Getting a TALEN-hold on mitochondrial disease

A more specific method for deleting mutant mitochondrial DNA in human cells in order to combat diseases associated with mitochondrial dysfunction is reported in a paper published this week in Nature Medicine. These results may eventually be useful in permanently treating patients with some mitochondrial diseases.

The mitochondria-organelles that supply energy for all human cells-have their own genomic DNA (mtDNA). Deleterious mutations in mtDNA can be inherited or built up over time, leading to reduced mitochondrial function and disease. Previous work has looked at selectively eliminating mutant mtDNA while sparing normal mtDNA as a way to permanently treat such diseases.

To better achieve this goal, Carlos Moraes and his colleagues have created specific transcription activator-like effector nucleases (TALENs), which are enzymes that can be engineered to bind to any DNA sequence of interest. Their TALENs enter mitochondria and uniquely recognize and cleave two different mutant mtDNAs associated with human disease. The authors next showed that use of their TALENs reduced the levels of mutant mtDNA in cultured human cells harboring these mutations, as well as restoring the normal energy-producing capacity of these cells.

Though in vivo validation and other technical hurdles will need to be overcome before such an approach can be used in the clinic, Moraes and colleagues note that life-long treatment with the TALENs is likely not needed as once a cell has eliminated most if not all of its mutant mtDNA, then the cell and its progeny are ‘cured’.

doi: 10.1038/nm.3261

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