9 July 2019
ESHRE recommends extreme caution on the use of spindle transfer in human oocytes as a clinical application to address fertility problems. This treatment, also known as mitochondrial donation, involves the replacement of chromosomes of donor oocytes with the chromosomes of the patients, with the aim of correcting cytoplasmic disorders. This technique was originally developed for the treatment of women carrying life-threatening mitochondrial diseases to prevent the birth of affected children. After expert evaluation, it was made legal in 2015 in the UK, where each application, available only from licensed centres, is considered on a case by case basis and authorized only for those cases with a clear medical need and having no alternative.
Recently, researchers from a Greek Institute reported the birth of a healthy boy following the use of spindle transfer in a 32-year-old woman without an inherited mitochondrial disease, who had failed four previous cycles of IVF. Whether there was an identifiable ‘cytoplasmic disorder’ is unclear.
In the absence of solid evidence proving that spindle transfer or other forms of cytoplasmic donation provides higher live birth rates than conventional assisted reproductive technology, the application of spindle transfer as a remedy for fertility treatment remains vague and unproven. The recent report in Science on the untested interplay between mitochondria and nucleus remains unclear in the possible generation of short and long term side effects (Science 364, eaau6520, 2019). The current lack of solid scientific evidence providing safety reassurance requires more study and continued vigilance.
At the present stage, and until this technology has been proven to be effective and safe, ESHRE strongly discourages the use of mitochondrial donation to alleviate an infertility condition. In line with the document issued by HFEA, the UK fertility regulator, and co-signed by ESHRE and other scientific societies on new introduction in IVF, we support the need for a responsible use of evidence-based treatments in fertility practice (https://www.hfea.gov.uk/media/2792/treatment-add-ons-consensus-statement-final.pdf).
3 May 2019
The Human Fertilisation and Embryology Authority (HFEA) has published a final consensus statement, endorsed by ESHRE, that is one element of a range of intitatives designed to set standards and inform patients about the use of treatment add-ons in the UK.
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22 March 2019
ESHRE supports the call for a moratorium on the use of CRISPR/Cas9 nucleases in the human embryo for clinical applications (Nature 567, 165-168 (2019)). This powerful genetic tool can be programmed easily to facilitate the correction of genetic mutations seamlessly and at high efficiency. Although the technology is already revolutionizing preclinical biomedical research, multiple independent reports have raised awareness that the CRISPR/Cas9 system can cause unexpected alterations to genomic DNA resulting in potentially damaging mutagenic events.
Firstly, the nuclease can cause mutation to the genome at closely matched sequences to the target gene, so called off-target mutations. Secondly, recent reports have shown that the enzyme can also cause unexpected large deletions and rearrangements at the actual target site, which could have considerably larger mutagenic effects . Lastly, when applied within the fertilized zygote, the persistence of the enzymes after the first cell-cleavage event can lead to a mosaic outcome, where different cells within a single embryo would harbour different mutations. The downstream consequences of non-specific mutagenesis off-target, genomic rearrangement on-target, and unpredictable mosaicism, are clearly hard to predict but have considerable potential to limit the safety of the CRISPR/Cas9 system for therapeutic intervention.
The ethics of germline genome editing are being widely discussed and debated, but all stakeholders agree that this technology can only be considered for clinical application if it is deemed safe. Research scientists are busy trying to understand the frequency and prevalence of these unexpected events and are developing new technologies to help eliminate them. Until such a time when the risks can be quantified or next generation tools developed which eliminate these disadvantageous consequences, ESHRE strongly supports the view that clinical application of CRISPR/Cas9 gene editing within the human zygote should not be performed.
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