Gene-Editing Technology Accelerates Cardiovascular Research: Clinical Applications Being Explored.

Abstract

HomeCirculationVol. 137, No. 9Gene-Editing Technology Accelerates Cardiovascular Research Free AccessNewsPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessNewsPDF/EPUBGene-Editing Technology Accelerates Cardiovascular ResearchClinical Applications Being Explored Bridget M. Kuehn, MSJ Bridget M. KuehnBridget M. Kuehn Search for more papers by this author Originally published27 Feb 2018https://doi.org/10.1161/CIRCULATIONAHA.117.033382Circulation. 2018;137:973–974The emergence of an inexpensive and efficient tool for gene editing is accelerating the pace of cardiovascular research and beginning to show potential as a treatment tool.The new gene-editing technology leverages a bacterial defense mechanism against viral infections. Bacteria store sections of viral DNA in repeated sequences called CRISPR within their own genomes and use those sequences to identify and destroy viruses. Now, scientists are inserting genes they would like to target into CRISPR and pairing it with CAS9, an enzyme that cuts DNA. This process allows scientists to efficiently remove or replace a targeted gene.“It’s been a transformative technology,” said Kiran Musunuru, MD, PhD, MPH, an associate professor of cardiovascular medicine and genetics at the University of Pennsylvania’s Perelman School of Medicine.Gene editing has been a common tool in research for decades—particularly for producing model organisms with a particular genetic mutation. However, older techniques were more time-consuming, expensive, and more error-prone. CRISPR-CAS is allowing scientists to more easily and quickly produce model animals or human cell lines with specific genetic variants allowing experiments to proceed at an unprecedented pace or scale. Some preliminary studies have suggested that it also may be a useful tool for treating some forms of heart disease.From Mice to MenThe most immediate impact of CRISPR-CAS9 has been speeding the production of model organisms or cell lines for cardiovascular studies.Scientists have been creating gene knockout or knockin mice lines for many years, but the process can take ≤2 years, Musunuru explained. Now scientists can take a single-celled mouse embryo, inject it with CRISPR-CAS9, and then implant the gene-edited embryo in a surrogate mother to produce a genetically altered mouse in a couple of months.“It dramatically speeds up the pace of this research,” Musunuru said. “If nothing else that is revolutionary.”The new CRISPR-based process can also be used to produce genetically altered rats, pigs, monkeys, and other organisms that are better models for cardiovascular disease. Previous techniques were not routinely used in these species, Musunuru said.“Mice aren’t great for studying atherosclerosis and heart attacks,” he said.CRISPR-CAS9 can be used to edit disease-linked genes in human cells grown in the laboratory to observe the molecular effects of various genetic alterations. For example, Musunuru and his colleagues have used genome-editing technology to show that the SORT1 gene regulates the secretion of low-density lipoprotein precursors from liver cells.The technique also might be useful to help systematically catalogue the affects of all possible variants of a particular gene. Such a catalogue of gene variant affects may become increasingly useful as whole-genome sequencing becomes more common in clinical practice.“Anytime a physician has a patient with a variant they [could] go to that database and see what the variant does,” Musunuru explained. “It’s a much more proactive way of looking after someone’s health.”Download figureDownload PowerPointThe Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CAS9 technology has cut the time it takes to produce a genetically engineered mouse from years to months, helping to accelerate the pace of cardiology research.Fixing a Broken HeartPreliminary data suggest that CRISPR-CAS9 may also have potential as a therapy for certain cardiovascular diseases. However, important questions remain about the safety and efficacy of potential gene-editing therapies.Renzhi Han, PhD, an associate professor of cardiac surgery at The Ohio State University Wexner Medical Center in Columbus, and colleagues recently published a proof of concept study in Circulation Research showing that CRISPR-based gene editing could be used to excise a mutation that causes Duchenne muscular dystrophy in live neonatal mice. Mutations in the gene encoding the protein dystrophin lead to weakness in the cardiac and skeletal muscles of individuals with Duchenne muscular dystrophy. But the researchers found that eliminating just a portion of the mutant gene in mice could boost the production of dystrophin in the heart by 40%.If the therapy is similarly effective in human clinical trials, then it may be able to extend the lifespan of individuals with Duchenne muscular dystrophy, who typically survive into their 20s and 30s, Han said.“My prediction is that this therapy would convert severe forms of the disease to a much milder form,” he said.Scientists must first verify the safety of the treatment. One of the primary concerns with using gene editing therapeutically is the potential for off-target mutations, Han explained. For example, if CRISPR misses and hits a tumor-suppressing gene, then it could lead to cancer, Musunuru said. Another concern is the body’s immune response to the virus used to deliver CRISPR. Han and his colleagues are currently studying ways to help reduce off-target activity and control potentially harmful immune responses.Gene therapy may be a promising approach for some other genetic cardiomyopathies, Han said, but he cautioned that it is still a work in progress.“This technology right now is not perfect,” Han said. “DMD [Duchenne muscular dystrophy] is a special case in that you can take a section out of the mutant gene and the protein can still function.”In other cardiomyopathies, it would be necessary to swap out a mutant copy of the gene for a functioning one, which is more difficult, Musunuru said.“The same success probably can’t be expected in other forms of [single-gene] heart diseases,” Musunuru said. “In other diseases, we will need to make precision repairs.”Gene-editing therapies are likely to work best in cell types that are easy to access and that multiply readily—unlike adult heart cells (eg, immune cells that can be removed from the blood and replaced after gene editing). Liver cells seem like another promising target.Musunuru and his colleagues demonstrated in a Circulation Research article that they could use CRISPR gene editing in the livers of mice to cause loss-of-function mutations in the PCSK9 gene. Humans with just 1 functional copy of the PCSK9 gene have a lower risk of heart disease, he explained. In the mice, low-density lipoprotein cholesterol levels decreased 35% to 40%, suggesting that a 1-time gene therapy treatment for high cholesterol might be feasible. He and his colleagues will next study whether the therapy is similarly effective in human liver tissue grown in mice.The unknown safety profile of gene editing in humans makes trials of gene editing in otherwise healthy people unlikely in the near term. Nevertheless, Musunuru noted that ongoing advancements in the technology are likely to improve its safety and precision.“The one really encouraging thing is that the technology is moving so quickly it is hard to predict what will be available 10 years from now,” he said.Footnoteshttp://circ.ahajournals.org Previous Back to top Next FiguresReferencesRelatedDetails February 27, 2018Vol 137, Issue 9 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.117.033382PMID: 29483173 Originally publishedFebruary 27, 2018 PDF download Advertisement