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Gene Therapy Targeting Pkp2 Deficiency Attenuates Cardiac Fibrosis: Insights From Single-Cell Transcriptomics in
Xinyue Ding1, Hui Zhang1, Xuan Zhao1
1Institute of Cardiovascular Translational Medicine Putuo Hospital, Shanghai University of Traditional Chinese Medicine Shanghai China.
Medcomm
|September 22, 2025
Summary
Plakophilin-2 (PKP2) deficiency drives heart failure fibrosis. Restoring PKP2 via AAV9 gene therapy reversed fibrosis and reprogrammed cardiac fibroblasts, offering a novel heart failure treatment.
Area of Science:
- Cardiology
- Molecular Biology
- Regenerative Medicine
Background:
- Heart failure (HF) involves cardiac fibrosis and functional decline, posing a significant therapeutic challenge.
- Cardiac fibrosis, the excessive accumulation of extracellular matrix in the heart, is a hallmark of heart failure progression.
- Desmosomal proteins, like plakophilin-2 (PKP2), play crucial roles in cardiac structure and function.
Purpose of the Study:
- To investigate the role of plakophilin-2 (PKP2) in heart failure pathogenesis.
- To establish and utilize a human-induced pluripotent stem cell (hiPSC)-derived cardiac organoid model for heart failure research.
- To evaluate the therapeutic potential of adeno-associated virus serotype 9 (AAV9)-mediated PKP2 restoration in preclinical heart failure models.
Main Methods:
- Development of a cardiac organoid heart failure model using hiPSCs.
- Analysis of PKP2 expression in HF models (organoids, rats, mice).
- In vivo gene therapy using AAV9-PKP2 in Pkp2-knockout rats and HF mice.
- Single-cell RNA sequencing to analyze cardiac fibroblast populations.
- Bioinformatic analysis to identify regulatory pathways.
Main Results:
- Significant downregulation of PKP2 observed in cardiac organoid HF models, HF rat, and HF mouse.
- AAV9-mediated PKP2 restoration attenuated cardiac fibrosis and slowed disease progression in vivo.
- PKP2 deficiency was associated with an enrichment of profibrotic cardiac fibroblasts.
- AAV9-PKP2 administration induced a phenotypic switch of activated cardiac fibroblasts to an antifibrotic state.
- Protein tyrosine phosphatase receptor type C (Ptprc) identified as a key regulator in this process.
Conclusions:
- PKP2 is a critical regulator of cardiac fibroblast activation and pathological fibrosis in heart failure.
- AAV9-PKP2 gene therapy demonstrates significant potential for treating heart failure by targeting cardiac fibrosis.
- This study highlights PKP2 as a novel therapeutic target for heart failure management.
