Hopes raised for new genetic therapy to prevent inherited diseases
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Version 0 of 1. Researchers in the US have raised hopes for a simple genetic therapy that could prevent devastating diseases being passed on from mothers to their children. A team at the Salk Institute in California demonstrated in mice that a single injection into embryos could rewrite faults in the DNA of mitochondria, the biological batteries that are needed to keep tissues healthy. Most cells in the body carry hundreds or thousands of mitochondria which are inherited only from mothers. Harmful mutations in mitochondrial DNA cause progressive and often fatal diseases that typically affect the heart, brain and muscles. There are no cures for mitochondrial diseases, but recent changes to UK law permit an experimental procedure called mitochondrial transfer, in which embryos are created with healthy mitochondria from a female donor. The procedure is controversial because the embryos carry DNA from three people, and the medical risks - which are not fully known - would affect many generations hence. The US researchers showed that simple and widely-available genome editing procedures could correct faulty mitochondria in mouse embryos and dramatically reduce the number they passed down to future generations. The study came out just as Chinese scientists claimed to have used similar procedures to genetically modify human embryos for the first time. The Chinese group tried to correct the genetic defect that causes beta-thalassaemia, a life-threatening blood disorder, but found that the technique used was inefficient and unsafe. The embryos used for the experiment were not able to grow into healthy babies and would have been discarded by IVF clinics. In the US experiments, scientists first injected freshly-fertilised mouse embryos with enzymes that cut DNA at specific points. The mice had two types of mitochondria that differed by one letter of the genetic code. When the enzymes were injected, they behaved like molecular scissors that cut out the target letter in one type of mitochondria, leaving the rest largely untouched. In a second series of experiments, the scientists inserted faulty human mitochondria into mouse eggs and then tried to correct the mutations. The human mitochondria carried defects that cause two different types of debilitating disease: Leber’s hereditary optic neuropathy (LHOND), and neuromuscular weakness, ataxia, and retinitis pigmentosa (NARP). This time, the researchers created bespoke enzymes in the lab that targeted the harmful mutations without damaging DNA elsewhere in the cells. These were less effective than those used in the first experiments, but still reduced mitochondrial mutations by around half, the scientists write in the journal Cell. Many mitochondrial diseases only take hold if the person, or their specific organs, carry a sufficiently high proportion of faulty mitochondria, said Juan Carlos Izpisua Belmonte, who led the work. Belmonte explained that mitochondrial diseases are negligible if at least half of the mitochondria are healthy. Buoyed by their findings, the US group has begun tests on surplus human eggs donated by fertility clinics. The modified eggs will be used to create stem cells which in turn will be grown into muscle, brain and heart cells to see if they function properly. “This technology is not perfect, it cannot eliminate all the bad DNA, but by eliminating some, it’ll be enough to prevent the transmission of these diseases to the kids of affected mothers,” said Belmonte. The next round of experiments should reveal any problems caused by accidental cuts made to healthy genes. These are almost inevitable, and predicting how serious these “off-target” changes could be is a major hurdle scientists. “Only when we are sure that the muscle, brain and heart cells function properly, can we can put this on table,” Belmonte said. “Society needs to decide if we want to go forward with techniques like this.” Belmonte believes the new procedure, if found to be safe and effective, has major advantages over mitochondrial transfer. The procedure is simple, meaning it could be performed at hundreds of labs around the world, rather than only a handful. And it does not call for a donor and the creation of babies with DNA from three people. Joanna Poulton, professor of mitochondrial genetics at the University of Oxford, said that while genome editing could one day become viable for women at risk of passing on mitochondrial diseases, egg donation and pre-implantation diagnosis of embryos were still the best options. She also cautioned that genome editing might not be suitable for all women. Some mitochondrial diseases, such as LHOND, do not have a well-established threshold below which the mutations are not a serious problem, so it is hard to know how much reducing the mutated mtDNA will help, she said. Bruce Whitelaw, professor of animal biotechnology at Edinburgh University’s Roslin Institute, said: “Conceptually this is an alternative to the ‘three person embryo’ strategy.” “Society needs to grapple with this,” he added. “You could imagine every IVF clinic in the country being able to do this. But is the genome editor technology robust enough yet? I think that’s an open question. I genuinely believe it will be in the near future, so we have to have the debate now: what applications are beneficial and which ones does society has concerns about?” |