Genome editing, this biomedical technology that provides the ability to make precise cuts of DNA or RNA, using bacteria or particles that will target the elements of genetic information to be modified, had yet found few applications in Heart Health. It's done with this work by a team from Baylor College of Medicine (Houston) which shows the full potential of technology to prevent hereditary heart diseases, including hereditary cardiac arrhythmic disorders at the origin of a proportion significant cause of sudden cardiac death.
Every year, at least 3 million people worldwide die of sudden cardiac death. While sudden cardiac death is more common in older people, younger people can also be significantly affected. Among “1 to 40 year olds”, the annual incidence reaches 9/100,000. In this group, inherited heart diseases, including inherited cardiac arrhythmic disorders, are frequently the cause of these sudden deaths.
The team specializing in cardiac conditions and in particular in hereditary arrhythmias, which are difficult to treat, was inspired, at the start of the study, by a young patient suffering from a hereditary cardiac arrhythmic disorder called “polymorphic ventricular catecholaminergic tachycardia”. This patient presented with recurrent arrhythmias with rapid and irregular heartbeats and fainting. Several members of his family also suffered from severe arrhythmia, some had died of sudden cardiac death.
In patients with inherited heart conditions, the current therapeutic options are not optimal: anti-arrhythmic drugs or the implantable defibrillator are not very suitable for these patients, underline the researchers who therefore looked “on the side” of gene therapies: previous genetic studies have shown that the cause of this type of arrhythmia is a mutation in the RYR2 gene and that mutations in this gene account for nearly 60% of all cases of polymorphic ventricular catecholaminergic tachycardia. This gene codes for proteins that form a channel that regulates the flow of calcium into heart muscle cells or cardiomyocytes. Cardiomyocytes need a good flow of calcium to contract and relax in a coordinated fashion. Genetic mutations that produce faulty RYR2 proteins lead to faulty calcium channels that promote uncontrolled calcium leakage. During exercise or under emotional stress, a heart with defective RYR2 proteins is unable to properly regulate calcium flow, which can lead to life-threatening arrhythmias.
Editing the CRISPR / Cas9 genome to the rescue of the heart: the objective was indeed to develop a permanent treatment for polymorphic ventricular catecholaminergic tachycardia in humans by modifying the DNA and in particular the defective DNA of the patient. The researchers therefore developed vectors to introduce CRISPR/Cas9 (AAV-CRISPR) into the hearts of living animals with the aim of eliminating the disease-causing copy of the RYR2 gene, called R176Q. 10 days after birth, mice carrying the R176Q mutation and normal mice received a single injection of AAV-CRISPR treatment vs. placebo. 5 to 6 weeks later, the results are very encouraging:
- none of the mice carrying the disease-causing mutation treated with CRISPR actually developed arrhythmia;
- on the other hand, 71% of mice carrying the mutation and having received a placebo virus vector developed an arrhythmia;
- modifying the defective copy of the gene via CRISPR significantly reduced levels of dysfunctional RYR2 proteins;
- in this case, the only “healthy copy” of the remaining RYR2 gene is sufficient to ensure normal cardiac function;
- finally, no treatment-related adverse events were observed.
Genome editing therefore holds great promise for preventing inherited arrhythmia, the researchers conclude, adding: " Precision genome editing represents the future of tissue-directed gene therapies, and serious heart disease is a ideal starting point .
.jpg)
