CRISPR prevents cardiac death

(Stem Cells News image)

In his lab at Baylor College of Medicine, Dr. Xander Wehrens and his colleagues study cardiac conditions, including inherited cardiac arrhythmia disorders. In addition to being often associated with a high incidence of sudden cardiac death, these disorders can be difficult to treat (…)

Genetic studies have shown that the cause of the young patient’s arrhythmia is a mutation in gene RYR2. Mutations in this gene account for nearly 60 percent of all CPVT cases. This gene encodes proteins that form a channel that regulates calcium flow in heart muscle cells called cardiomyocytes. Cardiomyocytes require proper calcium flow to contract and relax in a coordinated manner.

Gene mutations that produce defective RYR2 proteins lead to defective calcium channels that promote uncontrolled calcium leak. During exercise or emotional stress, a heart with defective RYR2 proteins will not regulate calcium flow properly, and this can lead to potentially life-threatening arrhythmias (…)

Wehrens teamed up with Dr. William Lagor, associate professor of molecular physiology and biophysics, who is an expert in gene therapy using Adeno-Associated Viral (AAV) vectors. These viruses can be used to deliver the CRISPR/Cas9 genome editing machinery directly into the heart.

Wehrens and Lagor engineered AAV vectors to deliver CRISPR/Cas9 (AAV-CRISPR) into the hearts of live animals. They reasoned that eliminating the disease-causing copy of the RYR2 gene, called R176Q, could correct this lethal arrhythmia disorder in mice. To test this new approach, AAV-CRISPR was used to selectively disrupt the mutant RYR2 gene in the R176Q mouse model of CPVT.

Ten days after birth, mice carrying the R176Q mutation and normal mice received a single injection of AAV-CRISPR or placebo treatment. Five to six weeks later, the researchers evaluated the mice, and found very encouraging results.

None of the mice carrying the disease-causing R176Q mutation that were treated with AAV-CRISPR developed arrhythmias. In contrast, 71 percent of the mice that carried the mutation and received a placebo virus did develop arrhythmias. Editing of the defective copy of the gene using AAV-CRISPR greatly reduced the abundance of the dysfunctional RYR2 proteins. Furthermore, the single ‘healthy copy’ of the RYR2 gene that remained was enough to support proper heart function. No adverse events linked to treatments were observed in the groups of normal or affected mice (…)

from:blogs.bcm.edu/2018/10/30/preventing-sudden-cardiac-death-with-genome-editing
from:ahajournals.org/doi/10.1161/CIRCRESAHA.118.313369

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