Correction of a pathogenic gene mutation in human embryos

Gene editing technique successfully corrects mutation in human embryos

Researchers in the United States have successfully used a gene editing technique in early stage human embryos to correct a mutation that causes hypertrophic cardiomyopathy.

The embryos in the study were not allowed to develop for more than a few days and were never intended to be implanted into a womb. Further research is needed to establish the safety of the method before it can be adopted clinically. However, if the technique proves to be safe, it could potentially be used for other genetic disorders such as cystic fibrosis or Huntington’s disease.

2017 Study Abstract

Genome editing has potential for the targeted correction of germline mutations. Here we describe the correction of the heterozygous MYBPC3 mutation in human preimplantation embryos with precise CRISPR–Cas9-based targeting accuracy and high homology-directed repair efficiency by activating an endogenous, germline-specific DNA repair response. Induced double-strand breaks (DSBs) at the mutant paternal allele were predominantly repaired using the homologous wild-type maternal gene instead of a synthetic DNA template. By modulating the cell cycle stage at which the DSB was induced, we were able to avoid mosaicism in cleaving embryos and achieve a high yield of homozygous embryos carrying the wild-type MYBPC3 gene without evidence of off-target mutations. The efficiency, accuracy and safety of the approach presented suggest that it has potential to be used for the correction of heritable mutations in human embryos by complementing preimplantation genetic diagnosis. However, much remains to be considered before clinical applications, including the reproducibility of the technique with other heterozygous mutations.

Sources and Press Releases
  • Correction of a pathogenic gene mutation in human embryos, nature, doi:10.1038/nature23305, 02 August 2017.
  • Gene editing technique successfully corrects mutation in human embryos, BMJ 2017;358:j3726, 03 August 2017.
  • Featured image Schematic of MYBPC3∆GAGT gene targeting by injection of CRISPR–Cas9 into human zygotes at the S-phase of the cell cycle. MII oocytes were fertilized by sperm from a heterozygous patient with equal numbers of mutant and wild-type (WT) spermatozoa. CRISPR–Cas9 was then injected into one-cell zygotes. Embryos at the 4–8-cell stage were collected for genetic analysis. Injection during S-phase resulted in mosaic embryos consisting of non-targeted mutant, targeted NHEJ-repaired and targeted HDR-repaired blastomeres. credit nature.
  • Brave New World? Not Even Close, scientificamerican, August 2, 2017.
  • Deadly gene mutations removed from human embryos in landmark study, theguardian, August 2, 2017.
  • Embryo editing technique is ‘ethically dubious’, fertility expert warns, christian, August 8, 2017.

U.K. researcher receives approval to genetically modify human embryos

HFEA approval for new “gene editing” techniques

Scientists in Britain have been give the go-ahead to edit the genes of human embryos for research purposes, using a technique that some say could eventually be used to create “designer babies”.

The Human Fertilisation and Embryology Authority (HFEA) has approved a research application from the Francis Crick Institute to use new “gene editing” techniques on human embryos (see Licence Committee – minutes).

The aim of the research, led by Dr Kathy Niakan, a group leader at the Crick, is to understand the genes human embryos need to develop successfully.

The work carried out at the Crick will be for research purposes and will look at the first seven days of a fertilised egg’s development (from a single cell to around 250 cells).

The knowledge acquired from the research will be important for understanding how a healthy human embryo develops.

This knowledge may improve embryo development after in vitro fertilisation (IVF) and might provide better clinical treatments for infertility, using conventional medical methods.

Paul Nurse, director of the Crick, said:

“I am delighted that the HFEA has approved Dr Niakan’s application. Dr Niakan’s proposed research is important for understanding how a healthy human embryo develops and will enhance our understanding of IVF success rates, by looking at the very earliest stage of human development – one to seven days.”

In line with HFEA regulations, any donated embryos will be used for research purposes only and cannot be used in treatment. These embryos will be donated by patients who have given their informed consent to the donation of embryos which are surplus to their IVF treatment.

The genome editing research now needs to gain ethical approval and, subject to that approval, the research programme will begin within the next few months.

Press releases

  • Britain gives scientist go-ahead to genetically modify human embryos, reuters, Feb 1, 2016.
  • CRISPR Editing of Human Embryos Approved in the U.K., genengnews, Feb 1, 2016.
  • In a world first, UK scientists just got approval to edit human embryos, vox, February 1, 2016.
  • U.K. Approves First Studies of New Gene Editing Technique CRISPR on Human Embryos, time, Feb 1, 2016.
  • UK researcher gets go-ahead to create embryos using CRISPR, siliconrepublic, Feb 1, 2016.

Human Gene Editing important issues and need for appropriate regulatory oversight

Scientists urge caution on human gene editing

image of statue Human-Gene-Editing
The 2015 International Summit on Human Gene Editing concluded that it would be “irresponsible” to use a powerful tool for editing human genes until more is known about the consequences and ethics of passing genetic changes to future generations.

Abstract – 2015 International Summit Statement

Clinical Use: Germline.

Gene editing might also be used, in principle, to make genetic alterations in gametes or embryos, which will be carried by all of the cells of a resulting child and will be passed on to subsequent generations as part of the human gene pool. Examples that have been proposed range from avoidance of severe inherited diseases to ‘enhancement’ of human capabilities. Such modifications of human genomes might include the introduction of naturally occurring variants or totally novel genetic changes thought to be beneficial.

Germline editing poses many important issues, including:

  1. the risks of inaccurate editing (such as off-target mutations) and incomplete editing of the cells of early-stage embryos (mosaicism);
  2. the difficulty of predicting harmful effects that genetic changes may have under the wide range of circumstances experienced by the human population, including interactions with other genetic variants and with the environment;
  3. the obligation to consider implications for both the individual and the future generations who will carry the genetic alterations;
  4. the fact that, once introduced into the human population, genetic alterations would be difficult to remove and would not remain within any single community or country;
  5. the possibility that permanent genetic ‘enhancements’ to subsets of the population could exacerbate social inequities or be used coercively;
  6. and the moral and ethical considerations in purposefully altering human evolution using this technology.

It would be irresponsible to proceed with any clinical use of germline editing unless and until

  1. the relevant safety and efficacy issues have been resolved, based on appropriate understanding and balancing of risks, potential benefits, and alternatives,
  2. and there is broad societal consensus about the appropriateness of the proposed application.

Moreover, any clinical use should proceed only under appropriate regulatory oversight. At present, these criteria have not been met for any proposed clinical use: the safety issues have not yet been adequately explored; the cases of most compelling benefit are limited; and many nations have legislative or regulatory bans on germline modification. However, as scientific knowledge advances and societal views evolve, the clinical use of germline editing should be revisited on a regular basis.

Sources and More information

2015 International Summit on Human Gene Editing

Scientists debate ethics of human gene editing at international summit

International Summit on Human Gene Editing
Deep and disturbing questions’ surrounding diseases and designer babies examined at summit as experiments get closer to altering human heredity.

A major component of the National Academy of Sciences and the National Academy of Medicine’s Human Gene-Editing Initiative is an international summit to take place December 1-3 in Washington, D.C. Co-hosted with the Chinese Academy of Sciences and the U.K.’s Royal Society, the summit will convene experts from around the world to discuss the scientific, ethical, and governance issues associated with human gene-editing research.

More information

Should genetically modified human embryos be allowed?

Are genetically modified embryos “essential” for science?

It is “essential” that the genetic modification of human embryos is allowed, says a group of scientists, ethicists and policy experts. But critics say once the technology is allowed for research purposes, it is inevitable it will end up creating a market for enhanced, genetically modified babies.

Research involving genetic modification of human embryos, though controversial, is essential to gain basic understanding of the biology of early embryos and should be permitted, an international group of experts said.

The statement was issued by members of the so-called Hinxton Group, a global network of stem cell researchers, bioethicists and policy experts who met in the UK last week.

But critics say once the technology is allowed for research purposes, it is inevitable it will end up creating a market for enhanced, genetically modified babies.

Sources and more information
  • Statement on Genome Editing Technologies and Human Germline Genetic Modificationhinxtongroup, September 3-4, 2015.
  • Genetically modified human embryos should be allowed, expert group says, theguardian, 10 September 2015.
  • Genetically modified embryos “essential” for science, in-cyprus, 10/09/2015.
  • ‘Genetic modification of embryos is essential’: Report claims editing genomes holds huge potential and shouldn’t be feared, DailyMail, 10 September 2015.