Variants in a gene that plays a key role in heart function can cause potentially life-threatening arrhythmia syndromes known as calmodulinopathy. Calmodulinopathy is rare and causes arrhythmias that are poorly treated by current options. Boston Children's cardiologist William Pu, MD, believes he has found a promising custom genetic treatment: antisense oligonucleotides that deplete the disease-causing gene product .
Antisense oligonucleotides (ASO) are an emerging pharmaceutical option that target a disease at the RNA level, and Pu's research points to its potential for improving the care of arrhythmias. Three different genes (CALM1, CALM2, and CALM3) produce the identical protein, calmodulin (CaM). A damaging variant in one of these three genes causes calmodulinopathy.
As Pu's research showed, in both human cell and mouse disease models caused by a damaging variant in CALM1, an ASO effectively depleted the CALM1 gene product, and without affecting CALM2 or CALM3. This corrected arrhythmias caused by the CALM1 variant, yet was safe because CALM2 and CALM3 continued to produce normal levels of calmodulin protein. "The study shows the strategy works," Pu says.
"Depleting both the wild type and the variant copies of the diseased gene is safe and effective for this disease because of the genetic redundancy provided by the other two unaffected genes." Targeting one gene to knock out many arrythmia variants Pu, associate chair of cardiology for Basic and Translational Cardiovascula.