IntraClear Founder and Chief Science Officer Ariel Feinerman explains how his team is bioengineering longevity and calls for an Open Source approach to longevity.

With an advisory board packed with longevity firepower (including Aubrey de Grey of the SENS Research Foundation, James Clement of Betterhumans and Gary Hudson of Oisín Biotechnologies), IntraClear Biologics is on a bioengineering longevity mission to “help humanity win the war against age-related diseases.”

Longevity.Technology: IntraClear is based in Tallinn, a city often dubbed the European Silicon Valley due to Estonia’s Government’s innovative policies and education initiatives and the fact that it has one of the highest start-ups per capita rates in the world.

With a research programme that includes developing a therapy for the removal of intracellular junk from the human body and developing a comprehensive panel of primary aging biomarkers, we were keen to talk to their Chief Science Officer, Ariel Feinerman, to find out more.

Feinerman comes to rejuvenation research from software engineering, and he regards aging as an engineering problem. “We don’t mine small molecules – we engineer biologics,” Feinerman emphasises. “We aren’t a pharmaceuticals company – we are a bioengineering company.”

Feinerman attributes IntraClear’s origin to three influences: Dr Aubrey de Grey who really sparked his interest in longevity, physician Alexander Morozov from Belarus, who drew his attention to lipofuscin and Yevgen Haletskyi from Kyiv [Kiev], Ukraine who listened to Feinerman and Morozov’s lectures and became interested in their programme. Haletskyi offered support and angel investment and IntraClear, with Haletskyi as its CEO, was born.

IntraClear is built around lipofuscin, common intracellular junk which is a fluorescent complex mixture of highly oxidised cross-linked macromolecules like lipids, sugars, proteins, and heavy metals ions.

“Even though lipofuscin has been known since 1912, researchers don’t fully know its composition and structure,” Feinerman explains. “Lipofuscin accumulates in all cells of the body, especially in the skin, brain and muscles, it inhibits proteasome and has cytotoxic effects. The accumulation of lipofuscin is associated with many aging pathologies, like neurodegenerative, neuromuscular, inflammatory, etc, and it heavily causes skin aging.”

“Our idea is simple but powerful. Our gene therapy will have two parts: mRNA from which cells can synthesise lipofuscin-breaking enzyme and a fusogenic liposome as a vehicle. No genes are inserted into the nucleus, so this gene therapy is transient and safe. After the mRNA has done its job, it will be quickly degraded by the cell’s own RNases,” says Feinerman, explaining that IntraClear is following the way of Oisín.

IntraClear is considering licensing the liposome vehicle tech Fusogenix from Entos Pharmaceuticals, but is also considering developing its own vehicle to ensure passage across the blood-brain barrier.

“It is particularly interesting how we will obtain the enzymes,” Feinerman tells us. “Firstly we will isolate lipofuscin from human tissues. Because lipofuscin is likely specific in each tissue we focus on the skin, muscles and brain, but if we cannot isolate lipofuscin using current technology, we will use physical methods like nanoscale NMR to investigate lipofuscin in vivo.

This is avery promising, although emerging technology, so we need to improve it ourselves. After we investigate the structure of lipofuscin using a variety of methods, including Raman and Infrared spectroscopy, we will use metagenomic analysis to search for bacteria which have lipofuscin-breaking enzymes. We know that such bacteria exist because someone eats lipofuscin in nature. For example, such bacteria can live in the guts of the corpse-eating insects.”

Lipofuscin has highly a cross-linked nature, which protects it from lysosomal enzymes. Research has shown that proteasome binds to the surface of lipofuscin but is unable to break it because of cross-links [1]. IntraClear plans to search for enzymes that can break those links, allowing cell lysosomal and proteasomal machinery to digest lipofuscin on its own. This is why a detailed understanding of the structure of lipofuscin is key.

“So rejuvenation therapies like ours will simultaneously prevent and reverse aging pathologies …”

“Aging is a two-part process: metabolism causes damage, while damage causes pathology,” Feinerman explains. “We cannot prevent metabolism from causing damage because for that we must change our metabolism hugely by rewriting the human genome, which is unlikely in the current perspective. But we can prevent damage from causing pathology by removing it using rejuvenation therapy. So rejuvenation therapies like ours will simultaneously prevent and reverse aging pathologies.”

As well as development of lipofuscin breaking therapy, IntraClear is developing an aging biomarkers panel for clinical use.

Using only very small samples of tissue, such as skin, for analysis, IntraClear is also planning to use non-invasive methods such as laser fluorescence spectroscopy. “The preliminary results are very interesting, for example, human seminal vesicles are rich in lipofuscin,” says Feinerman.

Feinerman continues: “There is a great demand for such a panel in the scientific and medical community. Our panel will be unique because it will use primary types of molecular and cellular damage as biomarkers of aging. Luckily, many necessary protocols already exist; they will need to be assembled together and ‘packaged’ into the panel.

“Because the costs and time for entering the market in many countries of Europe and the USA are unreasonably high we will choose the country with the most favourable rules for clinical trials and entering the market. Our main areas are Russia, Ukraine, Belarus, Asia and South America.”

As for commercialisation, says Feinerman, it will depend on future investors, and their guidance. “Personally, we prefer an Open Source approach because it can significantly reduce initial development costs. Instead of working solely, we can use open protocols and create therapy in the community of universities, civil researchers and other companies,” Feinerman explains.

“There are examples of Big Pharma buying small companies for patents on new technology and then canceling additional research …”

Feinerman feels an Open Source approach might prevent therapy from becoming closed or making the price too high. “There are examples of Big Pharma buying small companies for patents on new technology and then canceling additional research,” says Feinerman. “An Open Source approach means you cannot ‘close’ any technology; instead, everyone can improve protocols and everyone can use it without any licence fee!

We would like to believe that this is the right way, and there are investors who share our view. Instead of selling licences we would prefer to manufacture and sell therapy to the clinics or, perhaps, open our own rejuvenation clinic.”

“In addition,” explains Feinerman, “gene therapies are easy to replicate – you can even do it in your garage – so selling licences may be simply unprofitable in the near future.”

IntraClear has created the first version of the protocol for isolating lipofuscin and is looking for funds to verify it on a brain tissue. In parallel, work is continuing the primary aging biomarkers panel.

“When we finish our histological study we will have an excellent primary aging biomarker based on lipofuscin,” Feinerman explains. “Next year we wish to finish investigating the structure of lipofuscin. Although it is too early to say when our lipofuscin breaking therapy will reach the clinic, but we think that five years is reasonable estimate in the countries where we work.

We prefer to choose the most neglected areas of rejuvenation research to move them forward, and we need at least $3 million to finish lipofuscin breaking therapy.

“Currently, we have no external investments, but we are hoping that will change! We are an Estonian company but are researching in many countries including Russia, Belarus, Ukraine. Because of the low Russian rouble exchange rate, Russia has the best price / quality ratio in research, so that is helping matters!”

[1] https://www.liebertpub.com/doi/10.1089/ars.2014.6062

Images courtesy of IntraClear