Gensight: Developing a Mitochondrial Repair Therapy

In this post I'll point out Gensight, a company creating medical biotechnologies that are relevant to the goal of human rejuvenation, and which is about to undertake an IPO in order to pull in more significant funding for ongoing development. This company has over the past couple of years developed mitochondrial repair technologies based on research at the Corral-Debrinski lab in Paris partly funded by the SENS Research Foundation. This is a great example of what we'd like to see result from the Foundation's intervention in fields of research that need more support in order to move forward.

So the area of interest here is mitochondrial damage and how to remove the consequences of that damage. What does this mean? Mitochondria are the power plants of the cell, working to produce chemical energy stores in the form of adenosine triphosphate (ATP) molecules, though like every cellular component they play a role in many processes beyond their primary function. Evolution likes reuse. Each cell contains a herd of hundreds of mitochondria, which multiply like bacteria, sometimes fuse together, swap component parts of their machinery between one another, and are culled when worn or broken by cellular quality control mechanisms. Mitochondria are the descendants of ancient symbiotic bacteria and carry the remnants of that origin in the form of a small number of genes encoded in mitochondrial DNA. There were originally many more genes, but over evolutionary time they were either lost or migrated to the cell nucleus to reside in the nuclear DNA.

DNA is fragile and a cell is basically a balloon of constant chemical reactions. DNA gets damaged all the time, but the array of repair mechanisms that work to restore that damage are highly efficient: very little slips past. They are far more efficient in the cell nucleus than in mitochondria, however. Further, mitochondrial DNA seems to be more prone to damage for reasons that may include the fairly energetic chemical reactions required to build ATP, or may be an artifact of the way in which mitochondria multiply by division. There is still some debate on this front. What is known is that some forms of mitochondrial DNA damage can bypass quality control, leading very quickly to an entire cell being overtaken by dysfunctional mitochondria with the same broken DNA, unable to properly generate ATP by the usual path, and as a result the cell starts to export harmful, reactive molecules into the surrounding tissue. Enough of these cells and functional damage starts to accrue in tissues and organs: this is one of the contributing causes of degenerative aging.

What to do about this? The strategies are fairly obvious at a high level: replace the broken DNA, or supply new mitochondria, or supply the missing proteins that the broken genes encoded. There are many variants that mix and match between these themes, some are better than others, and some are quite far along in development. The SENS Research Foundation approach is allotopic expression: use gene therapy to put copies of all of the remaining mitochondrial genes into the cell nucleus and then work out how to get the protein produced from that genetic blueprint back to the mitochondria where it is needed - it is that second portion of the work that is the hard part.

Gensight is working on a variant of this approach, but like most groups producing technology of interest to our goals they are not actually focused on aging and longevity at all. Instead Gensight produce their technology to treat inherited mitochondrial disease in which a necessary mitochondrial gene is missing or damaged in wide swathes of a patient's tissues. They are primarily focused on Leber's hereditary optic neuropathy (LHON), a degenerative blindness condition that has been a proving ground for research into mitochondrial repair over the past decade or so. You might recall that the SENS Research Foundation collaborated with Marisol Corral-Debrinski back in the day, helping to fund research on the technology that Gensight is now developing for clinical application.

So the good news here is that a solid, young biotech company with quite a lot of funding is having a serious go at producing a robust platform for repairing the consequences of mitochondrial DNA damage. The next step to follow on from Gensight's progress in reducing this all to practice will be to adapt the core technology to work for all mitochondrial genes of interest, those whose damage is involved in degenerative aging. Given the way companies, business cycles, and intellectual property licensing tend to work out, and allowing some time for the standard confusion and occasional failure, I imagine that start to be underway in earnest somewhere between 2020 and 2025. If we're lucky, someone else will start work on a similar approach to mitochondrial damage in aging before then, however: commercially successful research tends to attract competing scientific programs.

Gensight scouts a $100M IPO for its ocular gene therapies

Parisian drug developer Gensight Biologics is swinging for a $100 million U.S. IPO to fund its work on potential one-time treatments for serious retinal diseases, angling to take advantage of a bullish market for biotechs. Gensight's top prospect is GS010, a treatment for certain forms of the rare Leber hereditary optical neuropathy, or LHON, which leads to sudden and irreversible loss of sight in teenagers and young adults. The treatment works by fixing a DNA glitch that leads to LHON, using a harmless virus to deliver a corrective copy of the ND4 gene. Gensight completed a Phase Ib study on GS010 this year, the company said, and plans to push its top prospect straight to Phase III in the second half with data expected in 2017.

Mitochondrial Targeting Sequence (MTS)

Our MTS technology platform enables efficient expression of a mitochondrial gene by nuclear deoxyribonucleic acid, or DNA, and delivery of messenger ribonucleic acid, or mRNA, to polysomes located at the mitochondrial surface. This allows for the synthesis, internalization and proper localization of the mitochondrial protein.

Mitochondrial DNA mutations, whether inherited or acquired, lead to impairment of the electron transport chain functioning. Impaired electron transport, in turn, leads to decreased adenosine triphosphate, or ATP, production, overall reduced energy supply to the cells, formation of damaging free-radicals, and altered calcium metabolism. These toxic consequences lead to further mitochondrial damage including oxidation of mitochondrial DNA, proteins and lipids, and opening of the mitochondrial permeability transition pore, an event linked to cell death. This cycle of increasing oxidative damage insidiously damages neurons, including those in the retina, over a period of years, eventually leading to neuronal cell death.

LHON originates from mutations in three NADH Dehydrogenase mitochondrial genes: ND1, ND4 and ND6. Because ND4 mutations account for more than 75% of the LHON population in North America and Europe, we chose to first focus on this specific mutation. We have demonstrated the feasibility of using the MTS technology platform for the treatment of LHON due to the ND4 gene mutation in animal studies. We plan to use our MTS technology platform to address other LHON mutations and have already initiated a research program for our next potential product candidate, GS011, which targets the ND1 gene mutation. We believe that our MTS technology platform can also be used to address diseases outside of ophthalmology that involve defects of the mitochondrion, such as neurodegenerative disorders.


You are much better off having companies with specific projects, such as fixing mitochondrial damages in specific instances. They are more likely to succeed on the short run... and success breeds success.

Posted by: Daniel Lemire at July 8th, 2015 7:02 PM

I'm hoping that this technology turns out to be applicable to all 13 protein coding genes located in the mitochondria.

Posted by: Jim at July 9th, 2015 9:56 AM

I'm really curious how Gensight's offerings differ from Stealth's.

Posted by: Slicer at July 9th, 2015 10:39 AM


Looks like standard issue small molecule drugs targeted to mitochondria, having marginal effects on the conditions being treated by altering the behavior of cells. E.g.:

I wouldn't be completely surprised to find out it's a mitochondrially targeted antioxidant, but probably not. They're certainly not very informative on their website as to what it is they're developing.

Posted by: Reason at July 9th, 2015 11:25 AM

On the same page:

“Ocuvia may be the new paradigm for ophthalmology, reversing disease rather than just slowing angiogenesis,” commented Dr. Pravin Dugel, Chairman for the American Academy of Ophthalmology Subspecialty Day, when describing Ocuvia’s clinical benefits and the role of mitochondria in eye diseases.

... reversing disease rather than just slowing angiogenesis ... if that the case, it's not bad at all.

Couple years ago they were called Stealth Peptides - and that gives a clue.
Anywa, if you do search the web you can still find older .pdfs with their presentations.

Here is one from couple years ago:

Posted by: Adrian Crisan at July 9th, 2015 9:01 PM

Stealth's Ocuvia is related to Bendavia, the marketing name for the Szeto-Schiller peptide known in scientific circles as SS-31. It's a mitochondrial antioxidant. Bendavia is named after Carl Benda, credited with the discovery of mitochondria. I don't know if Ocuvia is identical to Bendavia or not. No doubt it's similar, if not identical.

Posted by: niner at August 4th, 2015 6:02 PM
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