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A Novel Huntington's Disease Assessment Platform to Support Future Drug Discovery and Development.

ABSTRACT: Huntington's disease (HD) is a lethal neurodegenerative disorder without efficient therapeutic options. The inefficient translation from preclinical and clinical research into clinical use is mainly attributed to the lack of (i) understanding of disease initiation, progression, and involved molecular mechanisms; (ii) knowledge of the possible HD target space and general data awareness; (iii) detailed characterizations of available disease models; (iv) better suitable models; and (v) reliable and sensitive biomarkers. To generate robust HD-like symptoms in a mouse model, the neomycin resistance cassette was excised from zQ175 mice, generating a new line: zQ175Δneo. We entirely describe the dynamics of behavioral, neuropathological, and immunohistological changes from 15-57 weeks of age. Specifically, zQ175Δneo mice showed early astrogliosis from 15 weeks; growth retardation, body weight loss, and anxiety-like behaviors from 29 weeks; motor deficits and reduced muscular strength from 36 weeks; and finally slight microgliosis at 57 weeks of age. Additionally, we collected the entire bioactivity network of small-molecule HD modulators in a multitarget dataset (HD_MDS). Hereby, we uncovered 358 unique compounds addressing over 80 different pharmacological targets and pathways. Our data will support future drug discovery approaches and may serve as useful assessment platform for drug discovery and development against HD.

SUBMITTER: Wu J

PROVIDER: S-EPMC9740291 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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A Novel Huntington's Disease Assessment Platform to Support Future Drug Discovery and Development.

Wu Jingyun J Möhle Luisa L Brüning Thomas T Eiriz Iván I Rafehi Muhammad M Stefan Katja K Stefan Sven Marcel SM Pahnke Jens J

International journal of molecular sciences 20221125 23

Huntington's disease (HD) is a lethal neurodegenerative disorder without efficient therapeutic options. The inefficient translation from preclinical and clinical research into clinical use is mainly attributed to the lack of (i) understanding of disease initiation, progression, and involved molecular mechanisms; (ii) knowledge of the possible HD target space and general data awareness; (iii) detailed characterizations of available disease models; (iv) better suitable models; and (v) reliable and ...[more]

PMID: 36499090

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Project description:BackgroundNeglected tropical diseases (NTDs) are closely related to poverty and affect over a billion people in developing countries. The unmet treatment needs cause high mortality and disability thereby imposing a huge burden with severe social and economic consequences. Although coordinated by the World Health Organization, various philanthropic organizations, national governments and the pharmaceutical industry have been making efforts in improving the situation, the control of NTDs is still inadequate and extremely difficult today. The lack of safe, effective and affordable medicines is a key contributing factor. This paper reviews the recent advances and some of the challenges that we are facing in the fight against NTDs.Main bodyIn recent years, a number of innovations have demonstrated propensity to promote drug discovery and development for NTDs. Implementation of multilateral collaborations leads to continued efforts and plays a crucial role in drug discovery. Proactive approaches and advanced technologies are urgently needed in drug innovation for NTDs. However, the control and elimination of NTDs remain a formidable task as it requires persistent international cooperation to make sustainable progresses for a long period of time. Some currently employed strategies were proposed and verified to be successful, which involve both mechanisms of 'Push' which aims at cutting the cost of research and development for industry and 'Pull' which aims at increasing market attractiveness. Coupled to this effort should be the exercise of shared responsibility globally to reduce risks, overcome obstacles and maximize benefits. Since NTDs are closely associated with poverty, it is absolutely essential that the stakeholders take concerted and long-term measures to meet multifaceted challenges by alleviating extreme poverty, strengthening social intervention, adapting climate changes, providing effective monitoring and ensuring timely delivery.ConclusionsThe ongoing endeavor at the global scale will ultimately benefit the patients, the countries they are living and, hopefully, the manufacturers who provide new preventive, diagnostic and therapeutic products.

Dataset Information

A Novel Huntington's Disease Assessment Platform to Support Future Drug Discovery and Development.

Publications

A Novel Huntington's Disease Assessment Platform to Support Future Drug Discovery and Development.

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