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Therapeutic targeting of Nox2 and Nox4 in Duchenne Muscular Dystrophy

Award Number: R41HL151043
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2020
PERIOD OF PERFORMANCE END DATE: 08/31/2022

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Therapeutic targeting of Nox2 and Nox4 in Duchenne Muscular Dystrophy - ABSTRACT: Duchenne muscular dystrophy (DMD) caused by a genetic mutation that prevents the production of dystrophin, a protein that muscles need to work properly. DMD patients exhibit progressive muscle weakness occurs in both skeletal and cardiac muscle. Cardiac fibrosis is ultimately the leading cause of their premature death. There is no cure for DMD, thus it remains an unmet medical need. Any therapeutic strategy that improves symptoms, quality of life, or survival would have a broad and meaningful impact for DMD patients. Numerous studies have demonstrated that dystrophic muscle exhibits high levels of oxidative stress, which is associated with increased NADPH-oxidases (Nox's) – a major cellular sources of ROS generation. Nox2 is the primary source of ROS in skeletal muscle, whereas Nox4 has been identified as the primary source of ROS in cardiomyocytes and cardiac myofibroblasts. Recent studies patients have implicated Nox2 in skeletal muscle dysfunction, and Nox4 in cardiac fibrosis. However, despite strong evidence implicating Nox2 and 4 in DMD pathogenesis, a critical barrier to progress in this area is that selective Nox2 or Nox4 inhibitors have not been available. This STTR Phase I application is a collaboration between biotech startup company, Fibronox LLC, and two academic entities, University of Pittsburgh (UP) and University of Arizona (UA). The PI (Dr. Hecker) is the Founder and Chief Scientific Officer of Fibronox, and was the first to define a novel role for the oxidant- generating enzyme, Nox4, in mediating tissue fibrosis. Dr. Hecker recently identified the first selective Nox4 inhibitor lead drug candidate, where Fibronox has obtained exclusive licensing rights. Dr. Pagano (UP) has identified the first selective Nox2 inhibitor lead drug candidate. Using these innovative selective Nox2 and Nox4 inhibitors, it is now feasible, for the first time, to target the primary source of oxidant generation in DMD. Dr. Colson (UA) rounds out this team by providing expertise in skeletal and cardiac muscle mechanics. The overall goal of this project is to demonstrate proof-of-concept that pharmacologic targeting of Nox2 in DMD mice is sufficient to reduce ROS-mediated inflammation and improve skeletal muscle function, whereas pharmacologic targeting of Nox4 will reduce ROS-mediated cardiac fibrosis, leading to improved cardiac function and increased survival. Aim 1 studies will determine the therapeutic efficacy of Nox4 inhibitors on cardiac fibrosis, performance, and survival in DMD mice. Aim 2 studies will determine the therapeutic efficacy of Nox2 inhibitors on inflammatory responses and the ability to restore skeletal muscle function in a DMD mouse model. The long-term STTR goal is to address the unmet need for novel therapies for DMD. Our objective is to provide proof-of-concept for the development of these first-in-class selective Nox inhibitors for a DMD indication. These novel therapeutic strategies address the key pathological features of DMD: Nox2 inhibition to restore skeletal muscle function and Nox4 inhibition to reduce fibrosis and restore cardiac function. This two-pronged approach offers independent opportunities to improve DMD patient quality of life and survival.


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: 2023 ( Subtotal = $0 )
2023	2020	FIBRONOX, L.L.C.	1001 E 17TH ST	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	1	9/12/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	FIBRONOX, L.L.C.	195 13TH ST NE UNIT 1804	ATLANTA	GA	30309	FULTON	USA	Cardiovascular Diseases Research	000	1	4/6/2021	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $248,019 )
2020	2020	FIBRONOX, L.L.C.	1001 E 17TH ST APT 117	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	1	9/4/2020	NEW	$248,019
														Subtotal = $248,019

Grand Total All Awards = $248,019

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Therapeutic targeting of Nox2 and Nox4 in Duchenne Muscular Dystrophy

Award Number: R41HL151043

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2020

PERIOD OF PERFORMANCE END DATE: 08/31/2022

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