REVERSING PULMONARY FIBROSIS THROUGH DOPAMINE D1 RECEPTOR AGONISM

Project: Research project

Project Details

Description

Background: Idiopathic Pulmonary Fibrosis (IPF) is a progressive and ultimately fatal disease in which ongoing extracellular matrix (ECM) deposition and feedback biochemical and biomechanical signaling from this matrix promote disease progression. Our published and preliminary data demonstrate that YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), transcriptional effectors of the Hippo pathway, are pivotal regulators of fibroblast activation in IPF and control both ECM deposition and stiffening by fibroblasts. However, YAP and TAZ are downstream of multiple pathways and play critical roles in multiple lung cell types, complicating efforts to target them therapeutically. Therefore, we focus here on developing a fibroblast-targeted approach to YAP/TAZ inhibition.Rationale: We have identified GPCR (G Protein Coupled Receptor) agonism via Gs-coupled dopamine D1 Receptor (DRD1) as a fibroblast selective approach through which to inactivate YAP and TAZ. Our in vitro and in vivo preliminary data demonstrate that pharmacologic stimulation of DRD1 not only attenuates fibroblast activation, but functionally reverses their state from matrix depositing to matrix degradation and reversal of matrix stiffening. These responses depend on inhibition of YAP/TAZ, as they are lost in cells expressing constitutively active TAZ mutant protein. Published reports suggest that endogenous dopaminergic signaling is present in the normal lung; our preliminary data demonstrate that the dopamine synthetic pathway is transiently depressed during experimental fibrosis in mice and stably reduced in the lungs of subjects with IPF.Hypothesis: We hypothesize that peripheral dopamine D1 receptor agonism is an effective strategy for reversing pulmonary fibrosis by switching activated fibroblasts from a fibrosis-promoting to fibrosis-resolving state.Specific Aims and Objectives: In Aim 1, we will design, synthesize, and test novel and selective D1R agonists and demonstrate their efficacy in cultured human lung fibroblasts including those from subjects with IPF. Specifically, we propose development of novel D1 agonists from known D1 agonist scaffolds, focusing on modifications intended to reduce blood-brain barrier penetration (BBB) and potential neurological side effects. In Aim 2, we will identify the dose, route, and dosing interval effects of our novel D1R agonist(s) on biodistribution, pharmocokinetics, and on-target efficacy in mice. We will compare two routes of administration, intranasal and oral, testing dose response effects in reducing lung YAP/TAZ activation, while assessing overall biodistribution and pharmacokinetics, with particular focus on BBB penetration of candidate compounds. In preparation for preclinical testing, we will evaluate the dose-limiting toxicities of candidate compounds, with particular focus on cardiovascular, renal, and hepatic function. In Aim 3, we will evaluate the efficacy of D1R agonists in reversing fibrosis in both young and aged mice in two experimental pulmonary fibrosis modes, bleomycin injury and adenoviral-TGF-beta. We will benchmark new compounds against the approved therapeutics Pirfenidone and Nintedanib.Impact: By developing novel D1 agonists that do not cross the BBB, confirming their selectivity and potency in the lung; characterizing their biodistribution, pharmacokinetics (PK), and safety; and rigorously evaluating their efficacy in relevant preclinical lung fibrosis models, we will test our central hypothesis and establish the utility of a new approach to targeting YAP/TAZ to reverse fibroblast activation and progressive pulmonary fibrosis. If successful, this work will set the stage for further development of novel D1 agonists toward clinical testing in human populations, with potential long-term development of a new investigational drug for IPF and other fibrotic conditions.Relevance: Despite the prevalence and severity of IPF, existing therapies only modestly benefit patient symptoms and quality of life. Beyond IPF, fibrosis is associated with the pathologies responsible for ~40% of all deaths from chronic disease, with prominent roles for fibrosis in kidney, liver, and cardiovascular disease, as well as systemic sclerosis, all of which currently lack Food and Drug Administration-approved therapies that target organ fibrosis. Identification of novel disease-modifying targets and development of new therapeutics that directly interrupt and reverse fibrosis thus represent a substantial unmet healthcare need. Our proposal focuses specifically on development and testing of a novel therapeutic strategy for treating pulmonary fibrosis and is directly responsive to the Peer Reviewed Medical Research Program Funding Opportunity in the Topic Area: Pulmonary Fibrosis, Area of Encouragement: Development and/or testing of novel and/or innovative treatments, to include precision medicine approaches, to delay or modify the progression of pulmonary fibrosis.

StatusActive
Effective start/end date9/1/198/31/22

Funding

  • Congressionally Directed Medical Research Programs: $1,187,705.00

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