M102 activates both NRF2 and HSF1 transcription factor pathways and is neuroprotective in cell and animal models of amyotrophic lateral sclerosis

Keerie, AF; Martins, RR; Allen, CF; Bowden, K; Al Mashhadi, S; Marlow, T; Myszczynska, M; Thakur, N; Beal, SN; Shaw, A; Suresh, S; McKinnon, SN; Cooper-Knock, J; West, RJH; Bonsall, S; Daniel, A; Wells, T; Kumar, V; Ellis, BCS; Higgins, M; Dinkova-Kostova, AT; Shelkovnikova, TA; Kalfus, IN; Shan, N; Shaw, PJ; Ferraiuolo, L; Mead, RJ

Journal article

M102 activates both NRF2 and HSF1 transcription factor pathways and is neuroprotective in cell and animal models of amyotrophic lateral sclerosis

Abstract:: M102 is a central nervous system (CNS) penetrant small molecule electrophile which activates in vivo the NF-E2 p45-related factor 2-antioxidant response element (NRF2-ARE) pathway, as well as transcription of heat-shock element (HSE) associated genes. In the TDP-43Q331K transgenic mouse model of ALS dosed subcutaneously at 5 mg/kg OD or 2.5 mg/kg BD with M102, significant improvements in compound muscle action potential (CMAP) amplitude of hind limb muscles and gait parameters were observed at 6 months of age, with associated target engagement. An oral dose response study of M102 in SOD1G93A transgenic mice showed a dose-dependent improvement in CMAP of hindlimb muscles which correlated with preservation of lumbar spinal motor neurons at the same time point. These data enabled prediction of human efficacious exposures and doses, which were well within the safety margin predicted from Good Laboratory Practice (GLP) toxicology studies. A parallel program of work in vitro showed that M102 rescued motor neuron survival in co-culture with patient-derived astrocytes from sporadic, C9orf72 and SOD1 ALS cases. Markers of oxidative stress, as well as indices of TDP-43 proteinopathy were also reduced by exposure to M102 in these in vitro models. This comprehensive package of preclinical efficacy data across two mouse models as well as patient-derived astrocyte toxicity assays, provides a strong rationale for clinical evaluation of M102 in ALS patients. Combined with the development of target engagement biomarkers and the completed preclinical toxicology package, a clear translational pathway to testing in ALS patients has been developed.

Publication status:: Published

Peer review status:: Peer reviewed

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APA Style

Keerie, A. F., Martins, R. R., Allen, C. F., Bowden, K., Al Mashhadi, S., Marlow, T., Myszczynska, M., Thakur, N., Beal, S. N., Shaw, A., Suresh, S., McKinnon, S. N., Cooper-Knock, J., West, R. J. H., Bonsall, S., Daniel, A., Wells, T., Kumar, V., Ellis, B. C. S., … Mead, R. J. (2025). M102 activates both NRF2 and HSF1 transcription factor pathways and is neuroprotective in cell and animal models of amyotrophic lateral sclerosis. Molecular Neurodegeneration, 20(1), 118–118.

MLA Style

Keerie, AF, et al. “M102 Activates Both NRF2 and HSF1 Transcription Factor Pathways and Is Neuroprotective in Cell and Animal Models of Amyotrophic Lateral Sclerosis.” Molecular Neurodegeneration, vol. 20, no. 1, 2025, pp. 118–18.

Chicago Style

Keerie, AF, RR Martins, CF Allen, et al. 2025. “M102 Activates Both NRF2 and HSF1 Transcription Factor Pathways and Is Neuroprotective in Cell and Animal Models of Amyotrophic Lateral Sclerosis.” Molecular Neurodegeneration 20 (1): 118–18.
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