July 28, 2026 —
Researchers at Fudan University have reported preclinical data suggesting that an AAV9-based Pcsk5 gene therapy may promote cardiac repair after myocardial infarction, or heart attack, by enhancing blood vessel growth and improving heart function.
The study, published in Nature Communications, was led by Jieyu Guo and colleagues. The team investigated whether delivery of Pcsk5, the mouse gene encoding proprotein convertase subtilisin/kexin 5, could improve recovery after myocardial infarction.
Heart attacks often lead to permanent loss of cardiac muscle function due to tissue injury and scarring. Patients who survive myocardial infarction remain at increased risk of heart failure, kidney failure, and stroke, creating a major need for therapies that can support tissue repair and preserve cardiac function.
The researchers first analyzed patient data and found that PCSK5 levels were elevated after myocardial infarction. Higher PCSK5 expression six months after the cardiac event correlated with improved cardiac function, suggesting that the protein may play a role in heart repair.
To test this hypothesis, the team used adeno-associated virus serotype 9, or AAV9, to deliver Pcsk5 to cardiac tissue in mouse models of myocardial infarction. Compared with control-treated animals, mice receiving AAV-Pcsk5 showed improved systolic function and smaller infarct size 28 days after injury.
Mechanistic studies suggested that Pcsk5 may support recovery by promoting angiogenesis, or blood vessel formation. Gene expression analysis showed increased activity of angiogenesis-related genes, including VEGFA, in cells from AAV-Pcsk5-treated mice. The researchers also observed increased capillary and arteriole density in treated animals, while Pcsk5 knockout mice showed reduced blood vessel formation.
The study also explored whether semaglutide, a GLP-1 receptor agonist best known for metabolic disease treatment, could enhance the Pcsk5 pathway. Because GLP-1 signaling can activate the ERK pathway, and Pcsk5 was found to be regulated through ERK signaling, the researchers tested semaglutide as a complementary strategy.
In vitro studies in human cells showed that semaglutide increased PCSK5 expression and angiogenesis-associated genes. In mouse myocardial infarction models, semaglutide promoted capillary and arteriole growth, reduced infarct size, and improved systolic function. These benefits were lost in Pcsk5 knockout mice, suggesting that Pcsk5 may contribute to semaglutide’s cardiac effects.
The findings point to PCSK5 as a potential therapeutic target for cardiovascular ischemic disease and suggest that AAV-mediated Pcsk5 delivery, alone or in combination with GLP-1-based treatment, may support cardiac repair after myocardial infarction.
However, the study remains preclinical and includes important limitations. The experiments were conducted in male mice, leaving questions about efficacy in female models. Longer-term safety and durability studies will also be needed.
Translation to humans will require careful evaluation, particularly because systemic or cardiac-directed AAV9 approaches have raised safety concerns in other clinical contexts. Additional work will be needed to define the optimal patient population, dose, delivery strategy, and safety profile before any clinical testing.
While no clinical trial plans have been disclosed, the study adds to growing interest in cardiac AAV gene therapy and combination approaches that pair genetic medicines with established cardiometabolic pathways to improve outcomes after heart injury.
