Pyrimethamine significantly lowers cerebrospinal fluid Cu/Zn superoxide dismutase in amyotrophic lateral sclerosis patients with SOD1 mutations

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Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disease of upper and lower motor neurons causing progressive weakness of limbs, swallowing, and breathing, resulting in death within 3 to 5 years.1 The cause is uncertain in most patients but in approximately 10% of patients, the disease is familial.2 Since 1993, mutations in > 36 genes have been associated with causing ALS.3 Mutations in the cytoplasmic free radical scavenging enzyme Cu/Zn superoxide dismutase (SOD1) account for 3 to 23% of familial cases (familial ALS [fALS]) and 1 to 3% of sporadic cases.2 Transgenic mice overexpressing mutant human SOD1 develop a progressive motor neuron degenerative disease mimicking human ALS, whereas knockout of the murine SOD1 gene does not result in a similar phenotype.5 These findings combined with the observation that there is no relationship between the level of SOD1 activity and patient prognosis suggest that there is a toxic gain of function for the SOD1 mutant molecule with a predilection for the motor system.3 Reducing the content of mutant SOD1 attenuates disease progression proportionate to the suppression of mutant protein using interfering RNA.6 Collective evidence supports the hypothesis that lowering the total SOD1 protein content may be beneficial and influence the disease course in ALS. Attempts to lower SOD1 expression are currently being pursued using antisense oligonucleotides7 and by increasing consumption of SOD1 by activating heat shock proteins8 via the drug arimoclomol. Using U.S. Food and Drug Administration (FDA)‐approved drugs that also have the ability to lower SOD1 content is another approach.9 Monitoring the CSF SOD1 protein level has been identified as a reliable biomarker for SOD1 reduction within the anterior horn cell in transgenic rats with SOD1‐mediated ALS.7 In humans with ALS and SOD1 mutations, CSF SOD1 shows minimal variability and is a reliable biomarker for SOD1‐mediated fALS.10 We have previously reported that oral treatment with pyrimethamine in ALS patients with a mutation in SOD1 resulted in a reduction of SOD1 levels in peripheral blood leukocytes and, in both patients studied, a reduction in SOD1 protein content and activity in the cerebrospinal fluid (CSF).9 We now report a phase 1/2 study whose primary aim was to determine whether pyrimethamine lowers SOD1 in the CSF in ALS patients with a wide variety of SOD1 mutations and over a longer period of time, with a secondary aim to establish safety and tolerability.

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