You are here

Targeting inflammation and oxidative stress to treat acute lung injury with CNP-miR146a

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R43HL162137-01
Agency Tracking Number: R43HL162137
Amount: $299,271.00
Phase: Phase I
Program: SBIR
Solicitation Topic Code: NHLBI
Solicitation Number: PA20-260
Solicitation Year: 2020
Award Year: 2022
Award Start Date (Proposal Award Date): 2022-04-01
Award End Date (Contract End Date): 2023-03-31
Small Business Information
Boulder, CO 80304-1002
United States
DUNS: 101473954
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (949) 246-0875
Business Contact
Phone: (720) 300-0118
Research Institution

PROJECT SUMMARY - Acute respiratory distress syndrome (ARDS) accounts for 10% of ICU admissions
worldwide with a mortality as high as 46%. This incidence has risen dramatically in the last year due to the novel
coronavirus (SARS-CoV-2) causing COVID-19, and ARDS is the leading cause of death in COVID-19 patients.
In the United States, COVID-19 has infected over 30 million and killed 550,000 people already. Despite
improvements in critical care and early detection of lung injury, the management of ARDS remains largely
supportive, and while mechanical ventilation may provide the necessary life support, impaired pulmonary
mechanics and subsequent ventilator induced lung injury (VILI) can impose a second insult that worsens
outcomes. A range of systemic inflammatory insults, including trauma, sepsis, COVID-19, or local injury from
toxic exposure, are associated with acute lung injury (ALI) and the development of ARDS, and result in alterations
in lung compliance and lung fibrosis. While the etiology of ALI is multifactorial, a central pathogenic feature is a
persistent activation of inflammation and oxidative stress. Following ALI, lung macrophages produce pro-
inflammatory cytokines that result in the recruitment of additional inflammatory cells and the generation of
reactive oxygen species (ROS). This pro-inflammatory state is regulated by key pro-inflammatory cytokines such
as interleukin-6 (IL-6) and IL-8 which are stimulated by NFkB, a pro-inflammatory transcription factor. An
additional layer of control of inflammation is through miR-146a, a regulatory microRNA that serves as a
“molecular brake” on inflammation through inhibition of NFkB activation and downstream IL-6 and IL-8
expression. Ceria Therapeutics has developed a novel strategy to synergistically target both inflammation and
oxidative stress. Novel cerium oxide nanoparticles (CNPs) have been designed and synthesized that possess
ROS scavenging properties, conjugated with an anti-inflammatory miR-146a mimetic (CNP-miR146a), to target
both ROS and the inflammatory response. In compelling preliminary data in a bleomycin-induced model of ALI,
It was found that one-time administration of CNP-miR146a at the time of injury prevents inflammation and
fibrosis and results in improved pulmonary mechanics. However, the ability to rescue lung injury and
improve pulmonary mechanics after injury has occurred remain to be determined. Based on our hypothesis that
CNP-miR146a will rescue ALI by reducing inflammation and oxidative stress, decrease fibrosis, and thus improve
pulmonary mechanics, the objective of this proposal is to demonstrate the efficacy of our especially
formulated form of CNP-miR146a for intratracheal delivery (CTX-002) to rescue existing ALI in two
clinically relevant ALI animal models and to carry out a pilot safety assessment. The efficacy of CTX-002
in i) will be evaluated in a VILI-induced ALI model (Specific Aim 1) and ii) a two-hit model of live bacterial infection
(S. aureus) followed by VILI (Specific Aim 2). In Specific Aim 3 an acute 7-day tolerability and toxicokinetic study
in rats as a pilot safety assessment will be carried out.

* Information listed above is at the time of submission. *

US Flag An Official Website of the United States Government