Genetic “editing” a new tool to fight inherited disease

Left to right: Dr. Salvadora Cívico (Hospital Clínic), Dr. Josep M. Campistol (Chief of Neurology at the Hospital Sant Joan de Deu, Barcelona), Dr. Juan Carlos Izpisúa-Belmonte (Salk), Dr. Dolors Manau (Hospital Clínic), Dr. Núria Montserrat (IBEC) and Dr. Francesc Cardellach (Hospital Clínic).

This group of diseases affecting the mitochondria – small ‘power plants’ that generate energy in the body’s cells – are transmitted exclusively from mother to child. The only option today for parents who want to make sure their children don’t inherit mitochondrial diseases is to use pre-implantation genetic diagnosis to select embryos, although this still doesn’t guarantee a healthy baby.

In the study, published today in the journal Cell, researchers developed a simple technique to eliminate mitochondrial mutations in eggs or embryos at an early stage of development. “Currently there is no treatment for mitochondrial diseases,” says lead author Dr. Belmonte Izpisúa. “Our technology can offer new hope for carriers of mitochondrial pathologies that wish to have children free of the disease.”

Living cells may have hundreds or even thousands of mitochondria, and each contains its DNA, a small collection of 37 genes that are essential for function. Mutations in these genes cause a range of diseases and can lead to fatality at birth, a life expectancy of only a few years, or cause symptoms for decades.

“Most current strategies aim to develop drugs for patients already suffering from these diseases,” says Alejandro Ocampo, a research associate in Izpisúa Belmonte’s lab, and one of the first authors. “Instead, we’re trying to preventing transmission of these mutations early in embryonic development.”

The researchers focused on two types of molecules – nucleases – that can be designed to cut specific DNA strands and function like a sort of “molecular scissors”. The team from the Salk Institute designed nucleases that only cut the mitochondrial DNA in eggs or embryos containing mutations that cause disease, leaving healthy mitochondria intact.
Using mice containing two types of mitochondrial DNA, they selectively prevented the transmission of one type to the next generation using specific nucleases in both mouse eggs and embryos – and mouse babies born using this technique developed normally into adulthood. Furthermore, this method also enables the reduction of the levels of mitochondrial DNA responsible for two mutated human mitochondrial diseases. The team that participated in the study is now investigating the possibility of translating this technology to the clinic in human eggs and embryos.

Dr. Josep Maria Campistol, Medical Director of Hospital Clínic, IDIBAPS researcher and co-author of the study, stresses the importance of a combination of basic and clinical studies before the method can be transferred to patients. “We have the opportunity to do so with an institution like the Salk Institute, one of the world leaders in basic research.”

Nuria Montserrat, group leader at the Institute for Bioengineering of Catalonia, who contributed the characterization and design of cellular systems used in the study, said: “The collaboration with these two major Barcelona hospitals day to day in our research lab in IBEC gives us crucial contact with clinicians in the field of mitochondrial disease and other inherited disorders. The multidisciplinary approach of Dr. Izpisúa at Salk highlights the importance of pooling the different areas of study in which we work.”

Article: Reddy et al. (2015) “Selective Elimination of Mitochondrial Mutations in the Germline by Genome Editing” Cell,

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