Body shop: First repair of single-gene mutation in human embryos
Last Updated on August 10, 2017 by Joseph Gut – thasso
August 07, 2017 – Humans become reparable like a broken car in the body shop: For the first time, scientists have corrected a disease-causing mutation in early stage human embryos with gene editing (or genome editing). By doing so, researchers repaired in these early stage human embryos the genetic/molecular defect (i.e., gene mutation) that leads to hypertrophic cardiomyopathy (HCM) in outgrown individuals.
Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden death in otherwise healthy young athletes, and affects approximately 1 in 500 people overall. It is caused by a dominant mutation in the MYBPC3 gene, but often goes undetected until it is too late. Since people with a mutant copy of the MYBPC3 gene have a 50 percent chance of passing it on to their own children, being able to correct the mutation in embryos would prevent the disease not only in affected children, but also in their descendants.
In the work just published in in the journal Nature, the collaborative research team from the Salk Institute, Oregon Health and Science University, and Korea’s Institute for Basic Science generated induced pluripotent stem cells from a skin biopsy donated by a male with HCM and developed a gene-editing strategy based on CRISPR-Cas9 that would specifically target the mutated copy of the MYBPC3 gene for repair. The targeted mutated MYBPC3 gene was cut by the Cas9 enzyme, allowing the donor’s cells’ own DNA-repair mechanisms to fix the mutation during the next round of cell division by using either a synthetic DNA sequence or the non-mutated copy of MYBPC3 gene as a template.
Using in vitro fertilization (IVF) techniques, the researchers injected the best-performing gene-editing components into healthy donor eggs newly fertilized with the donor’s sperm. Then they analysed all the cells in the early embryos at single-cell resolution to see how effectively the mutation was repaired. This approach could pave the way for improved IVF outcomes as well as eventual cures for some of the thousands of (rare) diseases caused by mutations in single genes.
Though gene-editing tools have the power to potentially cure a number of diseases for good, there will arise a huge debate about the ethical and societal consequences of these procedures. Here, from the side of scientists, Dr. Izpisua Belmonte, one of the researchers in the team, is a member of the committee on human gene editing of the National Academies of Sciences, Engineering and Medicine. He helped author the 2016 roadmap “Human Genome Editing: Science, Ethics, and Governance.” The research in the current study was fully compliant with recommendations made in that document, and adheres closely to guidelines established by OHSU’s Institutional Review Board and additional ad-hoc committees set up for scientific and ethical review. Overall, the research team is aware that although promising, these are very preliminary results and more research will be needed to ensure no unintended effects to occur in order to realistically assess the risks as well as the benefits. It is these risks and benefits that will spark the debate in society on acceptance of refusal of procedures capable of profoundly manipulating the integrity of the human being.
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Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.
Of course, hypertrophic cardiomyopathy (HCM) is a very complex disease, and the above approach of repairing mutations in the MYBPC3 addresses just one of very many possible molecular targets.
HCM is a primary disease of the cardiac muscle that occurs mainly due to mutations (>1,400 variants) in genes encoding for the cardiac sarcomere. HCM, the most common familial form of cardiomyopathy, affecting one in every 500 people in the general population, is typically inherited in an autosomal dominant pattern, and presents variable expressivity and age-related penetrance. Due to the morphological and pathological heterogeneity of the disease, the appearance and progression of symptoms is not straightforward. Most HCM patients are asymptomatic, but up to 25% develop significant symptoms, including chest pain and sudden cardiac death. Sudden cardiac death is a dramatic event, since it occurs without warning and mainly in younger people, including trained athletes. Molecular diagnosis of HCM is of the outmost importance, since it may allow detection of subjects carrying mutations on HCM-associated genes before development of clinical symptoms of HCM. However, due to the genetic heterogeneity of HCM, molecular diagnosis is difficult. Currently, there are mainly four techniques used for molecular diagnosis of HCM, including Sanger sequencing, high resolution melting, mutation detection using DNA arrays, and next-generation sequencing techniques.
For the interested reader, see the table accessible under the following link to see the many genes thought to be associated with and causing HCM:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199654/table/t1-tacg-7-195/
Moreover, see this excellent review article here:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199654/