Developing treatments for cerebral small vessel disease: a scoping review of licensed interventions for potential repurposing

M Bath, Philip; P Phan, Elizabeth; Clay, Gwynneth; Dawson, Jesse; Malhotra, Paresh; Howard, Rob; Pal, Suvankar; M Wardlaw, Joanna; Quinn, Terry; Macleod, Malcolm

Abstract

Background
Cerebral small vessel disease (cSVD) is a progressive neurovascular-degenerative condition without specific treatment that causes lacunar stroke, most intracerebral haemorrhage, vascular cognitive impairment (VCI) and several neuropsychiatric conditions.

Objectives
To conduct a rapid multi-stage scoping review to identify licensed interventions that could be repurposed for testing in cSVD at phase-3.

Methods
First, we screened preclinical studies of potential relevance to cSVD and used a drug dictionary to identify studies of potential interventions. Separately, we screened clinical studies of relevance to cSVD and VCI. Following merging, we removed drugs that were unsuitable or impractical to assess long-term in the UK. We then performed mini-meta-analyses for shortlisted interventions assessing effects on cognition and scored these for their relevance to cSVD.

Results
The preclinical review created a long-list of 1,757 deduplicated interventions. Those that were not available in the UK, not expensive or impractical to administer long-term were merged with 62 interventions identified from 75 relevant clinical studies to create a medium-list of 52 interventions. Focussed literature review short-listed ten interventions for review by an independent scientific advisory group; they ranked three as most suitable for immediate testing: metformin, tadalafil and isosorbide mononitrate.

Conclusion
This rapid review identified three interventions that are suitable for testing in a late phase-3 (platform) trial involving patients with cSVD. The approach could be improved with partial automation, text mining and generative pre-trained transformer approaches which would help manage the large data volumes. Further, our data-driven approach could be combined with genetic or other mechanistic methods to further de-risk future trials.

Citation

M Bath, P., P Phan, E., Clay, G., Dawson, J., Malhotra, P., Howard, R., Pal, S., M Wardlaw, J., Quinn, T., & Macleod, M. (2024). Developing treatments for cerebral small vessel disease: a scoping review of licensed interventions for potential repurposing. F1000Research, 13, Article 1546. https://doi.org/10.12688/f1000research.157890.1

• Journal Article Type: Article
• Acceptance Date: Dec 20, 2024
• Online Publication Date: Dec 20, 2024
• Publication Date: Dec 20, 2024
• Deposit Date: Jan 2, 2025
• Publicly Available Date: Jan 3, 2025
• Journal: F1000Research
• Electronic ISSN: 2046-1402
• Publisher: F1000Research
• Peer Reviewed: Peer Reviewed
• Volume: 13
• Article Number: 1546
• DOI: https://doi.org/10.12688/f1000research.157890.1
• Keywords: cerebral small vessel disease; isosorbide mononitrate, metformin, tadalafil, treatment, repurposing
• Public URL: https://nottingham-repository.worktribe.com/output/43359430
• Publisher URL: https://f1000research.com/articles/13-1546/v1
• Additional Information: Grant Information: The author(s) declared that no grants were involved in supporting this work; Copyright: This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.