Validation of a novel drug target to treat RV failure

Right ventricular failure (RVF) is a serious clinical problem with a poor prognosis. RVF is the leading cause of
death in patients with pulmonary hypertension. RVF has diverse causes including LV failure, primary
cardiomyopathies, RV ischemia/infarction, pressure loading due to pulmonic stenosis or pulmonary hypertension
from multiple causes, and volume loading due to congenital heart disease and valvular pathologies.
Heart failure and chronic obstructive pulmonary disease are extremely common in Veterans and commonly
complicated by pulmonary hypertension and RVF. Pharmacologic treatments for RVF are limited.
We reported that chronic treatment with an agonist (A61603) for the alpha-1A-adrenergic receptor (α1A-AR)
prevented development of RVF. Furthermore, using a clinically relevant disease reversal experimental design,
we reported that chronic A61603 treatment reversed RVF, evidenced by: i) increased RV contraction in vivo; ii)
increased exercise capacity; iii) increased function of the contractile proteins; iv) decreased molecular markers
of cell damage (reactive oxygen species, and oxidative modification of muscle proteins); v) decreased cell death
(evidenced by lower serum levels of cardiac troponin-I); and vi) increased pro-survival cell signaling (ERK). Thus,
our preliminary studies demonstrate a robust and reproducible finding that chronic α1A-AR agonism has a
significant therapeutic effect in the setting of RVF.
However, the preliminary studies used a commercially available α1A-AR agonist with no intellectual property (IP)
value. Unfortunately, a commercially available agonist is not viable for clinical translation. Clinical translation of
therapeutic α1A-AR activation to treat RVF requires development of a clinically viable agonist. Therefore, the
goal of this project is to develop a clinically viable α1A-AR agonist. This project will take advantage of the VA
grant program “Merit Review Pilot Project Awards to Validate Clinically Significant Novel Therapeutic Target(s)”.
We note that the purpose of this 2-year grant program is narrowly focused on validation studies, and that the
grant program is not intended for mechanistic investigations. Accordingly, mechanistic investigations are not
proposed.
This project will validate the α1A-AR as a viable therapeutic target to treat RVF. Specifically, we will develop and
test novel proprietary α1A-AR agonists with IP value. These agonists will be clinically viable for translation.
Validation of the α1A-AR as a viable therapeutic target to treat RVF will use 2 specific aims:
Aim 1: Develop and test proprietary α1A-AR agonists that have IP value. The CRO will create 30 proprietary
α1A-AR agonists. The CRO will screen for proprietary agonists that mediate signaling in CHO cells that express
the α1A-AR, but not in cells that express the α1B-AR. We will test proprietary and active α1A-AR agonists in
NRVMs and quantify EC50 and the maximal effect (Emax) for both activation of ERK (the key transducer of
cardioprotection) and increased protein content (an anabolic effect of α1A-AR activation in cardiomyocytes).
Aim 2: Test the ability of proprietary α1A-AR agonists to reverse RVF. For the best proprietary α1A-AR
agonist identified in Aim 1 (highest potency and efficacy), we will determine the in-vivo optimal dosing for chronic
infusion to activate ERK signaling. We will determine if infusion of a proprietary α1A-AR agonist at an optimal
dose can reverse RVF.
This project will validate therapeutic α1A-AR activation as a treatment for RVF using a proprietary clinically viable
agonist. This project will pave the way for future development of a VA-sponsored drug. The proprietary α1A-AR
agonists developed with IP value, efficacy, potency, and selectivity will be positioned to attract licensing for
further development.
This project may lead to a new invention in the form of a novel proprietary α1A-AR agonist with IP value and with
an intended use to treat RVF and potentially, other forms of heart failure.

Grant Number: 5I21BX006858-02
NIH Institute/Center: VA
Principal Investigator: Anthony BAKER