Restriction endonucleases and transcription activator-like effector nucleases have been used to eliminate mutated DNA from mitochondria. Yellow: nucleases with mitochondria in a mouse egg. [Salk Institute for Biological Studies]
Restriction endonucleases and transcription activator-like effector nucleases have been used to eliminate mutated DNA from mitochondria. Yellow: nucleases with mitochondria in a mouse egg. [Salk Institute for Biological Studies]

Yet another preventative strategy is emerging to eradicate mitochondrial disease. Not long ago, mitochondrial replacement was all over the news, attracting attention—and arousing anxiety—because it is used to join materials from three people to create one healthy embryo. Now a new technique, germline gene editing, promises to resolve mitochondrial DNA defects more directly, via a single injection into a patient’s egg or one-cell embryo.

Instead of borrowing healthy mitochondria, the new technique uses gene-editing technology to eliminate mutations in a mother’s mitochondrial DNA, making it unnecessary to combine parents’ nuclear material with an egg donated by a third person. (In mitochondrial replacement, this egg is what provides the healthy mitochondria.)

The germline gene editing approach is being developed by Salk Institute researchers led by Juan Carlos Izpisua Belmonte, Ph.D. “Currently, there are no treatments for mitochondrial diseases,” noted Dr. Izpisua Belmonte, “Our technology may offer new hope for mitochondrial disease carriers wishing to have children without the disease.”

Dr. Izpisua Belmonte and his colleagues turned to two types of molecules: restriction endonucleases and transcription activator-like effector nucleases (TALENs). These nucleases can be engineered to cut specific strands of DNA, functioning as a type of molecular “scissors.” The Salk team designed nucleases to cut only mitochondrial DNA that contained specific, disease-causing mutations in eggs or embryos, leaving healthy mitochondria intact.

The Salk team described their work April 23 in Cell, in an article entitled, “Selective Elimination of Mitochondrial Mutations in the Germline by Genome Editing.” This article detailed how the scientists used mice containing two types of mitochondrial DNA and then prevented the transmission of one of the types to the next generation.

The scientists achieved this feat by using mutation-targeting nucleases in both eggs and one-cell embryos. Baby mice generated by this approach developed normally to adulthood. In addition, this method let the researchers successfully reduce the levels of mutated mitochondrial DNA responsible for two human mitochondrial diseases.

“As a proof of concept, we took advantage of NZB/BALB heteroplasmic mice, which contain two mtDNA haplotypes, BALB and NZB, and selectively prevented their germline transmission using either mitochondria-targeted restriction endonucleases or TALENs,” wrote the authors. “In addition, we successfully reduced human mutated mitochondrial DNA levels responsible for Leber’s hereditary optic neuropathy, and neurogenic muscle weakness, ataxia, and retinitis pigmentosa, in mammalian oocytes using mitochondria-targeted TALENs.”

Women wishing to prevent their children from inheriting mitochondrial diseases have typically relied on preimplantation genetic diagnosis to pick the healthiest embryos, but that is no guarantee of having a healthy baby.

“We might not be able to eliminate one hundred percent of the mutated copies of mitochondrial DNA,” remarked Pradeep Reddy, Ph.D., a research associate in the Izpisua Belmonte laboratory and first author of the new paper. “But you don't need to eliminate all of the mutated copies: just reducing the percentage significantly enough can prevent the disease in the next generation.”








This site uses Akismet to reduce spam. Learn how your comment data is processed.