Cu^II(atsm) significantly decreases microglial reactivity in patients with sporadic amyotrophic lateral sclerosis

Dear Prof. T. S. Jacques: The copper compound CuII(atsm) (a.k.a. CuATSM) is neuroprotective in diverse mouse models of neurodegenerative disease and has progressed to clinical trials as a novel drug candidate. The first assessment of central nervous system tissue from amyotrophic lateral sclerosis (ALS) patients treated with CuII(atsm) was recently reported in Neuropathology and Applied Neurobiology [1]. The paper presented histological results for motor cortex and spinal cord samples from 12 cases of ALS. All patients had been treated with riluzole, and six had additionally been treated with CuII(atsm) (NCT04082832). Three cases involved SOD1 mutations and were segregated from analyses such that sample size for sporadic cases was four on riluzole and five on CuII(atsm) plus riluzole. Thus, only very robust findings were likely to reach significance in this small cohort. Considering this, it is notable that the microglial marker Iba1 was reported as the only parameter out of 10 quantified that yielded a statistically significant result for a CuII(atsm) treatment effect; ALS patients on CuII(atsm) displayed a 64% decrease in spinal cord Iba1 immunoreactivity (p = 0.03). Reactive microglia are implicated as a cause of neuronal death in ALS and as a potential therapeutic target [2]. Prior assessment of 59 ALS cases showed the abundance of reactive microglia correlates with the rate of disease progression [3]. Given that microglial activation is a significant pathological feature of ALS, this result renders false the running title of Yang et al. (‘CuATSM does not alleviate ALS pathology in patients’) and the concluding statement that there was no significant pathological benefit associated with CuII(atsm). Treatment with CuII(atsm) decreases Iba1 immunoreactivity in ALS mouse models and provides robust alleviation of symptoms and increased survival [4]. We propose that this result, reproduced from pre-clinical in vivo studies through to clinical observation, should be emphasised as a landmark result for ALS drug development and CuII(atsm). While other results reported in Yang et al. did not reach significance, some potentially impactful trends nevertheless emerged. For example, although the generalised burden of phosphorylated TDP-43 (referred to as glial) was relatively unchanged, the reported number of neuronal cells with TDP-43 pathology was >80% lower in patients who had received CuII(atsm) [1]. TDP-43 pathology is a major histological feature of ALS and precedent exists for CuII(atsm) lowering TDP-43 pathology in vivo [4]. A similar trend was observed for neuronal p62 which was decreased 40% to 70% by treatment with CuII(atsm). Neuronal TDP-43 pathology and neuronal p62 burden are both implicated as significant correlates of neuronal loss and disease duration in ALS [5]. But despite these trends for alleviated pathology specifically in neurons, Yang et al. focused heavily on the unquantified appearance of p62-positive astrocytes in motor cortex from CuII(atsm)-treated cases which was not accompanied by a change in overall p62 glial burden. Collectively, the significant decrease in microglial activation accompanied by strong trends for lower neuronal TDP-43 and p62 pathology indicates that CuII(atsm) may well be associated with neuroprotective effects in ALS patients. Collaborative Medicinal Development LLC has licensed intellectual property related to this subject from the University of Melbourne. P.J.C. is an unpaid consultant for Collaborative Medicinal Development LLC. None of the authors has a financial conflict of interest to declare. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/nan.12938.