Abstract
The blood–brain barrier permeant, copper-containing compound, CuII(atsm), has successfully progressed from fundamental research outcomes in the laboratory through to phase 2/3 clinical assessment in patients with the highly aggressive and fatal neurodegenerative condition of amyotrophic lateral sclerosis (ALS). The most compelling outcomes to date to indicate potential for disease-modification have come from pre-clinical studies utilising mouse models that involve transgenic expression of mutated superoxide dismutase 1 (SOD1). Mutant SOD1 mice provide a very robust mammalian model of ALS with high validity, but mutations in SOD1 account for only a small percentage of ALS cases in the clinic, with the preponderant amount of cases being sporadic and of unknown aetiology. As per other putative drugs for ALS developed and tested primarily in mutant SOD1 mice, this raises important questions about the pertinence of CuII(atsm) to broader clinical translation. This review highlights some of the challenges associated with the clinical translation of new treatment options for ALS. It then provides a brief account of pre-clinical outcomes for CuII(atsm) in SOD1 mouse models of ALS, followed by an outline of additional studies which report positive outcomes for CuII(atsm) when assessed in cell and mouse models of neurodegeneration which do not involve mutant SOD1. Clinical evidence for CuII(atsm) selectively targeting affected regions of the CNS in patients is also presented. Overall, this review summarises the existing evidence which indicates why clinical relevance of CuII(atsm) likely extends beyond the context of cases of ALS caused by mutant SOD1.
Highlights
The blood–brain barrier permeant, copper-containing compound, CuII, has successfully progressed from fundamental research outcomes in the laboratory through to phase 2/3 clinical assessment in patients with the highly aggressive and fatal neurodegenerative condition of amyotrophic lateral sclerosis (ALS)
Treatment with mitochondrial toxins such as paraquat can induce the formation of a diverse array of features of TDP-43 pathology which are evident in ALS, including nuclear depletion, accumulation of C-terminal fragments, and accumulation in stress granules [78]
None of the in vitro and cell-free assays utilised when assessing the anti-ferroptotic potential of CuII involved mutant superoxide dismutase 1 (SOD1) [82]
Summary
Amyotrophic lateral sclerosis (ALS) is a ruinous progressive neurodegenerative disorder which selectively affects motor neurones within the central nervous system (CNS) [1]. Diagnosis relies heavily on the manifestation of clinical symptoms that arise and subsequently worsen as the number of functional motor neurones declines. The first ALS drug approved by the FDA in 1995 and current first-line treatment worldwide, is a glutamate antagonist that mitigates neuronal degeneration triggered by glutamate excitotoxicity [4]. The second FDA approved treatment for ALS in 2017, is a potent free-radical scavenger and protects cells against oxidative stress. The latter is a newly introduced neuroprotective agent yet to gain widespread regulatory approval [5,6]. While there is no cure for ALS, numerous potential therapeutic drugs including masitinib [7] and methylcobalamin [8], and therapeutic methods including stem cell [9] and gene therapies [10] are currently being investigated in pre-clinical studies and clinical trials
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