Chemistry:Di-deuterated linoleic acid ethyl ester
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| Routes of administration | Oral |
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| 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.
Mechanism of action
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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]
References
- ↑ "9-cis, 12-cis-11,11-D2-Linoleic acid ethyl ester". PubChem. https://pubchem.ncbi.nlm.nih.gov/compound/124037379.
- ↑ "Small amounts of isotope-reinforced polyunsaturated fatty acids suppress lipid autoxidation". Free Radical Biology & Medicine 53 (4): 893–906. August 2012. doi:10.1016/j.freeradbiomed.2012.06.004. PMID 22705367.
- ↑ "Site-specifically deuterated essential lipids as new drugs against neuronal, retinal and vascular degeneration". Drug Discovery Today 25 (8): 1469–1476. August 2020. doi:10.1016/j.drudis.2020.03.014. PMID 32247036.
- ↑ "Beyond ferrostatin-1: a comprehensive review of ferroptosis inhibitors". Trends in Pharmacological Sciences: S0165–6147(23)00182–7. September 2023. doi:10.1016/j.tips.2023.08.012. PMID 37770317.
- ↑ Clinical trial number NCT02445794 for "A First in Human Study of RT001 in Patients With Friedreich's Ataxia" at ClinicalTrials.gov
- ↑ "Randomized, clinical trial of RT001: Early signals of efficacy in Friedreich's ataxia". Movement Disorders 33 (6): 1000–1005. July 2018. doi:10.1002/mds.27353. PMID 29624723.
- ↑ 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
- ↑ Clinical trial number NCT03570931 for "A Study to Assess Efficacy and Safety of RT001 in Subjects With Infantile Neuroaxonal Dystrophy" at ClinicalTrials.gov
- ↑ "US FDA Grants Orphan Drug Designation for Retrotope's RT001 in the Treatment of Phospholipase 2G6 (PLA2G6)-Associated Neurodegeneration". Global Newswire. 2 November 2017. 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.
- ↑ "Experimental RT001 Now Available for ALS Under Expanded Access". ALS News Today. 2018-09-18. https://alsnewstoday.com/2018/09/18/experimental-rt001-available-for-als-under-expanded-access-program/.
- ↑ "RT001 Gets Orphan Drug Designation in Progressive Supranuclear Palsy". https://www.neurologylive.com/clinical-focus/rt001-gets-orphan-drug-designation-in-progressive-supranuclear-palsy-.
- ↑ "Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease". Nature Reviews. Neuroscience 20 (3): 148–160. March 2019. doi:10.1038/s41583-019-0132-6. PMID 30737462.
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