An in-born heart defect has been fixed using gene editing in human embryos, scientists reported this week.
Hypertrophic cardiomyopathy (HCM) is one of the commonest genetic heart disorders. Almost half of all cases are caused by an individual inheriting a faulty copy of a gene called MYBPC3. This triggers the heart muscle to enlarge abnormally, blocking the smooth flow of blood leaving the organ and electrical instability that can stop the heart. As such, it's a leading cause of sudden cardiac death among otherwise healthy young adults and has claimed the lives of a number of professional sportsmen in recent years.
The fact that that the condition can ferequently be pinned to a single gene means that it might be amenable to genetic therapy targeted at the developing embryo that can "edit" the mistake from the mutated MYBPC3 gene by pasting in a working sequence to correct the defect and prevent HCM from ever occurring.
This week this hope took a step closer to becoming reality when researchers in the US announced the results of a series of experiments carried out on human embryos.
Publishing in Nature, Oregon Health and Science University in Portland scientist Shoukhrat Mitalipov and his colleagues used the gene-editing tool CRISPR-Cas9 to fix a defective MYBPC3 gene in eggs fertilised with sperm from an HCM patient carrying the MYBPC3 gene. Out of 58 HCM-affected embryos tested, the faulty gene was fixed by the technique in 42 of them, a success rate of about 70%.
Reassuringly, the researchers did not detect any "off target" effects, meaning incorrect changes made elsewhere in the cells' genomes, from their studies. This is an oft-expressed concern about gene editing approaches: that there is the possibility that, in fixing one mutation, other mistakes are accidentally introduced elsewhere.
The key to the success of the present work, the researchers explain, was to inject the CRISPR-Cas9 gene editing chemicals into an unfertilised egg alongside the sperm used to fertilise it. In this way, the DNA of the sperm, which is carrying the defective MYBPC3 gene, is fixed before it pairs up with the egg DNA and begins to form embryonic cells. This limits the likelihood of some cells escaping correction and producing an embryo with a mixed genetic make-up called a mosaic. Indeed, only 1 of the 58 embryos treated by the Oregon team became a mosaic.
A surprise finding from the study was how the CRISPR-Cas9 construct engineered by the team actually fixed the genetic defect. CRISPR behaves like a molecular pair of scissors that slide along the DNA strand looking for a specific sequence of DNA letters to cut. Alongside these scissors, scientists also supply a short piece of DNA carrying the correct genetic sequence. The idea is that, when CRISPR finds its target and cuts the DNA, the correct sequence is then "patched" in instead.
But, in the treated embryos, the CRISPR system ignored the patch and instead copied the sequence from the copy of the healthy MYBPC3 gene carried by the egg. No one expected this and nor do they know why it happened. It could mean that genetic defects carried by sperm are easier to fix than those carried by eggs. The team will need to do the experiment to find out.
Nevertheless, the results are a landmark first. Apart from a handful of minor trials carried out in China, this is the first example of a successful editing process to fix a genetic disorder in a human embryo.
That said, the process is still at a very early stage. Critically, none of the human embryos tested were allowed to continue to develop, and the success rate of treatment is still only 70%, and one of the embryos still formed a mosaic or mixture of treated and untreated cells.
As many are cautioning over the hype, there is a considerable way to go before this technique is ready for the clinic...
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