Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation

Yshii, L.; Pasciuto, E.; Bielefeld, P.; Mascali, L.; Lemaitre, P.; Marino, M.; Dooley, J.; Kouser, L.; Verschoren, S.; Lagou, V.; Kemps, H.; Gervois, P.; de Boer, A.; Burton, O.; Wahis, J.; Tareen, S.; Roca, C.; Singh, K.; Whyte, C.; Kerstens, A.; Callaerts-Vegh, Z.; Poovathingal, S.; Prezzemolo, T.; Wierda, K.; Dashwood, A.; Xie, J.; Van Wonterghem, E.; Creemers, E.; Aloulou, M.; Gsell, W.; Abiega, O.; Munck, S.; Vandenbroucke, R.; Lemmens, R.; De Strooper, B.; Van Den Bosch, L.; Himmelreich, U.; Fitzsimons, C. P.; Holt, M.; Liston, A.

doi:10.1101/2022.02.28.482297

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bioRxiv · 10.1101/2022.02.28.482297

Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation

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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.

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Yshii, L., Pasciuto, E., Bielefeld, P., Mascali, L., Lemaitre, P., Marino, M., Dooley, J., Kouser, L., Verschoren, S., Lagou, V., Kemps, H., Gervois, P., de Boer, A., Burton, O., Wahis, J., Tareen, S., Roca, C., Singh, K., Whyte, C., Kerstens, A., Callaerts-Vegh, Z., Poovathingal, S., Prezzemolo, T., Wierda, K., Dashwood, A., Xie, J., Van Wonterghem, E., Creemers, E., Aloulou, M., Gsell, W., Abiega, O., Munck, S., Vandenbroucke, R., Lemmens, R., De Strooper, B., Van Den Bosch, L., Himmelreich, U., Fitzsimons, C. P., Holt, M., Liston, A.. 2022-03-02. Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation. https://doi.org/10.1101/2022.02.28.482297

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