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Polyunsaturated fatty acids – friends or foes? RETROTOPE strikes back.

Polyunsaturated fatty acids – friends or foes? RETROTOPE strikes back.

Publish date: 2016-06-06

Retrotope is an American biotechnology company which has a real chance to introduce to the marker the efficient drug against neurodegenerative diseases. Work area of Retrotope are therapies of metabolic diseases connected to oxidative stress conditions and lipid oxidation. Developed drug is currently in initial phase of clinical trials. The newest research results were presented during the Biotech Solutions for Health and Environment: MOBI4Health Conference & New IFB Building Opening, held 12-15 April in Gdansk, Poland.

Tags: MOBI4Health , Retrotope , polyunsaturated fatty acids , linoleic acid , reactive oxygen species

Retrotope company was founded in 2006 with private funds of Dr. Robert J Molinari, Prof. Charles Cantor and Mikhail Shchepinov. The research subject of Retrotope is aging and connected neurodegenerative processes often resulting from oxidative stress conditions. However, the company itself does not have any laboratories, factories or equipment. It is a virtual company based on cooperation with over a dozen of research partners. What is unique in Retrotope which makes it more successful than other pharmaceutic companies and why their drug candidate has a real chance to pass clinical trials? Drug RT001 is now in Phase I and II clinical trials as a candidate for Friedreich’s ataxia (FA) patients bringing very promising results. But let’s start from the beginning…

Oxygen fate

Oxygen is obligatory for life. Unfortunately, there is a second part of the story – at the same time it is a cause of metabolic oxidative stress and damages present mainly in mitochondria. It is estimated, that as much as 5% total energy of human organism is consumed to repair those oxidation damages resulting mainly from peroxidation of polyunsaturated fatty acids (PUFAs). But aren’t PUFAs a good fellows associated with a good health? Plant oils and famous omega acids present in fish are only few examples of PUFAs which should be eaten in high amounts. Are then PUFAs our friends or foes?

It is assumed, that relatively fast evolutional development of humans has begun when our ancestors stared to eat seafood, which is connected to beneficial impact of omega acids on brain development. However, the paradox of life is that the cause of our development is at the same time the cause of our aging and death. PUFAs are the target of peroxidation – a radical reaction of fatty acids oxidation, which products lead to damage od lipids, proteins and nucleic acids.

Why present attempts to treat neurodegenerative diseases fail?

There are probably many causes, but the crucial issue is the slow progression of the disease combined with the relative insensitivity of accepted clinical endpoints. Therefore, no drug has so far succeeded in showing sufficient efficacy to get regulatory approval, as far as FA is considered. The second important cause is a hermeticity of blood-brain barrier, which for many candidates is impassable.

Founders of Retrotope decided to solve the problem from the other side. Generation of reactive oxygen species is unavoidable – therefore, maybe we should not get rid of a primary cause of oxidative stress, but rather get rid of its target? Presented strategy is to prevent free radicals from PUFAs peroxidation. How? Very easily…

New drug for old disease

Friedreich’s ataxia is an orphan disease of a genetic background leading to a progressive degeneration of nervous system and heart muscle. The cause is a severe deficiency of frataxin – a mitochondrial protein participating in iron metabolism. Then frataxin is lacking, free iron is accumulated and high amounts of free radicals are generated in a classical Fenton’s reaction. As a result, free radicals cause lipid peroxidation and damage of mitochondria.

Peroxidation of unsaturated fatty acids occurs in defined chain position – it is initiated with “stealing” an electron from a highly reactive hydrogen atoms localized next to methylene bridge adjacent to a double bond. A novel strategy of prevention and treatment is to chemically modify the lipids, therefore to substitute the neuralgic hydrogen with deuterium, its heavy isotope. This approach is a real success – deuterated lipids do not undergo peroxidation and are efficiently accumulated in organism. Experiments with the use of animals showed efficient exchange of “normal” dietary fatty acids in brain, liver and retina, revealing no toxicity or behavioral changes.

Drug RT001 is a deuterated form of linoleic acid – 11.11-dideuterolinoleic acid. It was shown that very small amount of drug – thus 20% replacement in a whole linoleic acid content – prevents from peroxidation of lipids in cell membranes. RT001 is currently in Phase I and II clinical trials. The purpose of this study is to evaluate the safety, tolerability and pharmacokinetics of RT001 in patients with Friedreich's ataxia. The study is currently recruiting participants. In the future, deuterated PUFAs can be used to treat other diseases such as Parkinson’s and Alzheimer disease or diabetic retinopathy.

Ref. Hill S. et al. 2012

Last achievements of Retrotope were presented during the Biotech Solutions for Health and Environment: MOBI4Health Conference & New IFB Building Opening held 12-15 April in Gdansk, Poland. The talk about the genesis and efficient strategy to fight oxidative stress was given by Prof. Charles Cantor – a prominent molecular biologist, inventor and a habitué of events associated with MOBI4Health project.

Photo-review from a conference and opening ceremony of a new building of Institute of Biotechnology is available below:

https://www.facebook.com/MWB.UGiGUMed/posts/499759103559116

http://www.gdansk.pl/urzad/galeria?c=4381

Sources:

Monika Kossakowska-Zwierucho

 

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