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quinta-feira, 15 de abril de 2010

Freeing human eggs of mutant mitochondria

Published online 14 April 2010 | Nature | doi:10.1038/news.2010.180

Freeing human eggs of mutant mitochondria

Transmission of mitochondrial diseases from mother to offspring could be prevented.
 Transferring DNA from one fertilized egg to another could help prevent the transmission of some inherited diseases.
The British team carrying out the study used fertilized eggs donated by couples undergoing fertility treatment, and which were unsuitable for in vitro fertilization (IVF). At this early stage the sperm and egg nuclei, which contain most of the parental genes, have not yet fused. The researchers removed these nuclei and transferred them into another fertilized egg cell which had had its own nuclei removed.
As very little cytoplasm was transferred with the nuclei, the transfer left behind almost all the mitochondria from the donor egg. The researchers then grew the manipulated embryos for 6 to 8 days to determine whether they were able to continue development, and tested for the presence of donor mitochondrial DNA. Their work is published online by Nature today1.
Last year, researchers in the United States used a similar technique in monkeys; four embryos developed to term, and so far seem to be healthy and normal2.
"It's very exciting," says David Thorburn, a geneticist who studies mitochondrial diseases at the Murdoch Childrens Research Institute in Melbourne. "It's a real shot in the arm for families that have had their children die from these various diseases."

Proof of principle


As many as 1 in 250 people carry a potentially disease-causing mitochondrial mutation. Mutations in mitochondrial DNA, when passed down from a mother to her offspring, are linked to diseases causing neurological, muscle and heart problems, as well as deafness and type 2 diabetes.
Many people carry a mixture of normal and mutated mitochondrial DNA — a proportion of more than 50% or so of mutant mitochondria is needed to cause disease — but the percentage of mutated mitochondrial DNA that will be transmitted from mother to child is almost impossible to predict, says Thorburn.


Porting the nuclear DNA of an affected egg into an unaffected one could provide a solution for women at high risk of bearing severely affected children, says Douglass Turnbull at Newcastle University, one of the lead authors of the new study. Working with abnormally fertilized eggs unsuitable for IVF — for example, those fertilized by two sperm instead of one — Turnbull and his team transferred nuclei from 80 embryos just after fertilization. Of those, 18 continued to develop to beyond the eight-cell stage, and a small number of those reached the blastocyst stage of 100 cells. On average, the procedure carried over about 2% of mitochondrial DNA from the donor to the recipient embryo, which would not be enough to cause disease.
"We've proved in principle that this sort of technique can be used to prevent transmission of mitochondrial diseases in humans," says Turnbull. The task now, he says, is to show that the technique is safe and to boost the survival rate of manipulated embryos — factors that were difficult to assess in this study because abnormally fertilized eggs develop less well than normal embryos.

 

Human hopes


Nevertheless, twice the number of unmanipulated abnormally fertilized eggs developed to blastocyst stage compared with the manipulated eggs, suggesting that the technique needs some tweaking, notes Shoukhrat Mitalipov at Oregon Health & Science University in Portland, whose lab published the work on monkeys. Mitalipov's group used a slightly different method, transferring the nuclear DNA from unfertilized eggs. Using fertilized eggs may pose an ethical problem, he says, as the transplantation procedure destroys the donor embryo.


Turnbull and his colleagues are currently working with the Human Embryology and Fertilisation Authority, the UK body that licenses research on embryos, to determine what further studies must be done before a human embryo that has undergone the procedure can be brought to term. "There isn't a license in place to do this at the moment," he says. Mitalipov, too, plans to seek approval from the US Food and Drug Administration to use his technique in vivo, which is likely to prove challenging because gene therapy involving human eggs and sperm is highly restricted on ethical grounds.
Regardless of the technique, says Thorburn, the researchers will have to show that mixing different nuclei and cytoplasms does not affect normal development. Even succesful trials in monkeys will not prove that the technique will be succesful in humans, he notes. "I guess every IVF approach has been to some extent a leap of faith."

 http://www.nature.com/news/2010/100414/full/news.2010.180.html

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