Could Genetic Diseases Be Cured in the Womb?

Efforts to develop a working gene therapy for certain inherited diseases have reached a milestone with a new method for altering a human egg cell.

If the technique, which was unveiled by Oregon Health & Science University and involves transplanting mitochondrial DNA, is ever approved for use in patients, a child's genetic makeup could be altered to cure certain genetic diseases before the baby is even born. Even so, the researchers acknowledged that realistically the treatment wouldn't likely be approved for testing in humans for a while.

The gene-tweaking technique, which is detailed online today (Oct. 24) in the journal Nature, is designed to treat diseases caused by genetic mutations in the cells' energy-making structures called mitochondria, said lead researcher Shoukhrat Mitalipov of OHSU School of Medicine.

Mitochondrial diseases can lead to diabetes, degeneration of nerves, or blindness, so the diseases themselves are often mistaken for other problems. Once the disease is identified, various supportive therapies are available, but generally there is no cure because the disease is caused by genetic mutations that are locked in. [Top 10 Mysterious Diseases]

Swapping out DNA

Mitochondrial DNA (mtDNA) comes only from the mother and is contained in the cell's cytoplasm, between the nucleus and the membrane (unlike nuclear DNA, which sits in the cell's nucleus). In the new study, Mitalipov and colleagues took a donor egg cell and removed the nucleus. They replaced this nucleus with one from the mother's egg cell, resulting in a cell with the mother's DNA but the donor's mtDNA.

The cell was then fertilized, allowed to divide and become a blastocyst, or a small agglomeration of embryonic cells. From that, the researchers derived embryonic stem cells. The cells looked normal, just like the controls. [5 Amazing Stem Cell Discoveries]

This shows that the cells with the "new" mtDNA function just like ordinary egg cells, Mitalipov said in a press conference. "This shows the procedure is compatible with normal fertilization."

Since the mtDNA isn't in the nucleus, this type of gene therapy wouldn't change one's parents. (mtDNA does show up in some types of gene sequencing, but it is a very small number of genes — less than one in 10,000.)

Genetic diseases that result from problems with nuclear DNA wouldn't be affected by the therapy, so it isn't likely to be of any help for a disease such as cystic fibrosis or Down syndrome.

Ethics of gene therapy

The experiments on human cells build on work conducted in 2009 with macaque monkeys. In that case, the experiment involved two populations of healthy macaques, one from India and one from China. One group of macaques had their egg cells' nuclei transferred to donor cells from the other population. The result, Mitalipov said, was healthy macaque infants carrying the donor mtDNA. "The infants were normal even though they had foreign mtDNA," he said.

Mitalipov also experimented on frozen macaque egg cells and showed the technique works with them as well, though the success rate was lower.

If this treatment were used on humans, it would work only in future children, since it involves changing the genes of an embryo before development. That opens up a lot of ethical questions about parents who want to alter their child's genes — even if it is for health reasons.

"Your mitochondrial DNA really is a part of your identity," said Gerard D'Souza, assistant professor of pharmaceutics at the Massachusetts College of Pharmacy and Health Sciences, who wasn't involved in the current study. He noted that entire studies have traced ancestry via mitochondrial DNA, suggesting people think of it as a piece of who they are.

D'Souza added that Mitalipov's approach was a big departure from a lot of current thinking about gene therapy. For gene therapy to work, the genes (or the agents to repair them) have to be delivered to many cells at once. That's why viruses are often used as a vector, or carrier. "Rather than deliver DNA to multiple cells, he just let one cell become the individual," he said.

For his part, Mitalipov said he and his team are in discussions with the Food and Drug Administration about how to set up a clinical trial of the technique in humans. During the press briefing, Mitalipov said the technique is safe thus far, and the experiment passed muster with the university's institutional review board. The experiments were funded privately.

Still, it likely will be some time before a human trial is approved.

Among the ethical questions raised by the technique concern the hope that it would offer to people at risk for genetic disease. "People try all sorts of treatments," D'Souza said. "They realize nothing works, and only then do they check if it's a [mitochondrial genetic] disorder."

Charles Mohan, CEO of the United Mitochondrial Disease Foundation, said that if the new treatment becomes available to parents, it will allow them to at least make decisions about the health of their children in the first place. Right now, for anyone who carries the genes for mitochondrial disease, it's a roll of the genetic dice — even assuming one knows they have the genes in the first place. Mohan's daughter died from a mitochondrial disease at 15, and did not show symptoms until she was 10. Meanwhile, his son is now an adult, and healthy.

"It provides an alternative," he said. "If we had known earlier, what decisions would we have made?" Whatever the controversies about genetically engineering humans, a cure like this would at least mean that it's possible to make such decisions.

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