Mouse models of amyotrophic lateral sclerosis (ALS) enable testing of novel therapeutic interventions. However, treatments that have extended survival in mice have often failed to translate into human benefit in clinical trials. Compound muscle action potentials (CMAPs) are a simple neurophysiological test that measures the summation of muscle fiber depolarization in response to maximal stimulation of the innervating nerve. CMAPs can be measured in both mice and humans and decline with motor axon loss in ALS, making them a potential translational read-out of disease progression. We assessed the translational potential of CMAPs and ascertained time points when human and mouse data aligned most closely. We extracted data from 18 human studies and compared with results generated from SOD1G93A and control mice at different ages across different muscles. The relative CMAP amplitude difference between SOD1G93A and control mice in tibialis anterior (TA) and gastrocnemius muscles at 70 days of age was most similar to the relative difference between baseline ALS patient CMAP measurements and healthy controls in the abductor pollicis brevis (APB) muscle. We also found that the relative decline in SOD1G93A TA CMAP amplitude between 70 and 140 days was similar to that observed in 12 month human longitudinal studies in APB. Our findings suggest CMAP amplitudes can provide a "translational window", from which to make comparisons between the SOD1G93A model and human ALS patients. CMAPs are easy to perform and can help determine the most clinically relevant starting/end points for preclinical studies and provide a basis for predicting potential clinical effect sizes.
Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motor neurons in the central nervous system (CNS). Mutations in the metalloenzyme SOD1 are associated with inherited forms of ALS and cause a toxic gain of function thought to be mediated by dimer destabilization and misfolding. SOD1 binds two Cu and two Zn ions in its homodimeric form. We have applied native ambient mass spectrometry imaging to visualize the spatial distributions of intact metal-bound SOD1
Abstract: M102 is a central nervous system (CNS) penetrant small molecule electrophile which activates in vivo the NFE2-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 5mg/kg OD or 2.5mg/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 the 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 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.
Abstract Transgenic mouse models of amyotrophic lateral sclerosis, such as the widely used SOD1 G93A mouse, enable investigation of disease mechanisms and testing of novel therapeutic interventions. However, treatments that have been considered successful in mice have often failed to translate into human benefit in clinical trials, particularly when relying on the so-called ‘survival’ read-out. Compound muscle action potentials (CMAPs), are a simple neurophysiological test that measures the summation of muscle fibre depolarisation in response to maximal stimulation of the innervating nerve. CMAPs can be measured in both mice and humans and decline with motor axon loss in ALS, making them a potential translational read-out of disease progression which could help bridge the preclinical and clinical divide. Herein we assess the translational potential of CMAPs and ascertain at what time points human and mouse data aligned most closely. We extracted data from 18 human studies and compared with results generated from SOD1 G93A and control mice at different ages across different muscles. We found that the relative CMAP amplitude difference between SOD1 G93A and control mice in tibialis anterior and gastrocnemius muscles at 70 days of age was most similar to the relative difference between baseline ALS patient CMAP measurements and healthy controls in the abductor pollicis brevis (APB) muscle. We also found that the relative decline in SOD1 G93A tibialis anterior CMAP amplitude between 70-140 days was similar to that observed in 12 month human longitudinal studies in APB. Our findings suggest CMAP amplitudes can provide a ‘translational window’, from which to make comparisons between the SOD1 G93A model and human ALS patients. CMAPs are easy to perform and can help determine the most clinically relevant starting/end points for preclinical studies and provide a basis for predicting potential clinical effect sizes.
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