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Science corrects a faulty gene in embryos

Gene scissors were just successfully used experimentally, to cut open a strand of DNA to prevent a hereditary heart disease...

In July of 2017 a paper was submitted to the journal Nature reporting that a disease-causing mutation had been corrected in human embryos. The work was the result of an international team including the Center for Genome Engineering, within the Institute for Basic Science (IBS, South Korea), Oregon Health and Science University (OHSU, USA), Salk Institute for Biological Studies (USA), and the BGI-Qingdao Shenzhen Engineering Laboratory for Innovative Molecular Diagnostics (China).

Scientists have been studying the human egg and sperm to correct human in-fertily since Robert G. Edwards began treatments in London in 1969. Some concerns surrounding gene editing today sound quite familiar to protests made decades earlier about in vitro fertilization. The birth of the first in vitro baby in 1978 helped calm down the concerns. Now, the use of the gene-editing tool CRISPR-Cas9 in this case to repair a common genetic heart disease called 'hypertrophic cardiomyopathy' is generating a similar set of fears. Even when this technique would eliminate the disease from being inherited by succeeding generations.

Experiments on embryos carrying the mutation were conducted in the USA following all ethical guidelines. Institute for Basic Science (IBS) researchers provided CRISPR-Cas9 and analyzed the DNA of the embryos to make sure that the procedure worked correctly.

CRISPR-Cas9 combined with in vitro fertilization (IVF) and preimplantation genetic diagnosis (PGD) could be helpful for many other genetic diseases. However, the scientists stated that "genome editing approaches must be further optimized" before moving to clinical trials.
"We have succeeded in correcting the mutated gene which causes hypertrophic cardiomyopathy in human embryos with high efficiency and specificity. Research on human embryos has been a very sensitive subject. The application of this technology to clinical practice in the future requires not only additional research, but also social consensus."

Jin-Soo KIM PhD, Director of the Center for Genome Engineering, within the Institute for Basic Science (IBS).

Hypertrophic cardiomyopathy is a genetic disease that kills athletes and is one of more than 10,000 inheritable diseases caused by an error in a single gene. This genetic disease manifests only in adulthood and affects an estimated 1 in 500 people. It can lead to heart failure and sudden death in apparently healthy people. It is well known by sports doctors because training worsens the condition in athletes who suffer from this disease. It is an autosomal dominant genetic disease, meaning that patients with a single copy of the mutant gene are affected and have a 50% chance of transmitting it to their offspring. Current treatments rely mainly on symptomatic relief.

Forty percent of all familial hypertrophic cardiomyopathy is caused by a mutation of the MYBPC3 gene located on the 11th chromosome. In this study, researchers dealt with a mutation characterized by four missing base pairs in the MYBPC3 gene. Reintroducing these four base pairs with CRISPR-Cas9 into the embryo prevents this mutation from appearing in future generations.

The experiment on human embryos was conducted by the OHSU research team in the United States. Researchers worked with healthy egg cells, donated by women, and sperm of a man affected by hypertrophic cardiomyopathy.

The IBS team provided CRISPR-Cas9, a genetic tool that has already been shown to eliminate, add or replace pieces of DNA in specific genes. In this case, it allowed the correction of the hypertrophic cardiomyopathy mutation carried in the DNA of the sperm. CRISPR-Cas9 works much like a pair of genetic scissors designed to cut the DNA near the position of the mutation. Then, the cut is spontaneously repaired by the cell with different mechanisms: one repairs the DNA without leaving any trace, while the other also introduces some unwanted insertions or deletions of a few base pairs near the cutting site.
Previous studies injected CRISPR-Cas9 after IVF, but then faced mosaicism problems, which means the embryos end up having a mixture of cells with and without the repaired mutation. Mosaicism would lead to organisms with some tissues or organs that bear the targeted mutation and some that do not. In this study, the researchers injected sperm and CRISPR-Cas9 into the egg at the same time to improve the accuracy of the gene correction. Thanks to this strategy, mosaicism did not occur.

CRISPR-Cas9 cut the DNA at the correct position in all of the tested embryos (100%) ending up with 42 out of the 58 embryos (72.4%) not carrying the hypertrophic cardiomyopathy mutation. This technique increased the probability of inheriting the healthy gene from 50% to 72.4%. Importantly, while doing this research the scientists also discovered that human embryos have an alternative DNA repair system, so that Cas9-induced cuts in sperm DNA are able to be repaired using healthy egg DNA as a template. In the remaining 27.6% of embryos, the cellular cut-repairing mechanism introduced some unwanted insertions or deletions near the cut.

Having confirmed that the disease-causing mutation is repaired correctly in human embryos, IBS researchers then performed further analysis to make sure that the gene scissors did not cut any other sites of the human genome. The IBS team has previously developed a technique known as Digenome-seq to assess the accuracy of the gene scissors, as off-target cuts and editing mistakes could be a major problem and bring unwanted consequences. Sequencing the whole genome of the embryo did not find any off-target changes. The result was also confirmed with another DNA sequencing technique by researchers working at BGI-Qingdao and Shenzhen Engineering Laboratory for Innovative Molecular Diagnostics.

The embryo studies were conducted in the USA where this procedure is legal, in adherence to guidelines established by OHSU's Institutional Review Board and additional ad-hoc committees established for scientific and ethical review. The work is also consistent with recommendations issued in February 2017 by the National Academy of Sciences and the National Academy of Medicine joint panel on human genome editing.

Genome-editing tools, which include zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) systems, have emerged as an invaluable technology to achieve somatic and germline genomic manipulation in cells and model organisms for multiple applications, including the creation of knockout alleles, introducing desired mutations into genomic DNA, and inserting novel transgenes. Genome editing is being rapidly adopted into all fields of biomedical research, including the cardiovascular field, where it has facilitated a greater understanding of lipid metabolism, electrophysiology, cardiomyopathies, and other cardiovascular disorders, has helped to create a wider variety of cellular and animal models, and has opened the door to a new class of therapies. In this Review, we discuss the applications of genome-editing technology throughout cardiovascular disease research and the prospect of in vivo genome-editing therapies in the future. We also describe some of the existing limitations of genome-editing tools that will need to be addressed if cardiovascular genome editing is to achieve its full scientific and therapeutic potential.

All authors: Alanna Strong and Kiran Musunuru

Search terms: Cardiovascular diseases Cardiovascular genetics Gene therapy Stem-cell therapies

Funding for this study
Jin-Soo Kim's lab at Seoul National University is supported by the Institute for Basic Science (IBS). Studies conducted at OHSU were supported by OHSU institutional funds, including the Knight Cardiovascular Institute. Work in the laboratory of co-author Juan Carlos Izpisua Belmonte of the Salk Institute was supported by the G. Harold and Leila Y. Mathers Charitable Foundation, the Moxie Foundation, and The Leona M. and Harry B. Helmsley Charitable Trust. Work at BGI was supported by the Shenzhen Municipal Government.

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A normal and a hypertrophic heart. A gene mutation causes thickening of the muscle wall,
reducing blood flow from one chamber to another. Image credit: Blausen.com staff (2014).
Medical gallery of Blausen Medical 2014. WikiJournal of Medicine

Phospholid by Wikipedia