The combination of glycolic acid and D-lactate delays disease progression in SOD-1 ALS mice, partially rescues lethality in iTBPHpkk(108354) Drosophila and shows promising results in experimental treatments in two ALS patients.

Amyotrophic Lateral Sclerosis is the most common motor neuron disease. It is incurable and, at the time of this study, only two treatments with a limited therapeutical effect are available: riluzole and edavarone (not in Europe). These treatments have been shown to delay the progression of the disease by a maximum of 10%. We recently showed that glycolic acid (GA) and D-lactate (DL) are able to revert some of the phenotypes observed in iPSC-derived neurons from FUS- and SOD-1-ALS patients in vitro. Here we show that the administration of GA and DL is able to delay the progression of the disease in SOD1-G93A mice and protect spinal motor neurons against neuronal death. Interestingly, GA and DL were also able to attenuate the lethality in the TBPH silencing strain (iTBPHpkk(108354)) in Drosophila, showing a conserved role between species. Based on these results, we performed two experimental treatments in ALS patients carrying a disease-causing mutation in FUS and SOD-1 respectively. As GA and DL have been shown to be toxic (kidney stones, altered hepatic metabolism) and even lethal above certain doses in humans, we developed and used a specific formulation containing L-alanine to avoid these side effects. Our results show that, together with L-alanine as supportive treatment, GA and DL were well tolerated by the patients. Although promising, well designed and placebo-controlled clinical trials need to be performed in order to confirm the good tolerability and the therapeutic effects in ALS patients.