Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus.
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Wong Charis, Gregory Jenna M, Liao Jing, Egan Kieren, Vesterinen Hanna M, Ahmad Khan Aimal, Anwar Maarij, Beagan Caitlin, Brown Fraser S, Cafferkey John, Cardinali Alessandra, Chiam Jane Yi, Chiang Claire, Collins Victoria, Dormido Joyce, Elliott Elizabeth, Foley Peter, Foo Yu Cheng, Fulton-Humble Lily, Gane Angus B, Glasmacher Stella A, Heffernan Áine, Jayaprakash Kiran, Jayasuriya Nimesh, Kaddouri Amina, Kiernan Jamie, Langlands Gavin, Leighton D, Liu Jiaming, Lyon James, Mehta Arpan R, Meng Alyssa, Nguyen Vivienne, Park Na Hyun, Quigley Suzanne, Rashid Yousuf, Salzinger Andrea, Shiell Bethany, Singh Ankur, Soane Tim, Thompson Alexandra, Tomala Olaf, Waldron Fergal M, Selvaraj Bhuvaneish T, Chataway Jeremy, Swingler Robert, Connick Peter, Pal Suvankar, Chandran Siddharthan, Macleod Malcolm
Аннотация
METHODS: We conducted a two-stage systematic review to identify potential neuroprotective interventions. First, we reviewed clinical studies in MND, Alzheimer's disease, Huntington's disease, Parkinson's disease and multiple sclerosis, identifying drugs described in at least one MND publication or publications in two or more other diseases. We scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, we reviewed efficacy of drugs in MND animal models, multicellular eukaryotic models and human induced pluripotent stem cell (iPSC) studies. An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in MND-SMART.
RESULTS: From the clinical review, we identified 595 interventions. 66 drugs met our drug/disease logic. Of these, 22 drugs with supportive clinical and preclinical evidence were shortlisted at round 1. Seven drugs proceeded to round 2. The panel reached a consensus to evaluate memantine and trazodone as the first two arms of 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 iPSCs.