Deulinoleate ethyl explained

Deulinoleate ethyl (also known as di-deuterated ethyl linoleate, di-deuterated linoleic acid ethyl ester, 11,11-d-ethyl linoleate, or ethyl 11,11-d-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.

Mechanism of action

Deulinoleate ethyl is recognized by cells as identical to normal linoleic acid. But when taken up, it is converted into 13,13-d-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]

Deulinoleate ethyl 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 deulinoleate ethyl begun in 2018.[4]

Clinical development

Friedreich's ataxia

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. Deulinoleate ethyl 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.[5] Another randomized, double-blind, placebo-controlled clinical study began in 2019.

Infantile neuroaxonal dystrophy

An open-label clinical study for infantile neuroaxonal dystrophy evaluating long-term evaluation of efficacy, safety, tolerability, and pharmacokinetics of deulinoleate ethyl, which, when taken with food, can protect the neuronal cells from degeneration, started in the Summer 2018.

Phospholipase 2G6-associated neurodegeneration

In 2017, the FDA granted deulinoleate ethyl orphan drug designation in the treatment of phospholipase 2G6-associated neurodegeneration (PLAN).[6]

Amyotrophic lateral sclerosis

In 2018, deulinoleate ethyl was given to a patient with amyotrophic lateral sclerosis (ALS) under a "compassionate use scheme".[7]

Progressive supranuclear palsy

In 2020, the FDA granted orphan drug designation deulinoleate ethyl for the treatment of patients with progressive supranuclear palsy (PSP). PSP is a disease involving modification and dysfunction of tau protein; mechanism of action of deulinoleate ethyl both lowers lipid peroxidation and prevents mitochondrial cell death of neurons which is associated with disease onset and progression.[8]

Preclinical research

Alzheimer's disease

Deulinoleate ethyl has been shown to be effective in a model of Alzheimer's disease in mice.[9]

Notes and References

  1. Web site: 9-cis, 12-cis-11,11-D2-Linoleic acid ethyl ester . PubChem .
  2. Hill S, Lamberson CR, Xu L, To R, Tsui HS, Shmanai VV, Bekish AV, Awad AM, Marbois BN, Cantor CR, Porter NA, Clarke CF, Shchepinov MS . 6 . Small amounts of isotope-reinforced polyunsaturated fatty acids suppress lipid autoxidation . Free Radical Biology & Medicine . 53 . 4 . 893–906 . August 2012 . 22705367 . 3437768 . 10.1016/j.freeradbiomed.2012.06.004 .
  3. Demidov VV . Site-specifically deuterated essential lipids as new drugs against neuronal, retinal and vascular degeneration . Drug Discovery Today . 25 . 8 . 1469–1476 . August 2020 . 32247036 . 10.1016/j.drudis.2020.03.014 . 214794450 .
  4. Scarpellini C, Klejborowska G, Lanthier C, Hassannia B, Vanden Berghe T, Augustyns K . Beyond ferrostatin-1: a comprehensive review of ferroptosis inhibitors . Trends in Pharmacological Sciences . S0165–6147(23)00182–7 . September 2023 . 37770317 . 10.1016/j.tips.2023.08.012 . free . 1854/LU-01HJ90DJVXAJ7NPCGA09GG3NFR . free .
  5. Zesiewicz T, Heerinckx F, De Jager R, Omidvar O, Kilpatrick M, Shaw J, Shchepinov MS . Randomized, clinical trial of RT001: Early signals of efficacy in Friedreich's ataxia . Movement Disorders . 33 . 6 . 1000–1005 . July 2018 . 29624723 . 10.1002/mds.27353 . 4664990 .
  6. Web site: US FDA Grants Orphan Drug Designation for Retrotope's RT001 in the Treatment of Phospholipase 2G6 (PLA2G6)-Associated Neurodegeneration . Global Newswire . 2 November 2017 . 12 March 2019 . 1 April 2019 . https://web.archive.org/web/20190401203308/https://www.cnbc.com/2017/11/02/globe-newswire-us-fda-grants-orphan-drug-designation-for-retrotopeas-rt001-in-the-treatment-of-phospholipase-2g6-pla2g6-associated.html . dead .
  7. Web site: Inacio P . Experimental RT001 Now Available for ALS Under Expanded Access. 2018-09-18 . ALS News Today .
  8. Web site: RT001 Gets Orphan Drug Designation in Progressive Supranuclear Palsy .
  9. Butterfield DA, Halliwell B . Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease . Nature Reviews. Neuroscience . 20 . 3 . 148–160 . March 2019 . 30737462 . 10.1038/s41583-019-0132-6 . 9382875 . 59617957 .