A Systematic Approach to Identify Neuroprotective Interventions for Motor Neuron Disease

Charis Wong, Jenna Gregory, Jing Liao, Kieren Egan, Hanna M. Vesterinen, Aimal Ahmad Khan, Maarij Anwar, Caitlin Beagan, Fraser Brown, John Cafferkey, Alessandra Cardinali, Jane Yi Chiam, Claire Chiang, Victoria Collins, Joyce Dormido, Elizabeth Elliott, Peter Foley, Yu Cheng Foo, Lily Fulton-Humble, Angus B. GaneStella Glasmacher, Áine Heffernan, Kiran Jayaprakash, Nimesh Jayasuriya, Amina Kaddouri, Jamie Kiernan, Gavin Langlands, Danielle Leighton, Jiaming Liu, James Lyon, Arpan R. Mehta, Alyssa Meng, Vivienne Nguyen, Kyu Hyung Park, Suzanne Quigley, Yousuf Rashid, Andrea Salzinger, Bethany Shiell, Ankur Singh, Tim Soane, Alexandra Thompson, Olaf Tomala, Fergal M. Waldron, Bhuvaneish T. Selvaraj, Jeremy Chataway, Robert Swingler, Peter Connick, Suvankar Pal, Siddharthan Chandran, Malcolm R. Macleod

Research output: Working paperPreprint

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Background: Motor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial.

Objectives: Here we detail a systematic, structured, and unbiased evidence-based approach to guide selection of drugs for clinical evaluation in the Motor Neuron Disease – Systematic Multi-arm Adaptive Randomised Trial (MND-SMART, clinicaltrials.gov registration number: NCT04302870), an adaptive platform trial.

Methods: We conducted a two-stage systematic review and meta-analysis to identify potential neuroprotective interventions. In stage one, we identified drugs from the clinical literature tested in at least one study in MND or in two or more cognate diseases with potential shared pivotal pathways (Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, or multiple sclerosis). We scored and ranked 66 drugs thus identified using a predefined framework evaluating safety, efficacy, study size and quality of studies. In stage two, we conducted a systematic review of the MND preclinical literature describing efficacy of these drugs in animal models, multicellular eukaryotic models and human induced pluripotent stem cell studies; 17 of these drugs were reported to improve survival in at least one preclinical study. An expert panel then shortlisted and ranked 22 drugs considering stage one and stage two findings, mechanistic plausibility, safety and tolerability, findings from previous clinical trials in MND, and feasibility for use in clinical trials.

Results: Based on this process, the panel selected memantine and trazodone for testing in MND-SMART.

Discussion: For future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human induced pluripotent stem cells.
Original languageEnglish
Publication statusPublished - 13 Apr 2022

Bibliographical note

Funding Statement
For the purpose of open access, the authors have applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising from this submission. MND-SMART is funded by grants from MND Scotland, My Name'5 Doddie Foundation (DOD/14/15) and specific donations to the Euan MacDonald Centre. The Chandran lab is supported by the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. E.E is a clinical academic fellow jointly funded by MND Scotland (MNDS) and the Chief Scientist Office (CSO) (217ARF R45951). A.R.M. was a Lady Edith Wolfson Clinical Fellow, jointly funded by the Medical Research Council (MRC) and the Motor Neurone Disease Association (MR/R001162/1). A.Salzinger is funded by Marie Sklodowska-Curie actions Innovative Training Network (ITN). B.T.S is funded by Rowling fellowship.


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