A new gene therapy study in mice shows that replacing a dysfunctional gene could prolong survival in some people with the disease. cardiomyopathy arrhythmogenic right ventricle (ARVC), a rare inherited disease in which the muscular walls of the heart progressively weaken and put patients at risk of dangerous irregular heartbeats.
There research was published in the journal Circulation: Genomic and Precision Medicine.
Treating arrhythmogenic right ventricular cardiomyopathy with gene therapy
Experimental gene therapy targets the loss of function of a gene implicated in many cases of ARVC, plakophilin-2 (PKP2). The PKP2 gene provides instructions for making a protein that holds heart tissues together. When the gene, one of many thought to contribute to the disease, is defective and fails to make a functional protein, fibrous tissue and fat builds up inside of the walls of the heart, causing them to weaken.
The heart may also beat irregularly without any warning and sometimes stop working. Although current therapies can help restore normal heart rhythm and control symptoms, they fail to provide a cure.
In a collaboration between researchers at the NYU Grossman School of Medicine and scientists at Rocket Pharmaceuticals (a biotechnology company), the new work revealed that untreated mice, engineered to lose the function of the PKP2 gene, died within six weeks after the gene had been silenced.
All but one of the subjects who received a single dose of gene therapy, carrying the normal version of the gene, lived more than five months. Mice that received the replacement gene also saw a 70% to 80% reduction in fibrous tissue buildup, depending on the dose.
“Our findings offer experimental evidence that gene therapy targeting plakophilin-2 can halt the progression of a deadly heart condition,” says study co-author Chantal van Opbergen, Ph.D., a postdoctoral researcher at NYU Langone Health.
According to the authors of the gene therapy study, the most advanced stages of ARVC are characterized by irreversible heart damage, sometimes requiring a heart transplant. Researchers have long tried to slow the disease and prevent as much tissue loss as possible.
In previous research by the Langone team at New York University, the authors explored the mechanisms by which defects in the PKP2 gene can cause the unexpected appearance of a life-threatening irregular heartbeat (arrhythmias), similar to that seen in some patients with ARVC.
For the new study, the team used a mouse model of ARVC in which the genetic composition had been altered to render the PKP2 gene nonfunctional. As a proof of concept in the present work, they used an adeno-associated viral vector as a delivery mechanism to transfer the healthy gene into heart cells, thus providing the necessary PKP2 protein therapy.
These viral vectors are small, non-replicating particles that deliver the desired gene into target cells by exploiting their natural infection process, i.e. their ability to invade a cell and settle there.
Unlike infectious viruses, viral vectors do not multiply after their genetic material has been transferred to heart cells, which, with the healthy gene in place, now produce the normal protein. Rocket Pharmaceuticals designed and developed the viral vector used in the gene therapy study.
According to the results, the experimental gene therapy reduced arrhythmia episodes in mice by up to 50%, slowed the deterioration of the heart walls and maintained their ability to pump blood effectively.
“These findings suggest that this method of gene therapy can combat arrhythmogenic right ventricular cardiomyopathy in both the early and more advanced stages of the condition,” said study co-senior author Mario Delmar, M.D., Ph.D. Delmar is the Patricia M. and Robert H. Martinsen Professor of Cardiology in the Department of Medicine at NYU Langone Health and a professor in its Department of Cell Biology.
“Such promising gene therapy results in animal models pave the way for exploring this treatment option in humans,” said study co-senior author and cardiologist Marina Cerrone, MD.
Based in part on current study data, Rocket Pharmaceuticals has initiated a Phase 1 clinical trial to test the safety of the investigational gene therapy in ARVC patients with disease-causing PKP2 mutations, notes Cerrone, research associate professor in the Department of Medicine at New York University.
That said, Cerrone cautions that although targeting PKP2 targets one of the most common causes of ARVC, further experiments will be needed to correct other genetic mutations known to contribute to the disease.
Researchers at the Hubrecht Institute have laid the foundation for the development of a gene therapy for the genetic heart disease arrhythmogenic cardiomyopathy (ACM). Their approach, based on the replacement of the PKP2 gene, led to significant structural and functional improvements in laboratory models of the disease.
Multiple clinical trials will begin in 2024 in the United States to explore the clinical potential of this approach in ACM patients with PKP2 mutations.
ACM is a genetic heart disease that affects 1 in 2,000 to 1 in 5,000 people worldwide. It is characterized by arrhythmias and can lead to sudden cardiac arrest. Current treatment of the disease usually consists of antiarrhythmic drugs and implantable cardioverter defibrillators (ICDs), which focus solely on treating the symptoms rather than the root of the problem.
The disease is progressive, with an increasing portion of the heart muscle replaced by fatty tissue, and heart function deteriorates over time. This can eventually lead to heart failure. In severe cases, heart transplant can be performed as a last resort, but this is complicated by long waiting lists due to the
limited availability of hearts from suitable donors. There is therefore an urgent need for effective treatments that target the cause of ACM.
The mutations underlying ACM often occur in genes linked to desmosomes. These protein structures form the connections between adjacent cardiac muscle cells. They not only provide a structural connection, but also ensure that the heart muscle cells contract synchronously, allowing the heart to pump blood in a coordinated manner.
The gene most frequently affected in ACM is PKP2, which encodes the protein plakophilin-2, an essential part of desmosomes. The first author of the study, Eirini Kyriakopoulou, explains the effect of PKP2 mutations: “Patients with mutations in this gene often have lower levels of the protein plakophilin-2 in heart muscle cells.”
“The result is that desmosomes, which are normally built by meticulously binding all proteins together, begin to fall apart and are broken down by the cell. This weakens the connections between heart muscle cells, making it difficult for them to work together in synchrony, leading to the development of arrhythmias.”
Keeping in mind the molecular cause of ACM, researchers decided to develop a gene therapy approach that aimed to target this cause and not just the symptoms.
“For many patients with PKP2 mutations, the root of the problem is insufficient levels of plakophilin-2. Therefore, we explored the potential of gene therapy in ACM. We hypothesized that by introducing the healthy PKP2 gene into affected heart muscle cells, we might be able to restore plakophilin-2 levels to normal, thereby strengthening desmosomes and reducing the occurrence of arrhythmias in these patients,” says Kyriakopoulou.
Using gene therapy in several ACM laboratory models, Kyriakopoulou and his colleagues demonstrated both the feasibility and effectiveness of delivering the healthy PKP2 gene to diseased heart muscle cells. “We showed that plakophilin-2 levels were restored after delivery of the gene to cultured human heart muscle cells from stem cells. Additionally, it improved their sodium conduction, which is important for their ability to contract.”
“We then confirmed this improvement in contractility in engineered human cardiac muscles, which are ring-shaped structures that we can grow in the laboratory. Heart muscles with a PKP2 mutation contracted better after receiving the healthy PKP2 gene. Finally, we wanted to test this strategy in vivo, so we applied PKP2 gene replacement in our mouse model of ACM. This led to the recovery of their desmosomes and heart function,” explains Kyriakopoulou about the gene therapy.
After the promising laboratory results of gene therapy, the next step will be to study the clinical potential of this gene therapy approach in ACM patients with PKP2 mutations.
“Three companies in the United States have announced that they will begin clinical trials next year to test the therapeutic effect of gene therapy on patients, which is obviously great news,” says Kyriakopoulou. Researchers at the Hubrecht Institute hypothesize that gene therapy would be more useful in the early stages of the disease.
Kyriakopoulou says: “Once the disease has progressed to the point that parts of the heart muscle have already been replaced by fatty tissue, it is uncertain whether gene therapy can reverse the damage that already exists. Instead, we believe it may be possible to prevent the progression of the disease from early stages to more severe stages.”
Although the preclinical results of gene therapy and upcoming trials are very promising, Kyriakopoulou points out that commercial availability of this approach may still take several years. “In addition to the obvious need to confirm its effectiveness in patients, it is also essential to address and eliminate any safety concerns before considering the clinical application of gene therapy. However, our work provides an important foundation on which to build.”
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