Genetic in situ engineering of myeloid regulatory cells controls inflammation in autoimmunity.

Autor: Parayath NN; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA., Hao S; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA., Stephan SB; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA., Koehne AL; Translational Pathology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA., Watson CE; Translational Pathology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA., Stephan MT; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Bioengineering and Molecular Engineering & Sciences Institute, University of Washington, Seattle 98195, WA, USA. Electronic address: mstephan@fredhutch.org.
Jazyk: angličtina
Zdroj: Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 2021 Nov 10; Vol. 339, pp. 553-561. Date of Electronic Publication: 2021 Aug 24.
DOI: 10.1016/j.jconrel.2021.08.040
Abstrakt: The ability of myeloid regulatory cells (MRCs) to control immune responses and to promote tolerance has prompted enormous interest in exploiting them therapeutically to treat inflammation, autoimmunity, or to improve outcomes in transplantation. While immunomodulatory small-molecule compounds and antibodies have provided relief for some patients, the dosing entails high systemic drug exposures and thus increased risk of off-target adverse effects. More recently, MRC-based cell-therapy products have entered clinical testing for tolerance induction. However, the elaborate and expensive protocols currently required to manufacture engineered MRCs ex vivo put this approach beyond the reach of many patients who might benefit. A solution could be to directly program MRCs in vivo. Here we describe a targeted nanocarrier that delivers in vitro-transcribed mRNA encoding a key anti-inflammatory mediator. We demonstrate in models of systemic lupus erythematosus that infusions of nanoparticles formulated with mRNA encoding glucocorticoid-induced leucine zipper (GILZ) effectively control the disease. We further establish that these nanoreagents are safe for repeated dosing. Implemented in the clinic, this new therapy could enable physicians to treat autoimmune disease while avoiding systemic treatments that disrupt immune homeostasis.
(Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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