CuATSM is not tolerated at a high dose in a mice model of ALS

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It has been known for several decades that Cu(II)ATSM belongs to a class of molecules with anti-inflammatory and antioxidant effects. enter image description here By Jynto via Wikipedia

In 2016 the synthetic copper-containing compound, CuATSM, was proposed as yet another drug candidate for the treatment of amyotrophic lateral sclerosis (ALS).

Scientists in the Beckman group in Australia, were studying transgenic mice with a double mutation, SOD1 and CCS. They decided to try the compound Cu(II)ATSM in a transgenic mouse, which is unable to stand up at the end of its short lifespan.

The researchers dissolved Cu(II)ATSM in dimethylsulfoxide and spread it on the neck of the little animal, where it was quickly absorbed through the skin. A few hours later, the mouse was again able to move.

The researchers shown that with continuous treatment, the mice can live 18 months, that is to say almost half of the average life of non-transgenic laboratory mice, instead of dying after three months.

The media ans social networks were, as usual, dithyrambic about Cu(II)ATSM.

This 2016 article had an unusual style, for example it nearly suggested that it deserved the Prize4Life.

However, scientific publications, here and there from 2011 and 2013 had already shown the benefits of Cu(II)ATSM for ALS (1 ). In fact Cu(II)ATSM belongs to a class of molecules that have been identified very early as being useful in SOD1-related diseases.

« I'm not sure that this will have an impact on sporadic diseases » said Lucie Bruijn of the ALS Association. Bruijn noted that Cu(II)ATSM-based therapy worked best in mice overexpressing both mSOD1 and CCS, and weakly in animals overexpressing only mSOD1.

The same was true of Jeffrey Rothstein, another prominent ALS scientist.

Beckman said that if Cu(II)ATSM proved to be safe and effective, he considered that it could become a prophylactic drug that a person with a SOD1 mutation could take for decades.

Unscrupulous people then illegally sold on Internet the complex (or a counterfeit compound) to desperate people.

In September 2019, Collaborative Medicinal Development, a company of Cthulhu (sic) Ventures LLC started a clinical trial (NCT04082832) where Cu(II)ATSM is administrated orally as a suspension powder. As results obtained from Phase I clinical trials observed that 8/14 patients receiving the highest dose of CuATSM (> 72 mg/day) exhibited reversible transaminitis (an indicator of liver dysfunction), consequently leading to the recommended Phase II dose set at 72 mg/day (2 bottles) on an empty stomach each day before breakfast. The clinical trial end date was supposed to be December 2020, but as of mid-2021 for obvious reason, no results are yet released.. There are two other clinical trials at Macquarie University.

In this new study Australian scientists assessed CuATSM in SOD1 G93A mice (an ALS animal model), treating at 100 mg/kg/day by gavage, starting at 70 days of age. https://www.nature.com/articles/s41598-021-98317-w

This dose in this specific model has not been assessed previously.

The authors reported that a subset of mice initially administered CuATSM exhibited signs of clinical toxicity, that necessitated euthanasia in extremis after 3-51 days of treatment. It is unclear why only a subset of mice exhibited signs of toxicity. Of the seven CuATSM affected mice, the authors were able to obtain plasma samples for two, which subsequently showed elevated alanine aminotransferase (ALT) levels, which is consistent with what happened to the Phase I patients.

Following a 1-week washout period, the remaining mice resumed treatment at the reduced dose of 60 mg/kg/day.

At this revised dose, treatment with CuATSM slowed disease progression and increased survival relative to vehicle-treated littermates.

This work provides evidence that CuATSM produces positive disease-modifying outcomes in high copy SOD1 G93A mice, which might not mean much for humans, an provides an upper limit for the dose.

This is however an unlikely high dose, as when it is converted to the dose for a human weighting 100kg (220lbs), it means a daily dose of 6.7 mg/kg/day, thus 670 mg per day for this 100kg (220lbs) person.

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