Multiple Independent Groups are Carrying out Trials of Allotopic Expression of Mitochondrial Genes, the Basis for a Rejuvenation Therapy

One of the multiple classes of rejuvenation therapies that will have to be built in order to bring aging under medical control involves mitochondria. The medical community must either repair damage to mitochondrial DNA or make that damage irrelevant. Mitochondria are found in their hundreds in each of our cells, the evolved descendants of symbiotic bacteria that now perform many vital functions. They carry their own DNA, thirteen genes left over from the full genome of their ancestors. There are ways for this DNA to become damaged in the course of normal cellular operations, and some of that damage can spiral out of control to cause harm to cells and surrounding tissues. Over the years ever more cells fall victim to dysfunctional mitochondria, and the damage done mounts ever higher. This is one of the causes of aging and age-related disease.

There are, however, other types of disease that involve mitochondrial mutations, and in a world in which there is much left to be done to bring greater support to rejuvenation research, it is in the construction of therapies for inherited mitochondrial diseases where the foundational work is taking place for mitochondrial repair. Eight years ago, the Methuselah Foundation and later the SENS Research Foundation used the philanthropic donations of supporters like you and I to help fund the work of a French research group on allotopic expression of mitochondrial genes. This involves copying mitochondrial genes into the cell nucleus, edited in ways that ensure that the proteins produced find their way back to the mitochondria where they are needed. When accomplished, this can mean that damage to mitochondrial DNA no longer has any detrimental effect, as the necessary proteins are still being produced. The work of past years has since blossomed into Gensight, a venture-funded company putting considerable effort to bring this type of gene therapy to the clinic.

There is a lot of work to be done here. Each mitochondrial gene requires its own challenging recipe to make the process of allotopic expression work, but allotopic expression of even one gene of the thirteen can be used to cure inherited mitochondrial diseases involving mutations of that gene. So it is possible to build companies that work on that goal, and each mitochondrial gene successfully moved to the nucleus is one thirteenth of the way to building a rejuvenation therapy that can eliminate the contribution of mitochondrial DNA damage to aging, and rejuvenate the old who are already well down the road of suffering the consequences. At present the solidly accomplished count stands at three genes. ND4, where mutation is the one of the causes of Leber hereditary optic neuropathy (LHON) is the initial focus for Gensight, and was the first gene targeted in the research funded eight years ago. As of this year, Gensight is organizing a pair of phase III trials in LHON patients. Meanwhile, at the other end of the research and development pipeline, last month the SENS Research Foundation team announced success for ATP6 and ATP8, the end of a lengthy research initiative that has produced proof of allotopic expression for these two genes in cell cultures. Other mitochondrial genes have had allotopic expression demonstrated in yeast only, or the process of relocating proteins back to the mitochondria is only partly solved.

Gensight is not the only group working on human trials of allotopic expression of ND4 for the treatment of LHON. There are at least two other independent academic research groups with results from human trials to show that allotopic expression is a viable technology, and below you'll find links to their recent research results:

Efficacy and Safety of rAAV2-ND4 Treatment for Leber's Hereditary Optic Neuropathy

The aim of this study was to evaluate the efficacy and safety of a recombinant adeno-associated virus 2 (AAV2) carrying ND4 (rAAV2-ND4) in LHON patients carrying the G11778A mutation. Nine patients were administered rAAV2-ND4 by intravitreal injection to one eye and then followed for 9 months. Ophthalmologic examinations of visual acuity, visual field, and optical coherence tomography were performed. The visual acuity of the injected eyes of six patients improved by at least 0.3 log MAR after 9 months of follow-up. In these six patients, the visual field was enlarged but the retinal nerve fibre layer remained relatively stable.

Gene Therapy for Leber Hereditary Optic Neuropathy

In this prospective open-label trial, the study drug (self-complementary adeno-associated virus [scAAV]2(Y444,500,730F)-P1ND4v2) was intravitreally injected unilaterally into the eyes of 5 blind participants with G11778A LHON. Four participants with visual loss for more than 12 months were treated. The fifth participant had visual loss for less than 12 months. Treated participants were followed for 90 to 180 days and underwent ocular and systemic safety assessments along with visual structure and function examinations. Visual acuity remained unchanged from baseline to 3 months in the first 3 participants. For 2 participants with 90-day follow-up, acuity increased from hand movements to 7 letters in 1 and by 15 letters in 1, representing an improvement equivalent to 3 lines. No one lost vision, and no serious adverse events were observed.

This can all be taken as more proof to show that the SENS approach of targeted philanthropic support of critical research projects in fields that are languishing creates real results. Donating to the SENS Research Foundation and Methuselah Foundation produces meaningful results: together, we have made a difference. In this case work on allotopic expression has snowballed from a tiny, poorly supported sideline into a competitive research and development community focused on mitochondrial genes. The Gensight leadership isn't resting on its laurels and will next work on allotopic expression of ND1, one of the remaining mitochondrial genes. This is exactly what the other teams will do once they are at that stage of development. All in all this is the reassuring sight of progress, the construction of robust technology platforms that will inform the development of one very important branch of rejuvenation therapies in the years ahead, the ability to remove the harms done to us by our own mitochondria.


I'm very glad to see the progress being made toward allotropic expression of mitochondrial genes, but I have a question. As you know, most of the mitochondrial genes are located in the nucleus. Is there definitive evidence that nuclear mutations of mitochondrial genes are not a contributor to old age? Obviously the 13 genes that are located in the mitochondria are more prone to and suffer more damage due to their location and this must be fixed, but is it enough? Or is it possible that just like with mtDNA mutations, there are long lived cells(neurons,skeletal muscle,etc.) with dysfunctional mitochondria that harm the surrounding due to nuclear mutations of mitochondrial genes?

Posted by: Empirical at June 8th, 2016 12:18 AM

"Donating to the SENS Research Foundation and Methuselah Foundation produces meaningful results" This drum cannot possibly be beaten hard enough, but I've beaten to a pulp the drum of telling people that.

Posted by: Slicer at June 8th, 2016 1:22 AM

It should be pointed out that these two reports seem to be the first to discuss the results of the allotopic expression of mitochondrial genes in human patients. AFAIK, even Gensight hasn't published or talked about the results of their clinical trials.

Posted by: Florin Clapa at June 8th, 2016 1:49 AM
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