Three-person in-vitro fertilization sounds like something out of science fiction—or pulp fiction—but until recently it was the only known technique to prevent women who have damaging mitochondrial DNA mutations from passing on life-threatening disorders to their babies. And it is illegal in the U.S (clinical trials required by the FDA have not been completed). Now researchers at the University of Miami have demonstrated a new strategy that could one day treat these disorders both in adult carriers and in their already born children.
Every cell in your body has tiny "powerhouses" or mitochondria, which have their own sets of DNA, separate from the DNA in the nucleus. Unlike nuclear DNA, mitochondrial DNA (mitoDNA) is inherited directly from your mother, with no contributions from dad. As in nuclear DNA, mutations in mitoDNA can lead to big problems.
MitoDNA mutations have been tied to many diseases with broad symptoms such as seizures, muscle wasting, deafness, or diabetes. Doctors start screening for these diseases when two or more seemingly unrelated symptoms affect multiple organs. MitoDNA-linked disorders affect an estimated 1 in 2,500-3,000 individuals, according to the Foundation for Mitochondrial Medicine.
Often, a mother will not discover that she has mitochondrial mutations until her child is diagnosed. The problem becomes apparent during fetal development. When cells divide, the mitoDNA is segregated between two new mitochondria, and one may end up with more defective copies. This can result in a pancreas with a problem, but normal kidneys. If the mother had more equitable cell divisions, she may not have symptoms of a disease, while her child does. Three-way IVF may help subsequent children, but not first-borns with mitochondrial mutations.
The ideal treatment would alter the DNA in individuals born with these diseases. One way to do it would be to eliminate the mutated DNA. A study published last month in Nature Medicine uses a technology that does just that.1 Sandra Bacman and colleagues at the University of Miami use Transcription Activator-Like Effector Nucleases (TALENs) to delete mutated DNA. TALENs are engineered proteins that snip DNA at specific DNA sequences.
Bacman and colleagues designed TALENs that are effectively shuttled into the mitochondria (mitoTALENs). They showed that they can reduce mutated mitoDNA by making TALENs that cleave mutations common in mitochondrial diseases. This elegant proof-of-concept could be expanded and used to as a possible therapeutic in treating mitochondrial diseases in both affected individuals and their future offspring.
1Bacman SR, Williams SL, Pinto M, Peralta S, Moraes CT. (2013). Specific elimination of mutant mitochondrial genomes in patient-derived cells by mitoTALENs. Nat Med. 10.1038/nm.3261. This research was supported by NIH grants 5R01EY010804, 1R01AG036871 and 1R01NS079965.