Di-deuterated linoleic acid ethyl ester
Clinical data
Routes of
ATC code
  • none
Legal status
Legal status
  • Investigational
  • Ethyl (9Z,12Z)-9,12-11,11-d2-octadecadienoate
CAS Number
PubChem CID
Chemical and physical data
Molar mass310.517 g·mol−1
3D model (JSmol)
Density0.88 g/cm3
Boiling point173–177 °C (343–351 °F)
  • InChI=1S/C20H36O2/c1-3-5-6-7-8-9-10-11-12-13-14-15-16-17-18-19-20(21)22-4-2/h8-9,11-12H,3-7,10,13-19H2,1-2H3/b9-8-,12-11-/i10D2
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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.

Mechanism of action

Further information: Isotope effect on lipid peroxidation

An animated illustration of a chain reaction with slow elements

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]

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.[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]

Infantile neuroaxonal dystrophy

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]

Phospholipase 2G6-associated neurodegeneration

In 2017, the FDA granted RT001 orphan drug designation in the treatment of phospholipase 2G6-associated neurodegeneration (PLAN).[9]

Amyotrophic lateral sclerosis

In 2018, RT001 was given to a patient with amyotrophic lateral sclerosis (ALS) under a "compassionate use scheme".[10]

Progressive supranuclear palsy

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]

Preclinical research

Alzheimer's disease

RT001 has been shown to be effective in a model of Alzheimer's disease in mice.[12]


  1. ^ "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, et al. (August 2012). "Small amounts of isotope-reinforced polyunsaturated fatty acids suppress lipid autoxidation". Free Radical Biology & Medicine. 53 (4): 893–906. doi:10.1016/j.freeradbiomed.2012.06.004. PMC 3437768. PMID 22705367.
  3. ^ Demidov VV (August 2020). "Site-specifically deuterated essential lipids as new drugs against neuronal, retinal and vascular degeneration". Drug Discovery Today. 25 (8): 1469–1476. doi:10.1016/j.drudis.2020.03.014. PMID 32247036. S2CID 214794450.
  4. ^ Scarpellini C, Klejborowska G, Lanthier C, Hassannia B, Vanden Berghe T, Augustyns K (September 2023). "Beyond ferrostatin-1: a comprehensive review of ferroptosis inhibitors". Trends in Pharmacological Sciences: S0165–6147(23)00182–7. doi:10.1016/j.tips.2023.08.012. hdl:1854/LU-01HJ90DJVXAJ7NPCGA09GG3NFR. PMID 37770317.
  5. ^ Clinical trial number NCT02445794 for "A First in Human Study of RT001 in Patients With Friedreich's Ataxia" at ClinicalTrials.gov
  6. ^ Zesiewicz T, Heerinckx F, De Jager R, Omidvar O, Kilpatrick M, Shaw J, Shchepinov MS (July 2018). "Randomized, clinical trial of RT001: Early signals of efficacy in Friedreich's ataxia". Movement Disorders. 33 (6): 1000–1005. doi:10.1002/mds.27353. PMID 29624723. S2CID 4664990.
  7. ^ Clinical trial number NCT04102501 for "A Study to Assess Efficacy, Long Term Safety and Tolerability of RT001 in Subjects With Friedreich's Ataxia" at ClinicalTrials.gov
  8. ^ Clinical trial number NCT03570931 for "A Study to Assess Efficacy and Safety of RT001 in Subjects With Infantile Neuroaxonal Dystrophy" at ClinicalTrials.gov
  9. ^ "US FDA Grants Orphan Drug Designation for Retrotope's RT001 in the Treatment of Phospholipase 2G6 (PLA2G6)-Associated Neurodegeneration". Global Newswire. 2 November 2017. Archived from the original on 1 April 2019. Retrieved 12 March 2019.
  10. ^ Inacio P (2018-09-18). "Experimental RT001 Now Available for ALS Under Expanded Access". ALS News Today.
  11. ^ "RT001 Gets Orphan Drug Designation in Progressive Supranuclear Palsy".
  12. ^ Butterfield DA, Halliwell B (March 2019). "Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease". Nature Reviews. Neuroscience. 20 (3): 148–160. doi:10.1038/s41583-019-0132-6. PMC 9382875. PMID 30737462. S2CID 59617957.