The Challenges to Advancing Induced Pluripotent Stem Cell-Dependent Cell Replacement Therapy

Main Article Content

Alan B. Moy Anant Kamath Sara Ternes Jay Kamath

Abstract

Induced pluripotent stem cells (iPSC) represent a potentially exciting regenerative-medicine cell therapy for several chronic conditions such as macular degeneration, soft tissue and orthopedic conditions, cardiopulmonary disease, cancer, neurodegenerative disorders and metabolic disorders. The field of iPSC therapeutics currently exists at an early stage of development. There are several important stakeholders that include academia, industry, regulatory agencies, financial institutions and patients who are committed to advance the field. Yet, unlike more established therapeutic modalities like small and large molecules, iPSC therapies pose significant unique challenges with respect to safety, potency, genetic stability, immunogenicity, tumorgenicity, cell reproducibility, scalability and engraftment. The aim of this review article is to highlight the unique technical challenges that need to be addressed before iPSC technology can be fully realized as a cell replacement therapy. Additionally, this manuscript offers some potential solutions and identifies areas of focus that should be considered in order for the iPSC field to achieve its promise. The scope of this article covers the following areas: (1) the impact of different iPSC reprogramming methods on immunogenicity and tumorigenicity; (2) the effect of genetic instability on cell reproducibility and differentiation; (3) the role of growth factors and post-translational modification on differentiation and cell scalability; (4) the potential use of gene editing in improving iPSC differentiation; (5) the advantages and disadvantages between autologous and allogeneic cell therapy; (6) the regulatory considerations in developing a viable and reproducible cell product; and (7) the impact of local tissue inflammation on cell engraftment and cell viability.

Article Details

How to Cite
MOY, Alan B. et al. The Challenges to Advancing Induced Pluripotent Stem Cell-Dependent Cell Replacement Therapy. Medical Research Archives, [S.l.], v. 11, n. 11, nov. 2023. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/4784>. Date accessed: 17 apr. 2024. doi: https://doi.org/10.18103/mra.v11i11.4784.
Section
Research Articles

References

1. Gerteis J ID, Deitz D, LeRoy L, Ricciardi R, Miller T, Basu J. Multiple Chronic Conditions Chartbook. Agency for Healthcare Research and Quality. 2014;April
2. Khan AM, Green RS, Lytrivi ID, Sahulee R. Donor predictors of allograft utilization for pediatric heart transplantation. Transpl Int. Dec 2016;29(12):1269-1275. doi:10.1111/tri.12835
3. Thiessen C, Kulkarni S, Reese PP, Gordon EJ. A Call for Research on Individuals Who Opt Out of Living Kidney Donation: Challenges and Opportunities. Transplantation. Dec 2016;100(12):2527-2532. doi:10.1097/tp.0000000000001408
4. Thomson J, Itskovitz-Eldor J, Shapiro S, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282:1827.
5. Baker D, Hirst AJ, Gokhale PJ, et al. Detecting Genetic Mosaicism in Cultures of Human Pluripotent Stem Cells. Stem Cell Reports. Nov 8 2016;7(5):998-1012. doi:10.1016/j.stemcr.2016.10.003
6. Turinetto V, Orlando L, Giachino C. Induced Pluripotent Stem Cells: Advances in the Quest for Genetic Stability during Reprogramming Process. Int J Mol Sci. Sep 13 2017;18(9)doi:10.3390/ijms18091952
7. Van Voorhis BJ, Grinstead DM, Sparks AE, Gerard JL, Weir RF. Establishment of a successful donor embryo program: medical, ethical, and policy issues. Fertil Steril. Apr 1999;71(4):604-8. doi:10.1016/s0015-0282(98)00545-7
8. Crook JM, Peura TT, Kravets L, et al. The generation of six clinical-grade human embryonic stem cell lines. Cell Stem Cell. Nov 2007;1(5):490-4. doi:10.1016/j.stem.2007.10.004
9. Patel SJ, Yamauchi T, Ito F. Induced Pluripotent Stem Cell-Derived T Cells for Cancer Immunotherapy. Surg Oncol Clin N Am. Jul 2019;28(3):489-504. doi:10.1016/j.soc.2019.02.005
10. Cichocki F, van der Stegen SJC, Miller JS. Engineered and banked iPSCs for advanced NK- and T-cell immunotherapies. Blood. Feb 23 2023;141(8):846-855. doi:10.1182/blood.2022016205
11. Maddineni S, Silberstein JL, Sunwoo JB. Emerging NK cell therapies for cancer and the promise of next generation engineering of iPSC-derived NK cells. J Immunother Cancer. May 2022;10(5)doi:10.1136/jitc-2022-004693
12. Netsrithong R, Wattanapanitch M. Advances in Adoptive Cell Therapy Using Induced Pluripotent Stem Cell-Derived T Cells. Front Immunol. 2021;12:759558. doi:10.3389/fimmu.2021.759558
13. Takahashi K, Tanabe K, Ohnuki M, et al. Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors. Cell. 2007;131(November 30):861-872.
14. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663-676.
15. Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. Dec 21 2007;318(5858):1917-20. doi:10.1126/science.1151526
16. Nakagawa M, Koyanagi M, Tanabe K, et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol. Jan 2008;26(1):101-6. doi:10.1038/nbt1374
17. Nakagawa M, Takizawa N, Narita M, Ichisaka T, Yamanaka S. Promotion of direct reprogramming by transformation-deficient Myc. Proc Natl Acad Sci U S A. Aug 10 2010;107(32):14152-7. doi:10.1073/pnas.1009374107
18. Ikegaki N, Minna J, Kennett RH. The human L-myc gene is expressed as two forms of protein in small cell lung carcinoma cell lines: detection by monoclonal antibodies specific to two myc homology box sequences. Embo j. Jun 1989;8(6):1793-9. doi:10.1002/j.1460-2075.1989.tb03573.x
19. Bektas-Kayhan K, Unür M, Yaylim-Eraltan I, et al. Role of L-MYC polymorphism in oral squamous cell carcinoma in Turkey. Anticancer Res. Jul 2009;29(7):2519-24.
20. Yaylim-Eraltan I, Bozkurt N, Ergen A, et al. L-myc gene polymorphism and risk of thyroid cancer. Exp Oncol. Jun 2008;30(2):117-20.
21. Woltjen K, Michael IP, Mohseni P, et al. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature. Apr 9 2009;458(7239):766-70. doi:10.1038/nature07863
22. Jia F, Wilson KD, Sun N, et al. A nonviral minicircle vector for deriving human iPS cells. Nat Methods. Mar 2010;7(3):197-9. doi:10.1038/nmeth.1426
23. Anokye-Danso F, Trivedi CM, Juhr D, et al. Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell. Apr 8 2011;8(4):376-88. doi:10.1016/j.stem.2011.03.001
24. Fujie Y, Fusaki N, Katayama T, et al. New type of Sendai virus vector provides transgene-free iPS cells derived from chimpanzee blood. PLoS One. 2014;9(12):e113052. doi:10.1371/journal.pone.0113052
25. Isono K, Jono H, Ohya Y, et al. Generation of familial amyloidotic polyneuropathy-specific induced pluripotent stem cells. Stem Cell Res. Mar 2014;12(2):574-83. doi:10.1016/j.scr.2014.01.004
26. Kawagoe S, Higuchi T, Otaka M, et al. Morphological features of iPS cells generated from Fabry disease skin fibroblasts using Sendai virus vector (SeVdp). Mol Genet Metab. Aug 2013;109(4):386-9. doi:10.1016/j.ymgme.2013.06.003
27. Yang W, Mills JA, Sullivan S, Liu Y, French DL, Gadue P. iPSC Reprogramming from Human Peripheral Blood Using Sendai Virus Mediated Gene Transfer. StemBook. Harvard Stem Cell Institute. Copyright: © 2012 Wenli Yang, Jason A. Mills, Spencer Sullivan, Ying Liu, Deborah L. French, and Paul Gadue.; 2008.
28. Rosa A, Brivanlou AH. Synthetic mRNAs: powerful tools for reprogramming and differentiation of human cells. Cell Stem Cell. Nov 5 2010;7(5):549-50. doi:10.1016/j.stem.2010.10.002
29. Warren L, Manos PD, Ahfeldt T, et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell. Nov 5 2010;7(5):618-30. doi:10.1016/j.stem.2010.08.012
30. Mandal PK, Rossi DJ. Reprogramming human fibroblasts to pluripotency using modified mRNA. Nat Protoc. Mar 2013;8(3):568-82. doi:10.1038/nprot.2013.019
31. Yoshioka N, Gros E, Li HR, et al. Efficient generation of human iPSCs by a synthetic self-replicative RNA. Cell Stem Cell. Aug 1 2013;13(2):246-54. doi:10.1016/j.stem.2013.06.001
32. Okita K, Matsumura Y, Sato Y, et al. A more efficient method to generate integration-free human iPS cells. Nat Methods. May 2011;8(5):409-12. doi:10.1038/nmeth.1591
33. Yu J, Hu K, Smuga-Otto K, et al. Human induced pluripotent stem cells free of vector and transgene sequences. Science. May 8 2009;324(5928):797-801. doi:10.1126/science.1172482
34. Sullivan S, Stacey GN, Akazawa C, et al. Quality control guidelines for clinical-grade human induced pluripotent stem cell lines. Regen Med. Oct 2018;13(7):859-866. doi:10.2217/rme-2018-0095
35. Yin X, Li Y, Li J, et al. Generation and periodontal differentiation of human gingival fibroblasts-derived integration-free induced pluripotent stem cells. Biochem Biophys Res Commun. May 6 2016;473(3):726-32. doi:10.1016/j.bbrc.2015.10.012
36. Zhao T, Zhang ZN, Rong Z, Xu Y. Immunogenicity of induced pluripotent stem cells. Nature. May 13 2011;474(7350):212-5. doi:10.1038/nature10135
37. Kamath A, Ternes S, McGowan S, English A, Mallampalli R, Moy AB. Efficient method to create integration-free, virus-free, Myc and Lin28-free human induced pluripotent stem cells from adherent cells. Future Sci OA. Aug 2017;3(3):Fso211. doi:10.4155/fsoa-2017-0028
38. Kamath A, Ternes S, McGowan S, Moy AB. Virus-free and oncogene-free induced pluripotent stem cell reprogramming in cord blood and peripheral blood in patients with lung disease. Regen Med. Dec 2018;13(8):889-915. doi:10.2217/rme-2018-0041
39. Lee AS, Tang C, Cao F, et al. Effects of cell number on teratoma formation by human embryonic stem cells. Cell Cycle. Aug 15 2009;8(16):2608-12. doi:10.4161/cc.8.16.9353
40. Pasi CE, Dereli-Öz A, Negrini S, et al. Genomic instability in induced stem cells. Cell Death Differ. May 2011;18(5):745-53. doi:10.1038/cdd.2011.9
41. Kang X, Yu Q, Huang Y, et al. Effects of Integrating and Non-Integrating Reprogramming Methods on Copy Number Variation and Genomic Stability of Human Induced Pluripotent Stem Cells. PLoS One. 2015;10(7):e0131128. doi:10.1371/journal.pone.0131128
42. Hawkins FJ, Suzuki S, Beermann ML, et al. Derivation of Airway Basal Stem Cells from Human Pluripotent Stem Cells. Cell Stem Cell. Jan 7 2021;28(1):79-95.e8. doi:10.1016/j.stem.2020.09.017
43. Jacob A, Morley M, Hawkins F, et al. Differentiation of Human Pluripotent Stem Cells into Functional Lung Alveolar Epithelial Cells. Cell Stem Cell. Oct 5 2017;21(4):472-488.e10. doi:10.1016/j.stem.2017.08.014
44. Antonov SA, Novosadova EV. Current State-of-the-Art and Unresolved Problems in Using Human Induced Pluripotent Stem Cell-Derived Dopamine Neurons for Parkinson's Disease Drug Development. Int J Mol Sci. Mar 25 2021;22(7)doi:10.3390/ijms22073381
45. Bianchi F, Malboubi M, Li Y, et al. Rapid and efficient differentiation of functional motor neurons from human iPSC for neural injury modelling. Stem Cell Res. Oct 2018;32:126-134. doi:10.1016/j.scr.2018.09.006
46. Toba Y, Deguchi S, Mimura N, et al. Comparison of commercially available media for hepatic differentiation and hepatocyte maintenance. PLoS One. 2020;15(2):e0229654. doi:10.1371/journal.pone.0229654
47. Li Y, Yang X, Plummer R, et al. Human Pluripotent Stem Cell-Derived Hepatocyte-Like Cells and Organoids for Liver Disease and Therapy. Int J Mol Sci. Sep 28 2021;22(19)doi:10.3390/ijms221910471
48. Raju TS, Briggs JB, Borge SM, Jones AJ. Species-specific variation in glycosylation of IgG: evidence for the species-specific sialylation and branch-specific galactosylation and importance for engineering recombinant glycoprotein therapeutics. Glycobiology. May 2000;10(5):477-86. doi:10.1093/glycob/10.5.477
49. Wang Y, Wu Z, Hu W, Hao P, Yang S. Impact of Expressing Cells on Glycosylation and Glycan of the SARS-CoV-2 Spike Glycoprotein. ACS Omega. Jun 22 2021;6(24):15988-15999. doi:10.1021/acsomega.1c01785
50. Goh JB, Ng SK. Impact of host cell line choice on glycan profile. Crit Rev Biotechnol. Sep 2018;38(6):851-867. doi:10.1080/07388551.2017.1416577
51. Kaushik S, Mohanty D, Surolia A. Role of glycosylation in structure and stability of Erythrina corallodendron lectin (EcorL): a molecular dynamics study. Protein Sci. Mar 2011;20(3):465-81. doi:10.1002/pro.578
52. Kayser V, Chennamsetty N, Voynov V, Forrer K, Helk B, Trout BL. Glycosylation influences on the aggregation propensity of therapeutic monoclonal antibodies. Biotechnol J. Jan 2011;6(1):38-44. doi:10.1002/biot.201000091
53. Li H, d'Anjou M. Pharmacological significance of glycosylation in therapeutic proteins. Curr Opin Biotechnol. Dec 2009;20(6):678-84. doi:10.1016/j.copbio.2009.10.009
54. Öberg F, Sjöhamn J, Fischer G, et al. Glycosylation increases the thermostability of human aquaporin 10 protein. J Biol Chem. Sep 9 2011;286(36):31915-23. doi:10.1074/jbc.M111.242677
55. Opanasopit P, Shirashi K, Nishikawa M, Yamashita F, Takakura Y, Hashida M. In vivo recognition of mannosylated proteins by hepatic mannose receptors and mannan-binding protein. Am J Physiol Gastrointest Liver Physiol. May 2001;280(5):G879-89. doi:10.1152/ajpgi.2001.280.5.G879
56. Rajagopalan L, Organ-Darling LE, Liu H, et al. Glycosylation regulates prestin cellular activity. J Assoc Res Otolaryngol. Mar 2010;11(1):39-51. doi:10.1007/s10162-009-0196-5
57. Straumann N, Wind A, Leuenberger T, Wallimann T. Effects of N-linked glycosylation on the creatine transporter. Biochem J. Jan 15 2006;393(Pt 2):459-69. doi:10.1042/bj20050857
58. Su D, Zhao H, Xia H. Glycosylation-modified erythropoietin with improved half-life and biological activity. Int J Hematol. Mar 2010;91(2):238-44. doi:10.1007/s12185-010-0496-x
59. Arai S, Shibazaki C, Adachi M, et al. The non-glycosylated N-terminal domain of human thrombopoietin is a molten globule under native conditions. Febs j. May 2019;286(9):1717-1733. doi:10.1111/febs.14765
60. Costamagna D, Mommaerts H, Sampaolesi M, Tylzanowski P. Noggin inactivation affects the number and differentiation potential of muscle progenitor cells in vivo. Sci Rep. Aug 30 2016;6:31949. doi:10.1038/srep31949
61. Komekado H, Yamamoto H, Chiba T, Kikuchi A. Glycosylation and palmitoylation of Wnt-3a are coupled to produce an active form of Wnt-3a. Genes Cells. Apr 2007;12(4):521-34. doi:10.1111/j.1365-2443.2007.01068.x
62. Dumont J, Euwart D, Mei B, Estes S, Kshirsagar R. Human cell lines for biopharmaceutical manufacturing: history, status, and future perspectives. Crit Rev Biotechnol. Dec 2016;36(6):1110-1122. doi:10.3109/07388551.2015.1084266
63. Wong A. The ethics of HEK 293. Natl Cathol Bioeth Q. Autumn 2006;6(3):473-95. doi:10.5840/ncbq20066331
64. Lin YC, Boone M, Meuris L, et al. Genome dynamics of the human embryonic kidney 293 lineage in response to cell biology manipulations. Nat Commun. Sep 3 2014;5:4767. doi:10.1038/ncomms5767
65. Graham FL, Smiley J, Russell WC, Nairn R. Characteristics of a human cell line transformed by DNA from human adenovirus type 5. J Gen Virol. Jul 1977;36(1):59-74. doi:10.1099/0022-1317-36-1-59
66. Louis N, Evelegh C, Graham FL. Cloning and sequencing of the cellular-viral junctions from the human adenovirus type 5 transformed 293 cell line. Virology. Jul 7 1997;233(2):423-9. doi:10.1006/viro.1997.8597
67. Croset A, Delafosse L, Gaudry JP, et al. Differences in the glycosylation of recombinant proteins expressed in HEK and CHO cells. J Biotechnol. Oct 31 2012;161(3):336-48. doi:10.1016/j.jbiotec.2012.06.038
68. Böhm E, Seyfried BK, Dockal M, et al. Differences in N-glycosylation of recombinant human coagulation factor VII derived from BHK, CHO, and HEK293 cells. BMC Biotechnol. Sep 18 2015;15:87. doi:10.1186/s12896-015-0205-1
69. Fan Y, Winanto, Ng SY. Replacing what's lost: a new era of stem cell therapy for Parkinson's disease. Transl Neurodegener. 2020;9:2. doi:10.1186/s40035-019-0180-x
70. Kim J, Jeon J, Song B, et al. Spotting-based differentiation of functional dopaminergic progenitors from human pluripotent stem cells. Nat Protoc. Mar 2022;17(3):890-909. doi:10.1038/s41596-021-00673-4
71. 21 CFR Part 1271 (Human Cells, Tissues, and Cellular and Tissue-Based Products). https://wwwecfrgov/current/title-21/chapter-I/subchapter-L/part-1271.
72. 21 Part 600 (Biological Products: General) https://wwwecfrgov/current/title-21/chapter-I/subchapter-F/part-600.
73. 21 CFR Part 610 (General Biological Products Standards). https://wwwecfrgov/current/title-21/chapter-I/subchapter-F/part-610.
74. 21 CFR Part 211 (Current Good Manufacturing Practice). . https://wwwecfrgov/current/title-21/chapter-I/subchapter-C/part-211.
75. Guideline on quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells. https://wwwemaeuropaeu/en/documents/scientific-guideline/guideline-quality-non-clinical-clinical-aspects-medicinal-products-containing-genetically-modified_en-0pdf.
76. Baust JG, Snyder KK, Van Buskirk R, Baust JM. Integrating Molecular Control to Improve Cryopreservation Outcome. Biopreserv Biobank. Apr 2017;15(2):134-141. doi:10.1089/bio.2016.0119
77. Baust JM, Corwin W, Snyder KK, Van Buskirk R, Baust JG. Cryopreservation: Evolution of Molecular Based Strategies. Adv Exp Med Biol. 2016;951:13-29. doi:10.1007/978-3-319-45457-3_2
78. Baust JM, Corwin WL, VanBuskirk R, Baust JG. Biobanking: The Future of Cell Preservation Strategies. Adv Exp Med Biol. 2015;864:37-53. doi:10.1007/978-3-319-20579-3_4
79. Baust JM, Vogel MJ, Van Buskirk R, Baust JG. A molecular basis of cryopreservation failure and its modulation to improve cell survival. Cell Transplant. 2001;10(7):561-71.
80. Myles L, Church TD. An industry survey of implementation strategies for clinical supply chain management of cell and gene therapies. Cytotherapy. Mar 2022;24(3):344-355. doi:10.1016/j.jcyt.2021.09.012
81. Weltner J, Balboa D, Katayama S, et al. Human pluripotent reprogramming with CRISPR activators. Nat Commun. Jul 6 2018;9(1):2643. doi:10.1038/s41467-018-05067-x
82. Dominguez AA, Lim WA, Qi LS. Beyond editing: repurposing CRISPR-Cas9 for precision genome regulation and interrogation. Nat Rev Mol Cell Biol. Jan 2016;17(1):5-15. doi:10.1038/nrm.2015.2
83. Hockemeyer D, Jaenisch R. Induced Pluripotent Stem Cells Meet Genome Editing. Cell Stem Cell. May 5 2016;18(5):573-86. doi:10.1016/j.stem.2016.04.013
84. Ding Q, Regan SN, Xia Y, Oostrom LA, Cowan CA, Musunuru K. Enhanced efficiency of human pluripotent stem cell genome editing through replacing TALENs with CRISPRs. Cell Stem Cell. Apr 4 2013;12(4):393-4. doi:10.1016/j.stem.2013.03.006
85. Bhardwaj A, Nain V. TALENs-an indispensable tool in the era of CRISPR: a mini review. J Genet Eng Biotechnol. Aug 21 2021;19(1):125. doi:10.1186/s43141-021-00225-z
86. Mussolino C, Alzubi J, Fine EJ, et al. TALENs facilitate targeted genome editing in human cells with high specificity and low cytotoxicity. Nucleic Acids Res. Jun 2014;42(10):6762-73. doi:10.1093/nar/gku305
87. Dhatchinamoorthy K, Colbert JD, Rock KL. Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation. Front Immunol. 2021;12:636568. doi:10.3389/fimmu.2021.636568
88. Volpato V, Webber C. Addressing variability in iPSC-derived models of human disease: guidelines to promote reproducibility. Dis Model Mech. Jan 17 2020;13(1)doi:10.1242/dmm.042317
89. Kilpinen H, Goncalves A, Leha A, et al. Common genetic variation drives molecular heterogeneity in human iPSCs. Nature. Jun 15 2017;546(7658):370-375. doi:10.1038/nature22403
90. Carcamo-Orive I, Hoffman GE, Cundiff P, et al. Analysis of Transcriptional Variability in a Large Human iPSC Library Reveals Genetic and Non-genetic Determinants of Heterogeneity. Cell Stem Cell. Apr 6 2017;20(4):518-532.e9. doi:10.1016/j.stem.2016.11.005
91. Meneghini M, Bestard O, Grinyo JM. Immunosuppressive drugs modes of action. Best Pract Res Clin Gastroenterol. Oct-Dec 2021;54-55:101757. doi:10.1016/j.bpg.2021.101757
92. Deuse T, Hu X, Gravina A, et al. Hypoimmunogenic derivatives of induced pluripotent stem cells evade immune rejection in fully immunocompetent allogeneic recipients. Nat Biotechnol. Mar 2019;37(3):252-258. doi:10.1038/s41587-019-0016-3
93. Mattapally S, Pawlik KM, Fast VG, et al. Human Leukocyte Antigen Class I and II Knockout Human Induced Pluripotent Stem Cell-Derived Cells: Universal Donor for Cell Therapy. J Am Heart Assoc. Dec 4 2018;7(23):e010239. doi:10.1161/jaha.118.010239
94. Han X, Huang H, Gao P, et al. E-protein regulatory network links TCR signaling to effector Treg cell differentiation. Proc Natl Acad Sci U S A. Mar 5 2019;116(10):4471-4480. doi:10.1073/pnas.1800494116
95. Gornalusse GG, Hirata RK, Funk SE, et al. HLA-E-expressing pluripotent stem cells escape allogeneic responses and lysis by NK cells. Nat Biotechnol. Aug 2017;35(8):765-772. doi:10.1038/nbt.3860
96. Ye Q, Sung TC, Yang JM, Ling QD, He Y, Higuchi A. Generation of universal and hypoimmunogenic human pluripotent stem cells. Cell Prolif. Dec 2020;53(12):e12946. doi:10.1111/cpr.12946
97. Shi L, Li W, Liu Y, et al. Generation of hypoimmunogenic human pluripotent stem cells via expression of membrane-bound and secreted β2m-HLA-G fusion proteins. Stem Cells. Nov 2020;38(11):1423-1437. doi:10.1002/stem.3269
98. Chakravarti D, Caraballo LD, Weinberg BH, Wong WW. Inducible Gene Switches with Memory in Human T Cells for Cellular Immunotherapy. ACS Synth Biol. Aug 16 2019;8(8):1744-1754. doi:10.1021/acssynbio.8b00512
99. Stephenson J, Nutma E, van der Valk P, Amor S. Inflammation in CNS neurodegenerative diseases. Immunology. Jun 2018;154(2):204-219. doi:10.1111/imm.12922
100. Arévalo NB, Lamaizon CM, Cavieres VA, et al. Neuronopathic Gaucher disease: Beyond lysosomal dysfunction. Front Mol Neurosci. 2022;15:934820. doi:10.3389/fnmol.2022.934820
101. Francelle L, Mazzulli JR. Neuroinflammation in Gaucher disease, neuronal ceroid lipofuscinosis, and commonalities with Parkinson's disease. Brain Res. Apr 1 2022;1780:147798. doi:10.1016/j.brainres.2022.147798
102. Sheehy DF, Quinnell SP, Vegas AJ. Targeting Type 1 Diabetes: Selective Approaches for New Therapies. Biochemistry. Jan 29 2019;58(4):214-233. doi:10.1021/acs.biochem.8b01118
103. Monti P, Vignali D, Piemonti L. Monitoring Inflammation, Humoral and Cell-mediated Immunity in Pancreas and Islet Transplants. Curr Diabetes Rev. 2015;11(3):135-43. doi:10.2174/1573399811666150317125820