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Routes of administration | Oral |
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Chemical and physical data | |
Formula | C20H34D2O2 |
Molar mass | 310.517 g·mol−1 |
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Density | 0.88 g/cm3 |
Boiling point | 173–177 °C (343–351 °F) |
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Di-deuterated ethyl linoleate (also known as RT001, di-deuterated linoleic acid ethyl ester, 11,11-d2-ethyl linoleate, or ethyl 11,11-d2-linoleate)[1] is an experimental, orally-bioavailable synthetic deuterated polyunsaturated fatty acid (PUFA), a part of reinforced lipids. It is an isotopologue of linoleic acid, an essential omega-6 PUFA. The deuterated compound, while identical to natural linoleic acid except for the presence of deuterium, is resistant to lipid peroxidation which makes studies of its cell-protective properties worthwhile.
Further information: Isotope effect on lipid peroxidation |
Di-deuterated linoleic acid is recognized by cells as identical to the natural linoleic acid. But when taken up, it is converted into 13,13-d2-arachidonic acid, a heavy isotope version of arachidonic acid, that gets incorporated into lipid membranes. The deuterated compound resists the non-enzymatic lipid peroxidation (LPO) through isotope effect — a non-antioxidant based mechanism that protects mitochondrial, neuronal and other lipid membranes, thereby greatly reducing the levels of numerous LPO-derived toxic products such as reactive carbonyls.[2][3]
Di-deuterated linoleic acid (RT001) inhibits ferroptosis by stopping the autoxidation process through the kinetic isotope effect. The protective effect of D-PUFAs was verified in erastin- and RSL3-induced ferroptosis models, with demonstrated efficacy in various disease models, particularly neurodegenerative disorders and clinical trials of RT001 begun in 2018.[4]
A double-blind comparator-controlled Phase I/II clinical trial for Friedreich's ataxia, sponsored by Retrotope and Friedreich's Ataxia Research Alliance, was conducted to determine the safety profile and appropriate dosing for consequent trials.[5] RT001 was promptly absorbed and was found to be safe and tolerable over 28 days at the maximal dose of 9 g/day. It improved peak workload and peak oxygen consumption in the test group compared to the control group who received the equal doses of normal, non-deuterated ethyl linoleate.[6] Another randomised, double-blind, placebo-controlled clinical study began in 2019.[7]
An open-label clinical study for infantile neuroaxonal dystrophy evaluating long-term evaluation of efficacy, safety, tolerability, and pharmacokinetics of RT001, which, when taken with food, can protect the neuronal cells from degeneration, started in the Summer 2018.[8]
In 2017, the FDA granted RT001 orphan drug designation in the treatment of phospholipase 2G6-associated neurodegeneration (PLAN).[9]
In 2018, RT001 was given to a patient with amyotrophic lateral sclerosis (ALS) under a "compassionate use scheme".[10]
In 2020, the FDA granted orphan drug designation RT001 for the treatment of patients with progressive supranuclear palsy (PSP). PSP is a disease involving modification and dysfunction of tau protein; RT001’s mechanism of action both lowers lipid peroxidation and prevents mitochondrial cell death of neurons which is associated with disease onset and progression.[11]
RT001 has been shown to be effective in a model of Alzheimer's disease in mice.[12]