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In the TDP-43 Q331K 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 SOD1 G93A 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. 31:T5dd,GLP general toxicology studies in rats and NHPs were conducted at WuXi AppTec (Suzhou, China). The protocol and any amendments or procedures involving the care or use of animals in this study were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) prior to the initiation of such procedures. A staff veterinarian monitored the study for animal welfare issues. All mouse studies were carried out under a UK Home Office project license (PP3890603) ethically reviewed and approved by the local ethics committee (University of Sheffield Animal Welfare and Ethical Review Body). All individuals held the appropriate UK Home Office personal license and had appropriate training for procedures. All work was carried out under the terms of the UK Animals (Scientific Procedures) Act 1986 and animals were housed and maintained in line with Home Office Code of Practice for House and Care of Animals Used in Scientific Procedures. All procedures were reviewed by the University of Sheffield. Human CNS post-mortem tissue was obtained from the Sheffield Brain Tissue Bank with Research Ethics Committee approval (Sheffield Brain Bank –SBB-, Ethics Committee reference 08/MRE00/103). Human CSF was obtained from the University of Sheffield Biorepository with Research Ethics Committee approval number STH16573. Fibroblasts were collected from skin biopsies donated by ALS patients and controls with informed consent (Ethical Committee approval references: 12/YH/0330; 16/LO/2136).25:[[["$","script","0",{"type":"application/ld+json","dangerouslySetInnerHTML":{"__html":"{\"@context\":\"https://schema.org\",\"@type\":\"CollectionPage\",\"name\":\"HSF1 Activator: modality Research & Clinical Takeaways\",\"description\":\"Explore peer-reviewed papers on HSF1 Activator (modality). Clinician-written summaries and actionable practice insights. 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