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AAV-mediated conversion of human pluripotent stem cell-derived pacemaker.

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Biochemical and Biophysical Research Communications
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PubMed
Summary

Scientists reprogrammed heart cells into pacemaker cells using gene therapy. This new biological pacemaker (BPm) reduced reliance on electronic devices in pigs with heart block, paving the way for future treatments.

Keywords:
Adeno-associated virusBioartificial pacemakerGene transferHyperpolarization-activated cyclic nucleotide-gated (HCN) channel

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Area of Science:

  • Cardiovascular Biology
  • Regenerative Medicine
  • Gene Therapy

Background:

  • Nodal pacemaker (Pm) cardiomyocyte (CM) dysfunction causes heart rhythm disorders, often requiring electronic pacemaker implantation.
  • Current electronic pacemakers have limitations and can lead to complications.
  • Developing biological alternatives for pacing is a critical unmet need in cardiology.

Purpose of the Study:

  • To functionally reprogram human pluripotent stem cell (hPSC)-derived ventricular CMs into functional pacemaker CMs.
  • To evaluate the efficacy of a novel gene therapy approach for creating biological pacemakers (BPm).

Main Methods:

  • Engineered HCN1 channel (HCN1ΔΔΔ) with a deleted S3-S4 linker was overexpressed in hPSC-VCMs using adeno-associated virus serotype 9 (rAAV9).
  • Reprogrammed hPSC-PmCMs were characterized for automaticity and action potential parameters.
  • A preclinical porcine model of complete heart block was used to test the rAAV9-HCN1ΔΔΔ-based BPm.

Main Results:

  • Reprogrammed hPSC-PmCMs exhibited automaticity and action potential characteristics of native nodal PmCMs.
  • Implantation of the rAAV9-HCN1ΔΔΔ-based BPm in pigs with heart block significantly reduced dependence on electronic pacing.
  • The biological pacemaker successfully generated spontaneous heart rhythms in the preclinical model.

Conclusions:

  • Functional biological pacemakers can be created by reprogramming ventricular CMs using gene therapy.
  • This novel gene-modified cell therapy shows promise for treating heart rhythm disorders.
  • The study provides a strong foundation for the future clinical translation of biological pacemakers.