Gene therapy is a potential treatment for arrhythmogenic right ventricular cardiomyopathy (ARVC), a rare inherited disorder that weakens the heart’s walls and causes irregular heartbeats. A new study in mice shows that replacing a faulty gene can improve survival and reduce tissue damage in ARVC.
Introduction
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare inherited disorder that affects the heart’s structure and function. It is caused by mutations in genes that encode proteins that hold the heart tissues together. One of these genes is plakophilin-2 (PKP2), which is implicated in many cases of ARVC.
When PKP2 is defective, fibrous and fatty tissue builds up within the heart’s walls, causing them to weaken and thin. This can lead to dangerous irregular heartbeats (arrhythmias) that can sometimes be fatal. ARVC can also cause heart failure, sudden cardiac death, or the need for a heart transplant.
Current therapies for ARVC include medications, implantable devices, or surgery to restore the heart’s normal rhythm and control symptoms. However, these treatments do not provide a cure or prevent the progression of the disease.
Gene therapy is a promising approach that aims to correct the underlying genetic defect that causes ARVC. By delivering a normal version of the PKP2 gene into the heart cells, gene therapy may be able to restore the function of the protein and prevent or slow down the tissue damage.
A new study in mice shows that gene therapy targeting PKP2 can prolong survival and reduce fibrosis in ARVC.
Study details
The study was conducted by researchers from NYU Grossman School of Medicine and Rocket Pharmaceuticals, a biotechnology company. It was published in the journal Circulation: Genomic and Precision Medicine.
The researchers used a mouse model of ARVC in which the PKP2 gene was silenced, mimicking the loss of function seen in human patients. They then injected these mice with a single dose of an adeno-associated viral vector (AAV), which is a small, harmless virus that can carry genes into cells.
The AAV vector contained a normal version of the PKP2 gene, which was designed to replace the defective one in the heart cells. The researchers compared the outcomes of the treated mice with those of untreated mice or mice that received an AAV vector with an irrelevant gene.
Results
The results showed that gene therapy targeting PKP2 had significant benefits for the mice with ARVC.
- Survival: The untreated mice died within six weeks after PKP2 silencing, while all but one of the treated mice lived for more than five months.
- Fibrosis: The treated mice had a 70% to 80% reduction in fibrous tissue buildup in the heart’s walls, depending on the dose of gene therapy.
- Function: The treated mice had better cardiac function and contractility than the untreated mice or the control mice.
- Arrhythmia: The treated mice had fewer episodes of ventricular tachycardia, a type of fast and irregular heartbeat, than the untreated mice or the control mice.
Implications
The study provides experimental evidence that gene therapy targeting PKP2 can interrupt the progression of ARVC and improve survival and quality of life in mice. It also demonstrates the feasibility and safety of using AAV vectors to deliver genes into the heart.
The researchers hope that their findings will pave the way for clinical trials in human patients with ARVC caused by PKP2 mutations. Rocket Pharmaceuticals has initiated a Phase 1 trial to test the safety and efficacy of their experimental treatment in ARVC patients.
Gene therapy may offer a new option for patients with ARVC who have limited or no effective treatments available. By correcting the genetic defect at its source, gene therapy may be able to prevent or delay the onset of symptoms, reduce the risk of complications, and extend survival.
Conclusion
Gene therapy is a potential treatment for arrhythmogenic right ventricular cardiomyopathy (ARVC), a rare inherited disorder that weakens the heart’s walls and causes irregular heartbeats. A new study in mice shows that replacing a faulty gene can improve survival and reduce tissue damage in ARVC.