Destroying Mutant Mitochondrial DNA as a Strategy to Treat Mitochondrial Disease
The herd of bacteria-like mitochondria in each of our cells are vital cellular components, and come equipped with their own small genome, the mitochondrial DNA, one or more copies in each mitochondrion. If that DNA is broken, then harm results. Mitochondrial diseases bear only superficial similarities to the mitochondrial DNA damage that is a root cause of degenerative aging; while it is the case that mitochondrial DNA is mutated in both cases, the distribution of those mutations in cells and tissues is quite different. Nonetheless, it seems a reasonable proposition that a strategy of selectively destroying damaged mitochondrial DNA may work in each situation, though for different reasons.
In inherited mitochondrial disease, there is some split between healthy and damaged copies of mitochondrial DNA in cells. Destroy the bad genome copies and the good ones will hopefully replicate to make up that loss. In aging, just a few cells become entirely overtaken by clones of mitochondria with damaged genomes, but they exert a sizable negative influence on health via generation of oxidative molecules. Destroying all of the mitochondrial DNA in those cells might be expected to kill them, for all of the obvious reasons. Since there are few of them, destroying them is probably the most expedient approach to dealing with the issue. In both cases, effectiveness would be determined by how clean a sweep is made, though one might imagine temporary or partial benefits resulting from removing even half of the damaged mitochondrial genomes.
"Mitochondrial replacement therapy is a promising approach to prevent transmission of mitochondrial diseases, however, as the vast majority of mitochondrial diseases have no family history, this approach might not actually reduce the proportion of mitochondrial disease in the population. One idea for treating these devastating diseases is to reduce the amount of mutated mitochondrial DNA by selectively destroying the mutated DNA, and allowing healthy DNA to take its place."
To test an experimental gene therapy treatment, which has so far only been tested in human cells grown in petri dishes in a lab, the researchers used a mouse model of mitochondrial disease that has the same mutation as some human patients. The gene therapy treatment, known as the mitochondrially targeted zinc finger-nuclease, or mtZFN, recognises and then eliminates the mutant mitochondrial DNA, based on the DNA sequence differences between healthy and mutant mitochondrial DNA. As cells generally maintain a stable number of mitochondrial DNA copies, the mutated copies that are eliminated are replaced with healthy copies, leading to a decrease in the mitochondrial mutation burden that results in improved mitochondrial function.
The treatment was delivered into the bloodstream of the mouse using a modified virus, which is then mostly taken up by heart cells. The researchers found that the treatment specifically eliminates the mutated mitochondrial DNA, and resulted in measures of heart metabolism improving. Following on from these results, the researchers hope to take this gene therapy approach through clinical trials, in the hope of producing an effective treatment for mitochondrial diseases.