Publications by authors named "G Bernard Landwehrmeyer"

141 Publications

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

[Disease-modifying treatment approaches in Huntington disease : Past and future].

Nervenarzt 2021 Nov 11. Epub 2021 Nov 11.

Klinik für Neurologie, Universität Ulm, Oberer Eselsberg 45/1, 89081, Ulm, Deutschland.

Huntington disease (HD) is the most frequent monogenetic neurodegenerative disease and can be unequivocally diagnosed even in the preclinical stage, at least in all individuals in whom the CAG expansion mutation in the huntingtin gene (HTT) is in the range of full penetrance. Therefore, important preconditions for an intervention early in the disease process are met, rendering modification of the course of the disease in a clinically meaningful way possible. In this respect, HD can be viewed as a model disorder for exploring neuroprotective treatment approaches. In the past emphasis was placed on the compensation of a suspected neurotransmitter deficit (GABA) analogous to Parkinson's disease and on classical neuroprotective strategies to influence hypothetical common pathways in neurodegenerative diseases (e.g., excitotoxicity, mitochondrial dysfunction, oxidative stress). With the discovery of the causative HTT mutation in 1993, therapeutic research increasingly focused on intervening as proximally as possible in the chain of pathophysiological events. Currently, an important point of intervention is the HTT mRNA with the aim of reducing the continued production of mutant huntingtin gene products and thus relieving the body of their detrimental actions. To this end, various treatment modalities (single-stranded DNA and RNA, divalent RNA and zinc finger repressor complexes, orally available splice modulators) were developed and are currently in clinical trials (phases I-III) or in late stages of preclinical development. In addition, there is the notion that it may be possible to modify the length of the somatically unstable CAG mutation, i.e. its increase in the brain during the lifetime, thereby slowing the progression of HD.
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http://dx.doi.org/10.1007/s00115-021-01224-8DOI Listing
November 2021

Study Protocol for the Development of a European eHealth Platform to Improve Quality of Life in Individuals With Huntington's Disease and Their Partners (HD-eHelp Study): A User-Centered Design Approach.

Front Neurol 2021 13;12:719460. Epub 2021 Sep 13.

Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, Netherlands.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease that affects the quality of life (QoL) of HD gene expansion carriers (HDGECs) and their partners. Although HD expertise centers have been emerging across Europe, there are still some important barriers to care provision for those affected by this rare disease, including transportation costs, geographic distance of centers, and availability/accessibility of these services in general. eHealth seems promising in overcoming these barriers, yet research on eHealth in HD is limited and fails to use telehealth services specifically designed to fit the perspectives and expectations of HDGECs and their families. In the European HD-eHelp study, we aim to capture the needs and wishes of HDGECs, partners of HDGECs, and health care providers (HCPs) in order to develop a multinational eHealth platform targeting QoL of both HDGECs and partners at home. We will employ a participatory user-centered design (UCD) approach, which focusses on an in-depth understanding of the end-users' needs and their contexts. Premanifest and manifest adult HDGECs ( = 76), partners of HDGECs ( = 76), and HCPs ( = 76) will be involved as end-users in all three phases of the research and design process: (1) Exploration and mapping of the end-users' needs, experiences and wishes; (2) Development of concepts in collaboration with end-users to ensure desirability; (3) Detailing of final prototype with quick review rounds by end-users to create a positive user-experience. This study will be conducted in the Netherlands, Germany, Czech Republic, Italy, and Ireland to develop and test a multilingual platform that is suitable in different healthcare systems and cultural contexts. Following the principles of UCD, an innovative European eHealth platform will be developed that addresses the needs and wishes of HDGECs, partners and HCPs. This allows for high-quality, tailored care to be moved partially into the participants' home, thereby circumventing some barriers in current HD care provision. By actively involving end-users in all design decisions, the platform will be tailored to the end-users' unique requirements, which can be considered pivotal in eHealth services for a disease as complex and rare as HD.
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http://dx.doi.org/10.3389/fneur.2021.719460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476232PMC
September 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

HAP40 protein levels are huntingtin-dependent and decrease in Huntington disease.

Neurobiol Dis 2021 10 12;158:105476. Epub 2021 Aug 12.

Department of Gene Therapy, Ulm University, 89081 Ulm, Germany. Electronic address:

The huntingtin-associated protein 40 (HAP40) is an abundant interactor of huntingtin (HTT). In complexes of these proteins, HAP40 tightly binds to HTT in a cleft formed by two larger domains rich in HEAT repeats, and a smaller bridge domain connecting the two. We show that HAP40 steady-state protein levels are directly dependent on HTT (both normal and mutant HTT) and that HAP40 is strongly stabilized by the interaction with HTT resulting in an at least 5-fold increase in HAP40's half-life when bound to HTT. Cellular HAP40 protein levels were reduced in primary fibroblasts and lymphoblasts of Huntington Disease (HD) patients and in brain tissue of a full-length HTT mouse model of HD, concomitant with decreased soluble HTT levels in these cell types. This data and our previous demonstration of coevolution between HTT and HAP40 and evolutionary conservation of their interaction suggest that HAP40 is an obligate interaction partner of HTT. Our observation of reduced HAP40 levels in HD invites further studies, whether HAP40 loss-of-function contributes to the pathophysiology of HD.
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http://dx.doi.org/10.1016/j.nbd.2021.105476DOI Listing
October 2021
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