# Gene Transfer To Treat Heart Failure With Preserved Ejection Fraction

> **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2020 · —

## Abstract

This proposal focuses on development of new potential treatments for patients with heart failure and preserved
ejection fraction (HFpEF). Among symptomatic patients with HF, approximately half have preserved ejection
fraction, and their mortality is similar to those with HF with reduced EF (HFrEF). However, unlike the case with
HFrEF, there is currently no treatment for HFpEF that prolongs life, and few that reduce hospitalization rates
for heart failure. We need new therapies to address this unmet medical need. Discovering and developing such
an approach is the purpose of this proposal. Cardiovascular gene transfer is conceptually an attractive method
for treating heart failure, but difficulty in obtaining high yield transgene expression in the heart in a manner that
can be easily and safely applied has been challenging. However, we recently have demonstrated the
effectiveness of intravenous (IV) delivery of a long-term expression vector encoding a peptide, urocortin-2
(UCn2), with favorable cardiovascular effects through its paracrine action. A single intravenous injection in
normal mice of an adeno-associated virus vector (AAV8) encoding murine UCn2 (AAV8.UCn2) has favorable
effects on Tau and LV peak -dP/dt, two measures of left ventricular (LV) diastolic function. This approach
solves the problem of attaining high yield cardiac gene transfer and ultimately would enable patients to be
treated by intravenous injection during an office visit, and provides a novel means to increase diastolic
function. The goal of this proposal is to test the safety and efficacy of this method of therapy in animal models
of HFpEF.
In the 4-year tenure of our present VA Merit, we have published three papers on the effectiveness of gene
transfer of UCn2: one in normal mice, a second in mice with HFrEF, and a third that focuses on the safety and
metabolic effects of UCn2 gene transfer. Gene transfer of AAV8 encoding UCn2 yielded persistent increases in
plasma UCn2 (18 months following a single IV injection) and improved LV function in severe HF induced by
myocardial infarction. In these studies, we noted that UCn2 gene transfer increased LV peak -dP/dt (p<0.0001)
and reduced Tau (p=0.05). We now propose to test the safety and efficacy of IV delivery of AAV8.UCn2 in two
models of HFpEF: 1) trans-aortic constriction (TAC), which imposes a LV pressure stress and HFpEF in the
early phase; and 2) aged mice (18-months-old) many of which have diastolic dysfunction and meet criteria for
HFpEF. Although our primary goal is to improve LV diastolic function and to test this in physiological studies
after gene transfer, we also will determine mechanisms for the anticipated increase in diastolic function. In the
final year, we will initiate testing in rabbits as a segue to an eventual Investigational New Drug (IND)
application to initiate a clinical trial using AAV8.UCn2 to treat patients with HFpEF, a transition we have made
in our laboratory twice previously (ClinicalTrials.go...

## Key facts

- **NIH application ID:** 9898270
- **Project number:** 5I01BX003774-04
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** H. Kirk Hammond
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-04-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898270

## Citation

> US National Institutes of Health, RePORTER application 9898270, Gene Transfer To Treat Heart Failure With Preserved Ejection Fraction (5I01BX003774-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898270. Licensed CC0.

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