Regulators weigh benefits of ‘three-parent’ fertilization

Mitochondria (green) in egg cells carry an independent lineage of DNA that can pass on genetic defects.

P. MOTTA/DEPT. ANATOMY UNIV. ROME LA SAPIENZA/SPL

Regulators in the United States are considering whether to permit trials of a controversial assisted-reproduction technique intended to help women to avoid passing certain genetic defects on to their children.

On 22 October, the US Food and Drug Administration (FDA) is scheduled to meet in Silver Spring, Maryland, to discuss a method that could prevent transmission of defects in mitochondria cellular components that contain a small amount of DNA from mother to child. The defects, which can cause fatal developmental conditions, affect as many as 4,000 US births a year.

The technique places nuclear DNA from the egg of a woman with a mitochondrial defect into a donated egg that has had its nuclear DNA removed, but contains healthy mitochondrial DNA. Once the egg is fertilized, the resulting embryo would, in a sense, have three parents, because the donor mitochondrial DNA is passed down along with the mother and fathers nuclear DNA.

The FDA was asked to look into the issue by developmental biologist ShoukhratMitalipov at Oregon Health and Science University in Beaverton, who last year created early human embryos with the technique (see Nature http://doi.org/n76; 2012). When the manipulated eggs were fertilized, genetic abnormalities were detected in half of them but seemingly normal embryonic stem-cell lines could be extracted from 38% of the rest. Trying to obtain stem cells from unmanipulated eggs results in a similar success rate. Mitalipov had used the same technique in 2009 to create apparently healthy rhesus monkeys. Now he wants to begin a clinical trial in humans.

In 2001, the FDA began to regulate the technique as a form of gene therapy after researchers used fresh mitochondria in a handful of infertile women to help them to conceive (see Energizing eggs). The regulation was widely, but incorrectly, reported as a ban. The FDA asked researchers to apply for permission to test the approach in clinical trials. But none did until now. At the time, the agency said that the safety data were not convincing, citing examples of genetic abnormalities such as a missing X chromosome in a fetus created with the technique.

As the US Food and Drug Administration (FDA) debates the merits of mitochondrial replacement in eggs, some observers will be looking for hints as to how the agency may regulate another mitochondrial manipulation one with fewer ethical and safety concerns.

OvaScience, a biotechnology company in Cambridge, Massachusetts, wants to boost the success rate of in vitro fertilization (IVF) by infusing eggs with fresh mitochondria. The mitochondria are harvested from an IVF patients own egg precursor cells, a cell type discovered by Jonathan Tilly, a reproductive biologist at Northeastern University in Boston, Massachusetts. Tilly says that these precursor cells can be coaxed to develop into mature eggs in adult women, challenging the dogma that women are born with all the eggs they will ever have. Tillys results are disputed (see Nature 491, 318320; 2012), but OvaScience has long-term plans to harvest precursor cells and use them to create fresh eggs for women for whom conventional IVF has failed.

The companys first project, called AUGMENT, is to harvest precursor cells, isolate their mitochondria, and inject them into mature eggs to see if they can revive eggs from infertile women, as work with mitochondria from donor eggs has suggested. Mitochondrial DNA from egg-precursor cells is thought to contain fewer mutations than mitochondrial DNA in the eggs themselves. Because OvaScience would be using mitochondria from a patients own cells, the company hopes to sidestep ethical concerns raised by three-parent embryos.

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Regulators weigh benefits of ‘three-parent’ fertilization