In Vivo Cardiac Prime Editing Corrects RBM20 Mutation

Abstract

A bioRxiv preprint (Feb 2026) reports the first in vivo cardiac prime editing platform with tissue-specific delivery — efficient editing in the heart with no detectable editing in the liver. The work uses a dual-AAV approach to deliver prime-editing machinery, and demonstrates that prime editing of RBM20 corrects a pathogenic mutation and rescues cardiomyopathy phenotypes in a humanized RBM20 R636Q mouse model.

Key Contributions

• First in vivo cardiac prime editing platform with tissue specificity — addresses one of the chronic concerns in gene therapy: off-target tissue editing.
• Dual-AAV delivery of prime-editing machinery to cardiac tissue.
• RBM20 cardiomyopathy rescue — therapeutic validation in a humanized mouse model.
• No detectable liver editing — important for clinical translation safety profile.

Methodology

• Dual-AAV vector design — splits prime editing components across two viral capsids (capacity constraint of single AAV).
• Cardiac-specific promoters drive expression in heart tissue.
• Humanized RBM20 R636Q mouse model — carries the human pathogenic mutation.
• Editing efficiency measured in cardiac tissue + multiple control tissues (liver, kidney, etc.).

Results

• Efficient prime editing in cardiac tissue.
• No detectable editing in liver — important off-target metric.
• Cardiomyopathy phenotype rescue in heterozygous Rbm20 R636Q mouse model.
• Demonstrates therapeutic-grade efficacy in animal model.

Limitations

• Animal model — translation to human cardiac tissue has additional complexity.
• AAV-based delivery has known immunogenicity and re-dosing limitations.
• Specific editing efficiency numbers and durability are mouse-model results; human clinical data pending.
• Manufacturing scale-up for dual-AAV products is more complex than single-vector systems.

Full Content

The RBM20 cardiac prime editing result advances gene therapy on three axes simultaneously:

1. Tissue specificity: heart-specific editing without detectable liver editing addresses a major safety concern in gene therapy.
2. Prime editing maturity: pushes prime editing from precision laboratory tool toward in vivo therapeutic application.
3. Cardiomyopathy as a target: dilated cardiomyopathy from RBM20 mutations affects ~5,000 patients in the US — a target population large enough for commercial gene therapy programs.

This connects to the broader 2026 in vivo gene editing wave:

• Multiplexed in vivo base editing identifying gene-variant-context interactions (bioRxiv 2025.02)
• LNP-delivered base editing for phenylketonuria (humanized mouse models)
• Casgevy ex vivo CRISPR for sickle cell + beta thalassemia (FDA-approved, expanding to pediatric)
• Verve Therapeutics in vivo CRISPR for cholesterol (Cleveland Clinic trial)

The general trajectory: gene therapy is shifting from ex vivo (manipulate cells outside body, reinfuse) to in vivo (direct delivery), with tissue-specific delivery as the next safety milestone.

For clinical timelines, RBM20 cardiac prime editing has years of work ahead before first-in-human trials. But the proof-of-concept is significant: tissue-specific in vivo prime editing works in animals, and that opens a wide design space for cardiac, neural, and other organ-specific gene therapies.

Source: bioRxiv — In Vivo Cardiac Prime Editing Corrects the Pathogenic Mutation and Rescues Cardiomyopathy Phenotypes in a Novel Humanized RBM20 Mouse Model, February 2026