Work on Allotopic Expression of Mitochondrial Genes is Spreading
Gene expression is the process of generating proteins from the blueprints encoded in DNA. Most DNA is in the cell nucleus, but thirteen genes can be found in the mitochondria, the powerplants of the cell that were once, long ago, symbiotic bacteria. Alloptic expression is a form of genetic engineering wherein one or more of those mitochondrial genes is copied into nuclear DNA, and the resulting proteins transported back to the mitochondria where they are needed. It is that transportation that is the hard part, not yet accomplished for more than a couple of mitochondrial genes.
Why should we care about allotopic expression as anything more than a technical curiosity? Because mitochondrial DNA damage is one of the root causes of aging. Mutations that disable some mitochondrial genes, thus depriving mitochondria of necessary protein machinery, lead to a chain of unfortunate events that progressively produces ever more dysfunctional cells and damage to tissues and organs over the years. If researchers could create a backup source of the necessary proteins in the cell nucleus, then this contribution to aging could be completely removed - and even reversed in its later stages.
The SENS Research Foundation is more or less the only group coordinating work on allotopic expression for the treatment of aging, but a number of unaffiliated labs are using the approach in a more limited way in an attempt to address the genetic disease of Leber hereditary optic neuropathy (LHON). LHON is caused by a defective mitochondrial gene, so many of the efforts taken to cure it are also somewhat applicable to the issue of mitochondrial mutations in aging. Here researchers demonstrate effectiveness and safety of allotopic expression in this case:
We developed a novel strategy for treatment of Leber hereditary optic neuropathy (LHON) caused by a mutation in the nicotinamide adenine dinucleotide dehydrogenase subunit IV (ND4) mitochondrial gene. In a series of laboratory experiments, we modified the mitochondrial ND4 subunit of complex I in the nuclear genetic code for import into mitochondria. The protein was targeted into the organelle by agency of a targeting sequence (allotopic expression). The gene was packaged into adeno-associated viral vectors and then vitreally injected into rodent, nonhuman primate, and ex vivo human eyes that underwent testing for expression and integration.We tested for rescue of visual loss in rodent eyes also injected with a mutant G11778A ND4 homologue responsible for most cases of LHON. We found human ND4 expressed in almost all mouse retinal ganglion cells by 1 week after injection and ND4 integrated into the mouse complex I. In rodent eyes also injected with a mutant allotopic ND4, wild-type allotopic ND4 prevented defective adenosine triphosphate synthesis, suppressed visual loss, reduced apoptosis of retinal ganglion cells, and prevented demise of axons in the optic nerve. Injection of ND4 in the ex vivo human eye resulted in expression in most retinal ganglion cells. Primates undergoing vitreal injection with the ND4 test article and followed up for 3 months had no serious adverse reactions.