy and optogenetics
Intracellular Ca2+ homeostasis is altered in HD and is involved in the degeneration of striatal neurons. Prior to degeneration, however, the functionality of the neuronal network could already be impaired. We will study such network alterations in a HD mouse model as this could give insights into disease mechanisms and may provide a therapeutic target for potential corrective measures aimed at restoring normal network functionality. We will first analyze spontaneous cortical activity and then we will selectively stimulate/inhibit regions of interest from local neuronal populations to single cells or even subcellular structures to correct the altered network activity.
Functional Studies on Glutamate Signaling, in a Drosophila model for HD, using analogs of Glutamate or Glutamine to Ameliorate the Pathology of the Disease
Glutamate that is responsible for neuronal communication is also the culprit for their death. Neuronal death in Huntington’s disease results in involuntary movement, dementia, until death. We are using the fruit fly or Drosophila melanogaster as a model of Huntington’s disease. We are trying to identify small molecules with similar structure as the glutamate that allow the neurons to communicate but avoid their death. The new drugs will be administrated in the diet and their effect analyzed on animal climbing. Because of the short generation time of flies we hope to quickly address the efficiency of these new molecules on neuronal death and to extend our studies to other neuronal degeneration diseases.
A pilot evaluation of mindfulness-based cognitive therapy for people with Huntington's disease
It is acknowledged that many people at various stages of Huntington’s disease (pre-symptomatic and symptomatic) experience low mood, anxiety and other psychological difficulties. However, very little research has been conducted to investigate whether psychological therapies could help people with Huntington’s disease with these difficulties. While medication might be effective for some people, it is not suitable for all and psychological approaches should be developed. This study will provide the first indication of whether mindfulness-based cognitive therapy, a therapeutic approach with an established evidence base, would be acceptable and useful for people with Huntington’s disease with low mood.
Utilisation of rehabilitation services in Huntington's Disease
Patients with HD are at risk of falls. However, they may not be referred enough to physiotherapy for management of their mobility problems. We therefore plan to investigate the referral of HD patients in Europe for rehabilitation interventions as well as types of help and home adaptations required. In order to investigate this, we will use Registry data including UHDRS general history (age, age of onset, past medical history), UHDRS motor & function and health economics data. We will specifically consider physiotherapy, occupational therapy and speech therapy requirements. This may have implications for planning and justifying physiotherapy interventions and understanding the rehabilitation needs of patients with HD.
Repurposing an enzyme inhibitor for dual therapeutic benefits in Huntington’s disease
Huntington’s disease (HD) stems from mutation in the HD gene. These genetic abnormalities cause the disease, including motor defects and cognitive and memory decline. Surprisingly, one enzyme in the HD brain seems to be involved both at the DNA level and in the disease progression. This double activity offers the chance to inhibit the enzyme for dual therapeutic benefits. This project will repurpose an existing inhibitor of the enzyme and evaluate its effects in preclinical models for protection of the HD gene and in rescuing long-term memory defects and cognitive decline.
Supporting Activity Engagement in People with Huntington’s disease: A Phase II Evaluation
Keeping active can become very difficult for people with HD given the complex and varied problems that they are faced with on a daily basis. This exploratory randomised, controlled multi-site trial will evaluate the ENGAGE-HD physical activity intervention which is a pur-pose developed home-based activity programme delivered by a trained physical activity coach. The programme includes an exercise DVD and a purpose developed Physical Activity Workbook. People with HD who enrol in the programme will also be asked to attend 3 research assessments (focussing on movement, thinking and activities of daily living) over a 6 month period.
Exercise Rehabilitation Trial In Huntington's Disease (ExerRT-HD)
There is a growing interest in the potential that aerobic exercise may have for brain health, particularly for people with degenerative diseases such as HD. This multi-site study will evaluate the feasibility and potential benefit of a structured exercise intervention in people with early-mid stage HD. 42 people will be enrolled and randomized either to an exercise intervention or to continue as normal. All participants will undergo assessments at the beginning and end of the study. Participants in the intervention group will perform a 30-minute aerobic and 15-minute strengthening programme, 3x/week for 12 weeks, with trainers supervising just over half the sessions.
Safety and tolerability of tetrabenazine in Huntington’s disease in clinical use – data from the REGISTRY cohort
Neuroleptics and Tetrabenazine are both used in order to treat chorea in HD patients. So far Tetrabenazine is not known to cause tardive dyskinesia-a severe possible complication of long use of neuroleptics. However, other side effects as depression and increased suicidality might be possible. Little is known about interactions of Tetrabenazine with comedication, e.g. parallel use of tetrabenazine and neuroleptics. The aim of this retrospective study will be to explore safety, side-effect profiles, duration of therapy, reasons for discontinuation, and data of exposure to co-medication in individuals with HD who used Tetrabenazine in comparison to Tiapride, which is frequently used to treat chorea off-label.
Improving function in Huntington’s disease through neurofeedback: using real-time fMRI to enhance cortical plasticity in early stages of the disease
The current project is a pilot study on the use of neurofeedback training using real-time functional MRI as a non-invasive intervention in Huntington's Disease (HD). During neurofeedback training patients receive feedback about the level of activity in a brain area, affected by the disease, and learn to self-modulate their brain activation. The hypothesis is that by regulating and restoring function in affected brain regions, motor and cognitive function will also be restored. Following promising results in Parkinson's Disease and depression, the current study will focus on early stage HD and collect preliminary data on the feasibility of the intervention.
Targeting the role of the Rab family GTPases in Huntington’s disease
The misfolding and aggregation of mutant huntingtin protein is a critical initiating factor in Huntington’s disease. Several cellular processes are disturbed due to this aggregation, including vesicle trafficking, which is required for movement of cargo within and between cells, and has been implicated in disease pathogenesis. Rab family GTPases play a crucial role in these cellular processes, and two members of this family are known to be neuroprotective in HD models. However, a systematic survey of these GTPases in models of Huntington’s models has not been performed, and therapeutic strategies targeting these genes are lacking. In this project will will implement genetic approaches to systematically interrogate the therapeutic potential of Rab family GTPases in a human cell model of Huntington’s, with the aims of identifying novel therapeutic targets and clarifying the mechanisms underlying this process.
A survey of dietary intake in patients with Huntington's disease
A deficient nutritional status may be an important determining factor in patients with Huntington's disease, leading to increased comorbidity and social costs, and impaired quality of life. The aims of this study are to analyze the dietary intake of patients with presymtomatic and symptomatic Huntington's disease, and to determine the association of the severity of motor, cognitive, psychiatric symptoms, and comorbidity with poor nutritional status in these patients. The determination of the nutritional status of patients with Huntington's disease in its different stages, could help to introduce appropriate dietary measures to prevent complications, and to improve the quality of life of patients and caregiver burden.
Outreaching coordinated multidisciplinary care for Huntington's disease patients
Most Huntington’s disease patients, together with their families, experience crisis-like events during the course of this progressive disease. Crises like fractures, resignation, divorce, or suicide attempts, seem related to the symptoms of the disorder. Experts in the field state that proactive multidisciplinary coordinated care for HD patients could reduce crises. This study aims to describe the crises prevalence and to investigate quality of life and caregiver burden. Multidisciplinary coordinated care will be provided to patients in their own homes. The study is set up to investigate the applicability and feasibility of a test protocol in preparation for a larger study on efficacy of this type of care.
A comparative MRI study to determine the affect of extensive cognitive training on disease progression in HD mice
There is evidence from HD mouse studies that environmental enrichment can slow disease progression. In the present study we were interested to see whether long term cognitive training, so called “brain training” could slow the onset of, or reduce the severity of the disease in the YAC128 HD mouse line. Mice will be tested on a number of tests of motor and cognitive function and will then be scanned using magnetic resonance imaging (MRI) to determine whether “brain training” improves performance and whether the physiological changes underlying any performance benefit, can be identified with the MRI. This study could provide evidence as to the important brain structures responsible for the beneficial effects of environmental enrichment.
This multi-centre study will investigate the potential benefits of a physiotherapy programme for people with mid stage Huntington’s disease (HD) who currently receive no or minimal physiotherapy input. We will recruit 30 individuals who have been diagnosed with HD from clinics in Cardiff, Oxford, London, Birmingham, Manchester and Sheffield. Participants will be randomized into either an intervention group, in which they receive physiotherapy 2x/week for 8 weeks, or a control group. The effectiveness of the programme will be assessed using various measures, including general physical functioning, walking ability and balance. In addition, each participant will set individual, personal goals related to their functional abilities or fitness, in collaboration with a physiotherapist. In order to ensure consistency of care, the control group will be offered the intervention at the end of the study, provided that results so far give no reason to question safety or potential for benefit. If shown to be a acceptable and beneficial, the results from the proposed study can be utilized to provide a structured framework to guide physiotherapy service delivery according to clinical need for people with HD.
Feasibility and benefit of inspiratory muscle training in people with Huntington’s disease.
A recent cross sectional study of respiratory function suggests that people with Huntington’s disease may have reduced strength of the breathing muscles, in the middle and late stages of the disease. Research in other neurodegenerative disease has shown that these muscles can be strengthened by using a small hand held device that provides resistance to the in-breath. This randomised, controlled feasibility study will investigate the benefit and perceptions of respiratory muscle training in 20 people with HD who have established respiratory muscle weakness. The primary outcome will be sniff nasal inspiratory pressure; adherence will be recorded by the device.
A translational study on the beneficial effects of exercise on Huntington’s Disease symptomatology: The development of a mouse correlate of an ongoing patient trial.
There is a considerable body of evidence from studies on Parkinson’s and Alzheimer’s disease, that exercise can reduce symptom severity in patients. As a consequence, a study was designed to determine whether this was true for Huntington’s disease. Based on this human study, we have designed a comparable study in mouse models of the disease to see whether a model system of exercise intervention could be developed. A model system for mouse models of the disease would permit us to optimise human exercise programmes and maximise the potential of this intervention strategy.
Development of predictive models to identify patients to recruit for clinical trials
Differences in the expression and progression of symptoms in individuals with Huntington Disease presents a significant challenge for clinical trials that are aimed at early intervention. It is important that individuals recruited into clinical trials include those that show measureable symptoms that progress within a reasonably short time period. We have used data from REGISTRY to identify a cohort of individuals who show a robust increase in motor symptoms over relatively short period of time. The aim of the present study is to develop predictive models to identify those that will progress in this manner.
Author: Anthony Vaccarino
Phase IIa Study to determine safety and tolerability of SEN0014196 in HD patients
Inhibition of SirT1 (silencing information regulator T1) by the investigational compound SEN0014196 has been shown to increase the rate of clearance of mutant huntingtin, potentially leading to a disease-modifying effect. The compound has completed Phase I studies in healthy volunteers, and a short-term, pharmacodynamic study in HD patients is ongoing across 6 European study sites with the aim to ascertain target engagement. We now plan to conduct a randomized, double-blind, placebo-controlled multicentre Phase II trial with 140 patients across 18 study sites in three countries. The primary objective of this trial is to assess safety and tolerability of two fixed doses compared with placebo following treatment for 12 weeks. Secondary objectives include assessment of short-term clinical effects, modulation of pharmacodynamic markers and pharmacokinetics of SEN0014196 in HD patients.
Author: Goran Westerberg, Siena Biotech
Memantine treatment in the REGISTRY cohort
The aim of this retrospective study will be to explore potential efficacy signals in individuals with HD who use memantine. We will review availability of datasets from the REGISTRY, number of visits available (follow-up duration), and doses applied. Our primary endpoint will be rate of decline in HDRS total motor score. Secondary endpoints will be rate of decline in UHRDS cognitive score, UHDRS functional assessment and total functional capacity. We will review the feasibility to compare the clinical readouts available to a group of matched subjects from the REGISTRY cohort on no treatment with Memantine.
Author: Jan C. Frich
Depression in Huntington's disease, its treatment and associations
Depression is common and disabling in Huntington's disease. This project aims to look at rates of depression in the different sites and countries of the EHDN. We will also examine how commonly depression is treated in HD and the types of treatments, dosages and duration of treatment. Our final aim is to examine what factors influence the severity of depression in HD. These factors may include the CAG repeat length, type of HD, previous psychiatric history or a variety of other demographic factors. The study may thus shed light on treatment practices across Europe and identify risk factors for depression in HD.
Survey of Pharmaceutical interventions in JHD
There are no guidelines for the management of JHD. As a pre-requisite to further studies and future statements about the quality of care for JHD we want to know the current prescribing habits: two approaches have been used: interrogation of the REGISTRY data on medications which have prescribed and a survey of parent/carers in the UK. The results have been collected and a publication is planned.
Reliability and minimal detectable change of measures of participation, functional activities and impairments in individuals with Huntington’s disease
Huntington’s disease (HD) may be amenable to physiotherapy in terms of restoring or maintaining functional abilities. To date, there has been relatively little research to substantiate this suggestion. One of the first steps in developing intervention trials is to choose appropriate outcome measures. The purpose of this multi-centre project is to evaluate various potentially suitable measures. We will recruit a total of 80 patients with HD to undergo two assessments, with a one-week gap between, on a range of functional measures that have been chosen to reflect a range of impairments and activity limitations seen in people with HD.
Prescription habits in Huntington’s disease
An evidence-based treatment in Huntington’s disease (HD) is flawed by the lack of proven efficacy regarding pharmacological interventions presently used for symptomatic control. Disease modifying interventions are unavailable at this stage. Physicians or patients attitudes, biological factors or other variables may individually and regionally affect the way physician treat HD-related symptoms. The investigators aim at studying prescription habits in HD across the REGISTRY cohort: a first step comprehends the description of therapeutic habits in the cohort followed by the analysis of demographic and clinical variables and their contribution for the observed prescription patterns.