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Amelioration of rhinovirus induced asthma exacerbations by serpin B1

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41AI141068-01
Agency Tracking Number: R41AI141068
Amount: $223,334.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NIAID
Solicitation Number: PA17-303
Solicitation Year: 2017
Award Year: 2018
Award Start Date (Proposal Award Date): 2018-06-01
Award End Date (Contract End Date): 2019-05-31
Small Business Information
San Mateo, CA 94402-1129
United States
DUNS: 010286563
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (650) 348-1255
Business Contact
Phone: (650) 622-9702
Research Institution
9500 Gilman Drive, Mail Code 0934
LA JOLLA, CA 92093-0934
United States

 Nonprofit College or University

Asthma exacerbations are a major cause of ER visits and hospitalizations with annual direct costs of
approximately $billionyear in the USAViral infectionsin particular rhinoviralRVinfectionsare a major
precipitant of asthma exacerbations in allergic asthmaticsAs there are overRV serotypes andfor nowno
RV vaccinenovel strategies to inhibit RV induced airway inflammation are needed to prevent asthma
exacerbations associated with increased airway hyper reactivityAHRState of the art research recently
demonstrated that RV infection in allergic humans and mice can induce neutrophils to undergo NETosisa
newly recognized inflammatory process involving the expulsion of Neutrophil Extracellular TrapsNETandapos scomprising linearized double strandedds DNA bearing cytotoxic histones and granule proteins such as
myeloperoxidase and elastaseFurthermoreNETandapos s can be sensed by the innate or adaptive immune system
to boost typeimmunity and enhance the severity of asthma exacerbationsDegradation of NETs by DNase or
inhibition of elastase by alphaantitrypsinAAThave both proven effective at preventing allergic asthma
exacerbations in animal models but neither is a direct inhibitor of NETosisSerpin BsBis a protein both
structurally and functionally related to AATboth inhibit the neutrophil serine proteinasesNSPandapos selastasecathepsin G and proteinaseimplicated in inflammation and airway hyper reactivityAHRthat is abundantly
produced inside monocytes and neutrophils but unlike AAT directly blocks NETosis and regulates the expansion
of Thcytokine producing cells in vitroHoweverSerplus Technology LLC has recently shown that human and
mouse sB andapos s are subject to inactivation by reactive oxygen speciesROSthat convert the protein into an
elastase substrateTo prevent this inactivation we have created an oxidation resistant sBOxR sBthat retains
elastase inhibitory activity in the presence of ROS and hypothesize that it will be an effective in vivo inhibitor of
both elastase and NETosis during inflammatory episodes and will block RV induced NETosis thus diminishing
Thmediated T cell responses to more effectively control allergic asthma exacerbationsWe will test if OxR
sBcan prevent RV induced airway inflammation and AHR in house dust mite sensitized mice andif
successfulundertake further preclinical and clinical development such that it may improve control of
RV induced asthma exacerbations in allergic asthmaticsThe proposed research in phase I will focus onAimthe purification and biochemical characterization
of oxidation resistant mouse sb a andAimproviding proof of principle in an animal model of RV induced
asthmaThe outcome of these studies will guide the design of future efficacy studies in animals and humans PROJECT NARRATIVE
Viral infectionsin particular rhinoviralRVinfectionsare a major precipitant of asthma
exacerbations in allergic asthmatics and as there are overRV serotypes and no RV vaccine
as yetnovel strategies to inhibit the RV induced airway inflammation and increased airway hyperreactivityAHRare urgently requiredSerpin Bis an endogenous regulator of neutrophil
protease activity and Neutrophil Extracellular TrapNETformationkey inflammatory processes
important for induction of exacerbations in asthmatic humans and miceWe have discovered that
sBis subject to inactivation by reactive oxygen speciesROSand have made an ROS resistant
form of sBwhich we seek to prove can function in the asthmatic lung as an effective inhibitor of
inflammatory proteasescytokine productionand NETosis to ameliorate airway inflammation and
reduce AHR thus offering an additional therapeutic candidate to prevent or treat the underlying
pathology of asthma exacerbations

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

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