Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation
Year: 2022
Type: article
Abstract: The ability of immune-modulating biologics to prevent and reverse pathology has transformed recent clinical practice. Full utility in the neuroinflammation space, however, requires identification of both effective targets for local immune-modulation and a delivery system capable of crossing the blood-brain-barrier. The recent identification and characterization of a small population of regulatory T cells (Tregs) resident in the brain presents one such potential therapeutic target. Here we identified brain IL2 levels as a limiting factor for brain-resident Tregs. We developed a gene-delivery approach for astrocytes, with a small-molecule on-switch to allow temporal control, and enhanced production in reactive astrocytes to spatially-direct delivery to inflammatory sites. Mice with brain-specific IL2 delivery were protected from traumatic brain injury, stroke and multiple sclerosis models, without impacting the peripheral immune system. These results validate brain-specific IL2 gene-delivery as effective protection against neuroinflammation, and provide a versatile platform for delivery of diverse biologics to neuroinflammatory patients.
Source: Nature Immunology
Authors: Lidia Yshii, Emanuela Pasciuto, Pascal Bielefeld, Loriana Mascali, Pierre Lemaitre, Marika Marino, James Dooley, Lubna Kouser, Stijn Verschoren, Vasiliki Lagou, Hannelore Kemps, Pascal Gervois, Antina de Boer, Oliver T. Burton, Jérôme Wahis, Jens Verhaert, Samar H. K. Tareen, Carlos P. Roca, Kailash Singh, Carly E. Whyte, Axelle Kerstens, Zsuzsanna Callaerts-Vegh, Suresh Poovathingal, Teresa Prezzemolo, Keimpe Wierda, Amy Dashwood, Junhua Xie, Elien Van Wonterghem, Eline Creemers, Meryem Aloulou, Willy Gsell, Oihane Abiega, Sebastian Munck, Roosmarijn E. Vandenbroucke, Annelies Bronckaers, Robin Lemmens, Bart De Strooper, Ludo Van Den Bosch, Uwe Himmelreich, Carlos P. Fitzsimons, Matthew G. Holt, Adrian Liston
Institutions: VIB-KU Leuven Center for Brain & Disease Research, KU Leuven, Babraham Institute, University of Amsterdam, Hasselt University, Ghent University, VIB-UGent Center for Inflammation Research, Centre National de la Recherche Scientifique, Inserm, Institut Toulousain des Maladies Infectieuses et Inflammatoires, Universitair Ziekenhuis Leuven, University College London, Universidade do Porto, i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $11,390
Funders: Universiteit van Amsterdam, Fonds Wetenschappelijk Onderzoek, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Internationale Stichting Alzheimer Onderzoek, Vlaamse regering, Directorate for Biological Sciences, Horizon 2020 Framework Programme, Biotechnology and Biological Sciences Research Council
Awards: G1990583613, G2457175227, G2959449187, G546953014, Develop a mechanistic understanding of how transcriptional and posttranscriptional regulation of gene expression is coordinated by signal transduction pathways., G5800125675, G6160911136, G6311103324, Use of an AAV9-based system for vectored immunoprophylaxis (VIP) targeting SOD1 in amyotrophic lateral sclerosis (ALS)., Immune homeostasis and the immune response, G8677781744, G912825023
OpenAlex ID: W4281789855