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Genetic-code-expanded cell-based therapy for treating diabetes in mice

Nature Chemical Biology volume 18, pages 47–55 (2022)Cite this article

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Abstract

Inducer-triggered therapeutic protein expression from designer cells is a promising strategy for disease treatment. However, as most inducer systems harness transcriptional machineries, protein expression timeframes are unsuitable for many therapeutic applications. Here, we engineered a genetic code expansion-based therapeutic system, termed noncanonical amino acids (ncAAs)-triggered therapeutic switch (NATS), to achieve fast therapeutic protein expression in response to cognate ncAAs at the translational level. The NATS system showed response within 2 hours of triggering, whereas no signal was detected in a transcription-machinery-based system. Moreover, NATS system is compatible with transcriptional switches for multi-regulatory-layer control. Diabetic mice with microencapsulated cell implants harboring the NATS system could alleviate hyperglycemia within 90 min on oral delivery of ncAA. We also prepared ncAA-containing ‘cookies’ and achieved long-term glycemic control in diabetic mice implanted with NATS cells. Our proof-of-concept study demonstrates the use of NATS system for the design of next-generation cell-based therapies to achieve fast orally induced protein expression.

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Fig. 1: Design of the NATS in mammalian cells.
Fig. 2: NATS-mediated fast protein expression based on translational control in mammalian cells.
Fig. 3: NATS-mediated translational control in mice implanted with designer cells.
Fig. 4: Therapeutic efficacy of NATS designer cells in T1DM mice with oral ncAA delivery.
Fig. 5: Therapeutic efficacy of NATS designer cells in T1DM mice fed with ncAA cookies.
Fig. 6: Long-term therapeutic efficacy of the NATS designer cells in T1DM mice.

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Data availability

The authors declare that the main data supporting the study are provided within this article, its Supplementary Information and source data files. Source data are provided with this paper.

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Acknowledgements

This work was financially supported by Beijing Natural Science Foundation (grant no. JQ20034), the National Natural Science Foundation of China (grant nos. 21922701, 91853111 and 21778005), the National Major Scientific and Technological Special Project for ‘Significant New Drugs Development’ (grant no. 2019ZX09739001) and Shenzhen Institute of Synthetic Biology Scientific Research Program (grant no. DWKF20190004) to T.L., the National Natural Science Foundation of China (grant no. 31971346 and 31861143016), the National Key R&D Program of China, Synthetic Biology Research (no. 2019YFA0904500) and the Science and Technology Commission of Shanghai Municipality (grant no. 18JC1411000) to H.Y. We also thank L. Zhong at the Medical and Health Analysis Center, Peking University, for help with mass spectrometry experiments and analysis.

Author information

Author notes

  1. These authors contributed equally: Chao Chen, Guiling Yu, Yujia Huang.

Authors and Affiliations

  1. State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing, China

    Chao Chen, Yujia Huang, Wenhui Cheng, Yuxuan Li, Yi Sun & Tao Liu

  2. Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China

    Guiling Yu & Haifeng Ye

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Contributions

C.C., T.L., Y.H. and H.Y. designed the research. C.C., Y.H. and W.C. performed plasmid construction, cell culture and analytical assays. C.C., Y.H., W.C. and Y.L. performed hollow fiber-implanted mouse experiments. Y.S., Y.H. and W.C. performed pharmacokinetics experiments. C.C. and G.Y. performed cell line generation and microcapsule-implanted mouse experiments. C.C., G.Y. and Y.H. analyzed the data. C.C., Y.H., T.L. and H.Y. wrote the paper. H.Y. and Y.S. reviewed the paper. All authors read and approved the paper.

Corresponding authors

Correspondence to Haifeng Ye or Tao Liu.

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Peer review information Nature Chemical Biology thanks Zhen Gu, Mingqi Xie and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 POI expression mediated by the NATS system composed of aaRS/tRNA pair.

a, The chemical structure of OmeY and BocK and used in this study. b, Exploring the impact of amber codon position on the expression of a POI (SEAP) in HEK293T cells. MbPylRS/tRNAPyl pair was used for BocK incorporation. SEAP levels in culture supernatants were measured 48 h after stimulation with BocK. The signal-to-noise ratio is indicated above the bars. Data are presented as the mean ± SD; n = 3 independent samples.

Source data

Extended Data Fig. 2 SEAP expression Ratio of the NATS or Tet-On systems.

a, Fold-change of SEAP expression at the indicated time points with respect to SEAP expression at t0 were profiled after stimulation with 1 mM OmeY or Dox. b, Fold-change of SEAP expression at the indicated time points with respect to SEAP expression at t0 were profiled after stimulation with 1 mM OmeY or Dox. Data are presented as the mean ± SD; n = 3 independent samples.

Source data

Extended Data Fig. 3 The transcription–translation combination switch-mediated protein expression.

a, Schematic showing the design of the transcription-translation combination switch. A ncAA could trigger translation of tetracycline-controlled transactivator (tTA) bearing an ectopic amber codon, then Dox could stop SEAP transcription by regulating the activity of the tTA. b, The translation-transcription combination switch consists of triple plasmids, encoding an OmeYRS/tRNA pair, tTA with an amber codon, and wild-type SEAP. c, Exploration of the impact on amber codon position on the expression of a POI (transactivator tTA) in HEK293T cells. OmeYRS/tRNA pair was used for OmeY incorporation. SEAP levels in culture supernatants were measured 48 h after OmeY or Dox treatment. Data are presented as the mean ± SD; n = 3 independent samples. The signal-to-noise ratio is indicated above the bars. Red rectangle represents the final construct used in subsequent studies. d, Constructs of translation-transcription combination switch using bacterial TyrRS/tRNA, and fluorescence micrographs of designer cells cultivated within or without OmeY. Each experiment was repeated three times independently with similar results. e, Constructs of translation-transcription combination switch using archaea PylRS/tRNA, and fluorescence micrographs of designer cells cultivated within or without BocK. Each experiment was repeated three times independently with similar results.

Source data

Extended Data Fig. 4 POI expression of NATS stable cell line.

a, Sleeping Beauty transposon-based ncAA system used to introduce an orthogonal aaRS/tRNA pair and a gene-of-interest based on an ectopic amber codon. ITR, Inverted repeats; P, Promoter; BleoR, Bleomycin resistance marker; PuroR, Puromycin resistance marker. b, Selected cell line clone No. 76 was incubated in the presence of or absence of 1mM OmeY. The signal-to-noise ratio is indicated above the bars. c, Long-term OmeY-dependent SEAP expression. SEAP levels in culture supernatants were measured every two days after stimulation. d, Selection of NATS stable cell lines using hMSC-TERT cell as carrier. The selected cell clones were profiled for their OmeY-inducible SEAP production. Red rectangle represents the final construct used in subsequent studies. e, Fluorescence micrographs of iPSC cells harboring NATS system cultivated within or without OmeY. Each experiment was repeated three times independently with similar results. f, OmeY-inducible SEAP expression in different cell types. The signal-to-noise ratio is indicated above the bars. Data are presented as the mean ± SD; n = 3 independent samples.

Source data

Extended Data Fig. 5 Biosafety of long-term intake of OmeY or BocK.

a, Body weights of mice feeding with ncAA cookies (equal to OmeY or BocK 200 mg/kg) or standard chow were recorded every 3 days during a month. Two-way ANOVA. b, Blood chemical indexes and complete blood count were determined in mice after one-month feeding with ncAA cookies, or standard chow. Data are presented as the mean ± SEM; n = 8 mice. ns, not significant. Exact P values are provided in Source Data files. One-way ANOVA. ALT, Alanine transaminase; AST, Aspartate transaminase; TP, Total protein; ALB, Albumin; CREA Creatinine; UA, Uric acid; GR, Granulocytes; HCT, Hematocrit; HGB, Hemoglobin; LY Lymphocytes; MCH, Mean cell hemoglobin; MCV, Mean cell volume; MO, Monocytes; MPV, Mean platelet volume; PCT, Plateletcrit; PDW, Platelet Distribution Width; PLT, Platelet count; RBC, red blood cells; WBC, white blood cells.

Source data

Extended Data Fig. 6 Implantation of microencapsulated NATS designer cells.

a, Schematic diagram of fast POI response to oral administration of ncAAs. Male C57BL/6 mice aged 8-10 weeks were implanted with microencapsulated engineered cells harboring the NATS system. Upon oral intake of OmeY, mice rapidly produce the POI based on translational activation. b, Representative micrographs of microencapsulated NATS designer cells. c, Oral OmeY-inducible SEAP expression in mice implanted with microencapsulated cells harboring the NATS system. After cell implantation, mice received OmeY (200mg/kg) or vesicle by o.g. administration 3 times per day. Data are presented as the mean ± SEM; n = 5 mice. Two-tailed Student’s t-test, ***P < 0.001. Exact P values are provided in Source Data files.

Source data

Extended Data Fig. 7 Implantation of hollow fibers harboring NATS designer cells.

a, Exploration of the effect on SEAP production by cell densities. Data are presented as the mean ± SD, n = 3 independent samples. b, Dose-dependent OmeY-inducible SEAP production in mice implanted with hollow fibers harboring NATS designer cells. After cell implantation, mice received OmeY or vesicle by o.g. administration 3 times per day. Serum SEAP level were measured 48 h after implantation. Data are presented as the mean ± SEM; n = 5 mice. Two-tailed Student’s t test, *P < 0.05, **P < 0.01, ***P < 0.001. Exact P values are provided in Source Data files.

Source data

Extended Data Fig. 8 Standard Chow did not affect OmeY absorption.

a, Schematic diagram of the NATS-mediated rapid insulin response to feeding on ncAA ‘cookies;’. Mice were implanted with microencapsulated engineered cells harboring the NATS system. Through intake of ncAA ‘cookies’, mice absorb ncAAs, which trigger a fast insulin response based on translational activation. b, Photos of homemade ncAA ‘cookies’ for feeding the T1DM mice. c, Pharmacokinetic analysis of serum OmeY concentrations in mice after oral gavage (o.g.) administration. Each point represents the mean ± SEM from 5 mice. Two-way ANOVA. d, Treatment schedules for long-term therapies in T1DM by OmeY oral gavage or ncAA ‘cookies’.

Source data

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Chen, C., Yu, G., Huang, Y. et al. Genetic-code-expanded cell-based therapy for treating diabetes in mice. Nat Chem Biol 18, 47–55 (2022). https://doi.org/10.1038/s41589-021-00899-z

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