Belfast Telegraph

Monday 29 December 2014

Successful gene therapy trials raise hopes for end to inherited human disorders

Scientists are on the verge of ridding inherited diseases from future generations with a new technique for swapping genes between unfertilised human eggs before the resulting IVF embryos are implanted into the womb.

The technique has been successfully tested on laboratory monkeys and researchers believe it is now safe enough to apply for clinical trials on the many thousands of women at risk of giving birth to babies with some of the most debilitating inherited disorders.



Such a procedure would break new ground and raise fresh ethical concerns over the direction of IVF research because it would lead to permanent changes to the genetic make-up of children that would be passed on to subsequent generations of the same families.



This form of gene therapy, known as germline gene therapy, alters the DNA of sperm or eggs and is banned in Britain because of fears over its safety as well as the prospect of it leading to the creation of "designer babies". However, a clause in the new Human Fertilisation and Embryology Act, which comes into force on 1 October, could permit a type of germline gene therapy involving mitochondrial DNA – which exists outside the chromosomes – without the need for changes to primary legislation and a parliamentary vote.

Germline gene therapy: How it works

Mitochondria, the tiny "power houses" of cells and their DNA, which lies outside the nucleus, is inherited solely down the maternal line. It is estimated that 1 in every 200 babies are born with mitochondrial mutations, some of which can lead to serious, life-long illnesses, such as diseases of muscles and nerves, as well as diabetes and cancer. The study on monkeys involved "renewing" the mitochondria of their eggs by the wholesale transfer of the chromosomes of one of their eggs into the egg of a donor female that had its own chromosomes removed so that only her mitochondrial DNA was left.



The aim was to test the feasibility of taking eggs from women with one of the 150 known mitochondrial DNA disorders and using them to create healthy eggs by transferring their chromosomes into donor eggs with no chromosomes of their own. The resulting egg would have DNA from two females and, when fertilised with a sperm, would result in an embryo which has three genetic parents.



In the latest study, four healthy macaque monkeys have been born using the technique. The scientists involved said yesterday there is no evidence that the procedure is unsafe and that they were planning to apply for ethical approval to conduct clinical trials in humans within a few years.



"In theory, this research has demonstrated it is possible to use this therapy in mothers carrying mitochondrial DNA diseases so that we can prevent those diseases from being passed on to their offspring," said Shoukhrat Mitalipov, of Oregon Health and Science University in Beaverton, Oregon.



"We believe with proper governmental approvals, our work can rapidly be translated into clinical trials for humans, and approved therapies," said Dr Mitalipov, whose study with colleague Masahito Tachibana is published in the journal Nature.



Conventional gene therapy has been tried in humans for 20 years but changing the DNA of mitochrondria would raise new ethical concerns. "This is not a simple form of gene therapy. This type involves replacing genes in the germline which will of course transmit it to the next generation and there are concerns," Dr Mitalipov said.



"We are talking of gene defects that cause terrible diseases. So the only way to prevent these genetic defects is to replace these genes whether we like it or not. We realise it's gene therapy involving the germline."



Professor Peter Braude, a specialist in reproductive medicine at King's College London and director of the Centre for Preimplantation Genetic Diagnosis at Guy's Hospital, said that the study involved a series of technically difficult experiments that were meticulously executed. "For the first time, proof of principle has been demonstrated that transmission of mitochondrial disease might be avoided. It is a first step toward preimplantation correction of the serious medical disorders caused by defective DNA inherited maternally in the mitochondria," Professor Braude said.



"The transfer of the normal genetic material from a mother who has defective mitochondria, to a clean donated oocyte [egg] with normal mitochondria would allow it to be fertilised with her partner's sperm and for them to have a child free of the mitochondrial disease with the genetic material of the couple."



A spokesman for the Human Fertilisation and Embryology Authority said: "If, in the future, safe and effective treatments are then developed to prevent the transmission of mitochondrial disease, Parliament would have to pass secondary legislation to allow that treatment to take place under HFEA licence. Any specific proposals would be closely examined by a Licence Committee to ensure that appropriate safeguards were in place."

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