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Relaxin receptor agonists for treatment of liver fibrosis

Award Number: R01DK110167
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2017
PERIOD OF PERFORMANCE END DATE: 02/28/2023

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Relaxin receptor agonists for treatment of liver fibrosis - Fibrosis is an underlying cause of cirrhosis and hepatic failure resulting in end stage liver disease. There are currently no pharmacological treatments for advanced liver fibrosis. The abnormal proliferation and differentiation of mesenchymal stellate cells into myofibroblasts is the driving force of liver scaring, collagen accumulation, and extracellular matrix remodeling often associated with the increase of portal hypertension. In the last few years the beneficial effects of relaxin peptide treatment have been demonstrated in clinically relevant animal models of liver disease. It has been shown that relaxin suppresses the activation of quiescent hepatic stellate cells and their differentiation into collagen producing myofibroblasts. Additionally, treatment with relaxin caused a significant reduction of portal pressure in rats with induced liver fibrosis. Despite such favorable indications the use of relaxin is complicated due to its short half-life in vivo thus requiring continuous peptide delivery; a potential immune response to the injected peptide; and the high cost of the recombinant peptide. Relaxin signals through its cognate G protein-coupled receptor RXFP1 which is expressed in hepatic stellate cells. We have recently identified a first series of small molecule agonists of RXFP1. These molecules are highly specific potent activators of RXFP1; they have a long in vitro and in vivo half-life, a preferred ADME profile, and low cytotoxicity. The preliminary data suggest that the small molecule suppressed the expression of pro-fibrotic genes in primary human stellate cells while increasing expression of genes participating in extracellular matrix degradation. The current application is designed to validate the therapeutic anti-fibrotic effects of RXFP1 agonists using unique in vitro and in vivo models of liver fibrosis. First, we will test the efficacy of lead compounds to suppress fibrosis in activated human stellate cells and test their effects on various liver cells. The selected compounds will be tested in liver mini-organoids, the complex fully functional mini-organs produced for high-throughput analysis of therapeutic drug targets at the Wake Forest Institute for Regenerative Medicine. The most efficacious agonist with low cytotoxicity and no effects on normal hepatic cell function will be selected for animal testing. As RXFP1 agonists do not activate rodent receptors we have produced an RXFP1 humanized strain of mice with the endogenous mouse relaxin receptor replaced by a fully functional human receptor. Using this model we will test the anti-fibrotic properties of relaxin agonists in a toxic chemical liver CCl4 insult model and in a cholestatic liver injury model. These two models reflect different ontogeny and localization of liver fibrosis in humans. The results of our experiments will provide a foundation for future translational studies of relaxin receptor agonists for treating fibrosis in liver and other organs.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2021 ( Subtotal = $326,152 )
2021	2021	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	2/15/2021	NON-COMPETING CONTINUATION	$326,152
														Subtotal = $326,152

Issue Date FY: 2020 ( Subtotal = $333,955 )
2020	2020	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/11/2020	NON-COMPETING CONTINUATION	$333,955
														Subtotal = $333,955

Issue Date FY: 2019 ( Subtotal = $437,423 )
2019	2019	FLORIDA INTERNATIONAL UNIVERSITY	11200 S W 8TH ST MARC 430	MIAMI	FL	33199	MIAMI-DADE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/18/2019	NON-COMPETING CONTINUATION	$437,423
														Subtotal = $437,423

Issue Date FY: 2018 ( Subtotal = $434,786 )
2018	2018	FLORIDA INTERNATIONAL UNIVERSITY	11200 S W 8TH ST MARC 430	MIAMI	FL	33199	MIAMI-DADE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/28/2018	NON-COMPETING CONTINUATION	$391,308
2018	2018	FLORIDA INTERNATIONAL UNIVERSITY	11200 S W 8TH ST MARC 430	MIAMI	FL	33199	MIAMI-DADE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	4/23/2018	NON-COMPETING CONTINUATION	$43,478
														Subtotal = $434,786

Issue Date FY: 2017 ( Subtotal = $446,411 )
2017	2017	FLORIDA INTERNATIONAL UNIVERSITY	11200 S W 8TH ST MARC 430	MIAMI	FL	33199	MIAMI-DADE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/15/2017	NEW	$446,411
														Subtotal = $446,411

Grand Total All Awards = $1,978,727

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Relaxin receptor agonists for treatment of liver fibrosis

Award Number: R01DK110167

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/01/2017

PERIOD OF PERFORMANCE END DATE: 02/28/2023

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