6:51 PM
 | 
Oct 11, 2018
 |  BC Innovations  |  Targets & Mechanisms

Adult path for mitochondrial gene editing

How the possibility of mitochondrial gene editing in adults could accelerate translation

Two parallel studies show gene editing can target mutant mitochondria in adult mice, providing an alternative path for drug developers to the controversial approach of modifying embryos.

In back-to-back papers published in Nature Medicine on Sept. 24, teams from the University of Cambridge and the University of Miami demonstrated that gene editing by zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) can target mitochondrial genes in vivo in adult mice, raising the prospect the techniques could be used to treat a subset of mitochondrial diseases.

Previous studies have shown that ZFNs and TALENs can destroy mutant mitochondrial genes in mouse oocytes and single-cell embryos.

However, embryonic gene editing has been embroiled in controversy, and the method of mitochondrial replacement therapy (MRT), approved in the U.K. -- and colloquially referred to as “three-parent IVF” -- is outlawed in the U.S. (see “Editing Advantage” and “A Meeting About a Meeting”).

By providing proof of concept that virally delivered nucleases can target mutant mitochondrial genes after birth, the new findings bring the approaches under FDA’s gene therapy guidelines -- a step that could increase activity in the field.

Sangamo Therapeutics Inc. SVP and CTO Edward Rebar, an author on the Cambridge paper, believes the studies represent significant progress, despite the challenges of delivery and dosing that remain.

“What’s excited people is it has taken mitochondrial diseases from a space where they were not even contemplated as being addressable to the point where we can actually start asking these questions,” said Rebar.

Rebar would not disclose if Sangamo plans to develop the ZFN-based therapy in the study. U.K.’s Medical Research Council and Sangamo have joint IP covering the approach.

The Miami group’s technology is not patented. However, Cellectis S.A. has IP covering TALEN technology that could cover mitochondrial gene editing. Cellectis did not respond to requests for comment.

“What’s excited people is it’s taken mitochondrial diseases from a space where they were not even contemplated as being addressable to the point where we can actually start asking these questions.”

Edward Rebar, Sangamo

Carlos Moraes, a professor of neurology at the University of Miami’s Miller School of Medicine and lead author on the TALEN paper, told BioCentury he wants to bring a TALEN-based therapy into the clinic first for Kearns-Sayre syndrome or MERRF syndrome -- both rare neuromuscular disorders. He said the team is in partnering discussions with undisclosed companies.

But while the findings might open up a regulatory path, postnatal gene editing presents delivery complexities that embryonic editing does not.

Deletion of a mutant...

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