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β-Cyclodextrin-containing polymer treatment of cutaneous lupus and influenza improves outcomes

Kelly, Linsley and Olson, Lyra B. and Rempel, Rachel E. and Everitt, Jeffrey I. and Levine, Dana and Nair, Smita K. and Davis, Mark E. and Sullenger, Bruce A. (2022) β-Cyclodextrin-containing polymer treatment of cutaneous lupus and influenza improves outcomes. Molecular Therapy, 30 (2). pp. 845-854. ISSN 1525-0016. PMCID PMC8821959. doi:10.1016/j.ymthe.2021.10.003. https://resolver.caltech.edu/CaltechAUTHORS:20211015-162637553

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Abstract

Nucleic acid (NA)-containing damage- and pathogen-associated molecular patterns (DAMPs and PAMPs, respectively) are implicated in numerous pathological conditions from infectious diseases to autoimmune disorders. Nucleic acid-binding polymers, including polyamidoamine (PAMAM) dendrimers, have demonstrated anti-inflammatory properties when administered to neutralize DAMPs/PAMPs. The PAMAM G3 variant has been shown to have beneficial effects in a cutaneous lupus erythematosus (CLE) murine model and improve survival of mice challenged with influenza. Unfortunately, the narrow therapeutic window of cationic PAMAM dendrimers makes their clinical development challenging. An alternative nucleic acid-binding polymer that has been evaluated in humans is a linear β-cyclodextrin-containing polymer (CDP). CDP’s characteristics prompted us to evaluate its anti-inflammatory potential in CLE autoimmune and influenza infectious disease mouse models. We report that CDP effectively inhibits NA-containing DAMP-mediated activation of Toll-like receptors (TLRs) in cell culture, improves healing in lupus mice, and does not immunocompromise treated animals upon influenza infection but improves survival even when administered 3 days after infection. Finally, as anticipated, we observe limited toxicity in animals treated with CDP compared with PAMAM G3. Thus, CDP is a new anti-inflammatory agent that may be readily translated to the clinic to combat diseases associated with pathological NA-containing DAMPs/PAMPs.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.ymthe.2021.10.003DOIArticle
ORCID:
AuthorORCID
Kelly, Linsley0000-0001-7405-398X
Olson, Lyra B.0000-0003-2783-8244
Rempel, Rachel E.0000-0002-6113-1659
Everitt, Jeffrey I.0000-0003-0273-6284
Levine, Dana0000-0002-5029-8664
Nair, Smita K.0000-0002-2983-3597
Davis, Mark E.0000-0001-8294-1477
Sullenger, Bruce A.0000-0002-5113-5541
Additional Information:© 2021 The American Society of Gene and Cell Therapy. Received 22 April 2021, Revised 27 August 2021, Accepted 30 September 2021, Available online 8 October 2021, Version of Record 2 February 2022.
Funders:
Funding AgencyGrant Number
NIHUNSPECIFIED
Subject Keywords:nucleic acid binding polymer; DAMPs and PAMPs; influenza; lupus; pattern recognition receptors
Issue or Number:2
PubMed Central ID:PMC8821959
DOI:10.1016/j.ymthe.2021.10.003
Record Number:CaltechAUTHORS:20211015-162637553
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20211015-162637553
Official Citation:Linsley Kelly, Lyra B. Olson, Rachel E. Rempel, Jeffrey I. Everitt, Dana Levine, Smita K. Nair, Mark E. Davis, Bruce A. Sullenger, β-Cyclodextrin-containing polymer treatment of cutaneous lupus and influenza improves outcomes, Molecular Therapy, Volume 30, Issue 2, 2022, Pages 845-854, ISSN 1525-0016, https://doi.org/10.1016/j.ymthe.2021.10.003.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:111470
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:18 Oct 2021 18:09
Last Modified:13 Apr 2022 18:32

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