# Cardiac delivery of RNA to treat contractile disorder

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $793,828

## Abstract

The delivery of therapeutic nucleotides to the myocardium is notoriously challenging and remains an important
unmet clinical need. Based on the global success of mRNA vaccines, solid lipid nanoparticles are the most
widely used vehicle for RNA delivery. We recently identified species of lipid nanoparticles with unprecedented
cardiotropism (cLNPs) that are efficient at delivering inhibitory RNA cargos to the heart. This supports
development of cLNPs for the therapeutic inhibition of select cardiomyocyte targets. Our prior work suggests
that increases in stable, post-translationally detyrosinated microtubules, as mediated by vasohibins
(VASH1/2) in complex with their chaperone (SVBP), contribute to contractile dysfunction in human heart
failure and clinically relevant animal models. Accordingly, the proposed research tests the hypothesis that
cLNPs with inhibitory cargos that limit disease-associated microtubule network detyrosination can improve
contractile dysfunction in disease models where increased VASH1 or VASH2 expression has been linked to
systolic and/or diastolic dysfunction. To test this hypothesis, Aim 1 experiments will prioritize therapeutic
reagents by characterizing the extent and duration of on- and off-target effects of cLNPs with alternative
inhibitory cargos (siRNA, shRNA, and antisense oligonucleotides) against both constitutively expressed
transcripts or against Vash1, Vash2, or Svbp in healthy rats. Studies demonstrating functional inhibition will
be extended to human myocardium using ex vivo delivery of cLNPs to perfused cardiac wedge preparations
derived from heart transplant recipients. Aim 2 experiments will determine whether short-term inhibition of
Vash2 via delivery of cLNPs is sufficient to blunt contractile dysfunction in viable myocardium following acute
myocardial infarction. Aim 3 experiments test whether cLNPs achieving sustained delivery of Vash1 can delay
the progression of diastolic dysfunction in an animal model of heart failure with preserved ejection fraction.
Our overall study design uses novel and complementary experimental approaches that seek to rigorously
characterize inhibitory nucleic acid delivery via cLNPs, and then test them in clinically relevant models of
microtubule-dependent cardiac dysfunction. Use of both acute and chronic models of cardiac dysfunction,
and in turn acute and chronic therapeutic inhibition, respectively, exploits a range of therapeutic options of
cLNPs. Inclusion of delivery to human myocardium furthers ultimate clinical translation. Together this work
will establish whether inhibition of microtubule network remodeling is therapeutically beneficial in heart failure,
defne which molecular target is best suited for each of two therapeutic scenarios, and establish the versatility
of cLNP mediated delivery of inhibitory nucleic acids for the treatment of cardiac dysfunction.

## Key facts

- **NIH application ID:** 10981942
- **Project number:** 1R01HL169448-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Kenneth Ber Margulies
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $793,828
- **Award type:** 1
- **Project period:** 2024-07-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981942

## Citation

> US National Institutes of Health, RePORTER application 10981942, Cardiac delivery of RNA to treat contractile disorder (1R01HL169448-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10981942. Licensed CC0.

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