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Retrotope

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Retrotope, Inc.
Founded2006
Legal statusClinical stage pharmaceutical company
HeadquartersLos Altos, CA, United States
ServicesDrug development
Anil Kumar
Rick Winningham
Mikhail Shchepinov[1]
Websitewww.retrotope.com

Retrotope, Inc. is a drug development company advancing the idea that polyunsaturated fatty acids (PUFA) drugs fortified with heavy isotopes (reinforced lipids) protect living cells by making bonds within the delicate molecules inside and around cells harder to break. This makes the cells less prone to damage caused by reactive oxygen species (ROS), one of the principal causes of ageing and age-associated diseases.[2] Founded in 2006 by entrepreneurs and scientists with seed funding from private investors, Retrotope is developing a non-antioxidant approach to preventing lipid peroxidation, a detrimental factor in mitochondrial, neuronal, and retinal diseases.[3] The company employs the virtual business model[4] and works in scientific collaboration with more than 80 research groups in universities worldwide.[5]

Development

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An animated illustration of a chain reaction with slow elements

Retrotope's drug platform, deuterium-stabilized polyunsaturated fatty acids (PUFA), prevents lipid peroxidation damage from propagating, rapidly stopping the toxic chain reaction at its source. Because the fatty acids in mitochondrial and cellular membranes turn over rapidly, the dietary substitution of stabilized fatty acids creates cells fortified against damage due to kinetic isotope effect. 11,11-D2-ethyl linoleate suppresses lipid peroxidation even at relatively low levels of incorporation into membranes.[6] In 2010 Retrotope found that it more than 150 times increases the resistance of the yeast to oxidative stress,[7][8] later it was shown to be effective in an animal model of Alzheimer's disease.[9] A June 2018 study found that a diet of D-PUFA was shown to significantly decrease F2-isoprostanes (a cerebrospinal fluid found in elevated amounts in Huntington's disease) when fed to one-month old mice over the course of five months.[10] These findings caused discussion in popular science press about the use of deuterated nutrients against ageing,[11] but the most promising direction of further development was toward rare neurodegenerative diseases in which oxidative damage plays a part.[12]

Clinical trials

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Friedreich's ataxia

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The first deuterated PUFA made and studied by Retrotope, 11,11-D2-ethyl linoleate, has become the first Retrotope's drug RT001 that was taken into the clinic. It has passed Phase I/II clinical trial for the treatment of Friedreich's ataxia (FA),[13] in which RT001 was shown to be safe, well tolerated and beneficial in terms of improving motor capability in FA patients. However, this preliminary evidence must be interpreted with caution given the limited sample size and the short duration of the study.[14]

Phospholipase 2G6-associated neurodegeneration

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In 2017 FDA granted RT001 orphan drug designation in the treatment of phospholipase 2G6-associated neurodegeneration (PLAN).[15]

Infantile neuroaxonal dystrophy

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A Phase II open-label clinical study for long-term evaluation of efficacy, safety, tolerability, and pharmacokinetics of RT001 in the treatment of infantile neuroaxonal dystrophy started in the Summer 2018.[16]

Other clinical use

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Amyotrophic lateral sclerosis

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After a petition for access filed by investigators at major medical centers, in 2018 RT001 was given to a patient with amyotrophic lateral sclerosis (ALS) under a "compassionate use" scheme sponsored by Retrotope.[17]

Progressive supranuclear palsy

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In 2020 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.[18]

References

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  1. ^ "Lifeboat Foundation Bios: Dr. Mikhail S. Shchepinov". lifeboat.com.
  2. ^ 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.
  3. ^ "Retrotope Inc.: Private Company Information". bloomberg.com. Archived from the original on 2018-05-11.
  4. ^ Keshavan M (22 August 2014). "Fat-based Parkinson's drug headed to clinical trial with $6.5M in angel money". MedCity News.
  5. ^ "Collaborations". Retrotope.
  6. ^ 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.
  7. ^ Thomson H (27 October 2010). "Heavy hydrogen keeps yeast looking good". New Scientist.
  8. ^ Hill S, Hirano K, Shmanai VV, Marbois BN, Vidovic D, Bekish AV, et al. (January 2011). "Isotope-reinforced polyunsaturated fatty acids protect yeast cells from oxidative stress". Free Radical Biology & Medicine. 50 (1): 130–138. doi:10.1016/j.freeradbiomed.2010.10.690. PMC 3014413. PMID 20955788.
  9. ^ Elharram A, Czegledy NM, Golod M, Milne GL, Pollock E, Bennett BM, Shchepinov MS (December 2017). "Deuterium-reinforced polyunsaturated fatty acids improve cognition in a mouse model of sporadic Alzheimer's disease". The FEBS Journal. 284 (23): 4083–4095. doi:10.1111/febs.14291. PMC 5716852. PMID 29024570.
  10. ^ Hatami A, Zhu C, Relaño-Gines A, Elias C, Galstyan A, Jun M, et al. (August 2018). "Deuterium-reinforced linoleic acid lowers lipid peroxidation and mitigates cognitive impairment in the Q140 knock in mouse model of Huntington's disease". The FEBS Journal. 285 (16): 3002–3012. doi:10.1111/febs.14590. PMID 29933522.
  11. ^ Hamzelou J (13 May 2015). "Pill of super-protective 'heavy' fat may be key to eternal youth". New Scientist.
  12. ^ : Mikhail Shchepinov presenting at Undoing Aging 2019. YouTube.
  13. ^ 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.
  14. ^ Pirali T, Serafini M, Cargnin S, Genazzani AA (June 2019). "Applications of Deuterium in Medicinal Chemistry". Journal of Medicinal Chemistry. 62 (11): 5276–5297. doi:10.1021/acs.jmedchem.8b01808. PMID 30640460. S2CID 58610901.
  15. ^ "US FDA Grants Orphan Drug Designation for Retrotope's RT001 in the Treatment of Phospholipase 2G6 (PLA2G6)-Associated Neurodegeneration" (Press release). Retrotope. 2 November 2017. Retrieved April 25, 2020 – via GlobeNewswire.
  16. ^ Clinical trial number NCT03570931 for "A Study to Assess Efficacy and Safety of RT001 in Subjects With Infantile Neuroaxonal Dystrophy" at ClinicalTrials.gov
  17. ^ Inacio P (18 September 2018). "Retrotope's Experimental RT001 Now Available for ALS Under Expanded Access Program". ALS News Today.
  18. ^ Meglio M (23 February 2020). "RT001 Gets Orphan Drug Designation in Progressive Supranuclear Palsy". NeurologyLive.
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