RT Journal Article
SR Electronic
T1 Design and modular assembly of synthetic intramembrane proteolysis receptors for custom gene regulation in therapeutic cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.05.21.445218
DO 10.1101/2021.05.21.445218
A1 Iowis Zhu
A1 Raymond Liu
A1 Axel Hyrenius-Wittsten
A1 Dan I. Piraner
A1 Josef Alavi
A1 Divya V. Israni
A1 Ahmad S. Khalil
A1 Kole T. Roybal
YR 2021
UL http://biorxiv.org/content/early/2021/05/23/2021.05.21.445218.abstract
AB Synthetic biology has established powerful tools to precisely control cell function. Engineering these systems to meet clinical requirements has enormous medical implications. Here, we adopted a clinically driven design process to build receptors for the autonomous control of therapeutic cells. We examined the function of key domains involved in regulated intramembrane proteolysis and showed that systematic modular engineering can generate a class of receptors we call SyNthetic Intramembrane Proteolysis Receptors (SNIPRs) that have tunable sensing and transcriptional response abilities. We demonstrate the potential transformative utility of the receptor platform by engineering human primary T cells for multi-antigen recognition and production of dosed, bioactive payloads relevant to the treatment of disease. Our design framework enables the development of fully humanized and customizable transcriptional receptors for the programming of therapeutic cells suitable for clinical translation.Competing Interest StatementI.Z., R.L., and K.T.R. are co-inventors on patents for synthetic receptors (PRV 62/905,258, 62/905,262, 62/905,266, 62/905,268, 62/905,251, 62/905,263). R.L. and K.T.R. are co-inventors on patents for synthetic receptors PRV 62/007,807. R.L., I.Z., D.P., D.V.I., A.S.K. and K.T.R. are co-inventors for synthetic receptors PRV 63/007,795. K.T.R. is a cofounder of Arsenal Biosciences, consultant, SAB member, and stockholder. K.T.R. is an inventor on patents for synthetic Notch receptors (WO2016138034A1, PRV/2016/62/333,106) and receives licensing fees and royalties. The patents were licensed by Cell Design Labs and are now part of Gilead. He was a founding scientist/consultant and stockholder in Cell Design Labs, now a Gilead Company. K.T.R. holds stock in Gilead. K.T.R. is on the SAB of Ziopharm Oncology and an Advisor to Venrock. A.S.K. is a scientific advisor for and holds equity in Senti Biosciences and Chroma Medicine, and is a co-founder of Fynch Biosciences and K2 Biotechnologies.