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Clinical trials for ‘three-parent’ babies




*Gene editing corrects clotting in newborn, adult mice
The United Kingdom (U.K.) may soon become the first country to explicitly permit the birth of children from embryos modified to contain three people’s Deoxy ribo-Nucleic Acid (DNA)/genetic material. At the same time, new research backs up concerns that such a treatment — which aims to erase diseases transmitted by the DNA found in cellular structures called mitochondria — may not always be 100 per cent effective.

According to the report published in journal Nature, scientists advising the UK Human Fertilisation and Embryology Authority (HFEA) said on 30 November that, after two decades of research, the therapy is ready for limited clinical testing. It exchanges a mother’s faulty mitochondria for healthy ones from another woman’s egg. The result: a ‘three-parent’ baby with DNA from its father, mother and a third donor. The HFEA will decide whether to allow clinical trials of the therapy at a meeting on 15 December. If it does, the first procedures, approved on a patient-by-patient basis, could occur as soon as March or April 2017, a spokesperson said.

Also, CRISPR/Cas9, a powerful genome editing tool, is showing promise for efficient correction of disease-causing mutations. For the first time, researchers from the Perelman School of Medicine at the University of Pennsylvania, United States (U.S.), have developed a dual gene therapy approach to deliver key components of a CRISPR/Cas9-mediated gene targeting system to mice to treat hemophilia B. This disorder is also called factor IX deficiency and is caused by a missing or defective clotting protein. Their research will be presented during the 58th Annual American Society of Hematology Meeting and Exposition in San Diego from December 3 to 6, 2016.

Most single-gene diseases, such as hemophilia, are caused by different mutations scattered in a specific gene rather than a single predominant mutation, so the team needed to develop a vector that would be applicable for patients with any mutations.

The study is a preclinical proof of concept using a universal CRISPR/Cas9 gene targeting approach that could be applied to majority of the patients with a specific disease, in this case hemophilia B. According to the Centers for Disease Control and Prevention, hemophilia in general occurs in approximately 1 in 5,000 live births and there are about 20,000 people with hemophilia in the United States.

Meanwhile, the UK government legalized mitochondrial replacement therapy in 2015, but the HFEA, which was given the power to regulate the technique, had asked for more research before allowing any clinic to trial it. Fertility doctors said this year that they had already performed the procedure in countries such as Mexico and Ukraine, which do not have laws preventing it. That makes approval in the United Kingdom all the more urgent, some researchers say.

Dieter Egli, a stem-cell scientist at the New York Stem Cell Foundation who has studied mitochondrial-replacement therapies, thinks that it is very important to allow the therapies to go forward in UK clinics. He worries that people will increasingly seek the procedures on their own. “Maybe it’s not the best choice, but they will go elsewhere, even if it means greater risk, less oversight and less expertise. I think we can’t blame them for that.”

Studies testing the therapy in human eggs have suggested that it might not always prevent mitochondrial disease. And research published today by a group led by mitochondrial geneticist Shoukhrat Mitalipov, at Oregon Health & Science University in Portland further supports that concern. In mitochondrial replacement therapy, researchers transfer the nuclear genome of an egg that has mutant mitochondria into a healthy donor egg.

But a small number of mutant mitochondria — usually less than two per cent of the cell’s total — are also transferred, a phenomenon known as carry-over. Previous studies by Egli and others have suggested that these mutant mitochondria can out-compete the healthy donor mitochondria, rising to levels in cell culture that could cause disease if they occurred in a child’s tissue.

In the latest research, published in Nature, a team led by Mitalipov performed the procedure with eggs from four women carrying mitochondrial mutations that had caused diseases in their families (and in some cases in their children), and eggs donated by healthy women.
The resulting embryos were all virtually free of carry-over mitochondria, suggesting that the procedures had worked. But embryonic-stem-cell lines cultured from three of these 15 embryos regained the mother’s original set of mitochondria.

In other experiments, Mitalipov’s team simulated development by making brain, heart and other cells from stem cells derived from the new embryos. In some cases, the carry-over mitochondria came roaring back. If the same thing happens when an embryo is developing, it means that a child could retain some mutant mitochondria, Mitalipov says — and if they rose to high enough quantities, they could cause disease.

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Deoxy ribo-Nucleic Acid
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