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Bomba HN, Sheets KT, Valdivia A, et al. Personalized-induced neural stem cell therapy: Generation, transplant, and safety in a large animal model. Bioeng Transl Med. 2020;6(1):e10171doi: 10.1002/btm2.10171.
Bomba, H. N., Sheets, K. T., Valdivia, A., Khagi, S., Ruterbories, L., Mariani, C. L., Borst, L. B., Tokarz, D. A., & Hingtgen, S. D. (2021). Personalized-induced neural stem cell therapy: Generation, transplant, and safety in a large animal model. Bioengineering & translational medicine, 6(1), e10171. https://doi.org/10.1002/btm2.10171
Bomba, Hunter N, et al. "Personalized-induced neural stem cell therapy: Generation, transplant, and safety in a large animal model." Bioengineering & translational medicine vol. 6,1 (2021): e10171. doi: https://doi.org/10.1002/btm2.10171
Bomba HN, Sheets KT, Valdivia A, Khagi S, Ruterbories L, Mariani CL, Borst LB, Tokarz DA, Hingtgen SD. Personalized-induced neural stem cell therapy: Generation, transplant, and safety in a large animal model. Bioeng Transl Med. 2020 Jul 15;6(1):e10171. doi: 10.1002/btm2.10171. eCollection 2021 Jan. PMID: 33532581; PMCID: PMC7823134.
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Bioeng Transl Med. 2020 Jul 15;6(1):e10171. doi: 10.1002/btm2.10171. eCollection 2021 Jan.

Personalized-induced neural stem cell therapy: Generation, transplant, and safety in a large animal model.

Bioengineering & translational medicine

Hunter N Bomba, Kevin T Sheets, Alain Valdivia, Simon Khagi, Laura Ruterbories, Christopher L Mariani, Luke B Borst, Debra A Tokarz, Shawn D Hingtgen

Affiliations

  1. Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy The University of North Carolina at Chapel Hill Chapel Hill North Carolina USA.
  2. Department of Neurosurgery The University of North Carolina at Chapel Hill Chapel Hill North Carolina USA.
  3. Lineberger Comprehensive Cancer Center The University of North Carolina at Chapel Hill Chapel Hill North Carolina USA.
  4. Department of Clinical Sciences, College of Veterinary Medicine North Carolina State University Raleigh North Carolina USA.
  5. Comparative Medicine Institute North Carolina State University Raleigh North Carolina USA.
  6. Department of Population Health and Pathobiology, College of Veterinary Medicine North Carolina State University Raleigh North Carolina USA.

PMID: 33532581 PMCID: PMC7823134 DOI: 10.1002/btm2.10171

Abstract

In this study, we take an important step toward clinical translation by generating the first canine-induced neural stem cells (iNSCs). We explore key aspects of scale-up, persistence, and safety of personalized iNSC therapy in autologous canine surgery models. iNSCs are a promising new approach to treat aggressive cancers of the brain, including the deadly glioblastoma. Created by direct transdifferentiation of fibroblasts, iNSCs are known to migrate through the brain, track down invasive cancer foci, and deliver anticancer payloads that significantly reduce tumor burden and extend survival of tumor-bearing mice. Here, skin biopsies were collected from canines and converted into the first personalized canine iNSCs engineered to carry TNFα-related apoptosis-inducing ligand (TRAIL) and thymidine kinase (TK), as well as magnetic resonance imaging (MRI) contrast agents for in vivo tracking. Time-lapse analysis showed canine iNSCs efficiently migrate to human tumor cells, and cell viability assays showed both TRAIL and TK monotherapy markedly reduced tumor growth. Using intraoperative navigation and two delivery methods to closely mimic human therapy, canines received autologous iNSCs either within postsurgical cavities in a biocompatible matrix or via a catheter placed in the lateral ventricle. Both strategies were well tolerated, and serial MRI showed hypointense regions at the implant sites that remained stable through 86 days postimplant. Serial fluid sample testing following iNSC delivery showed the bimodal personalized therapy was well tolerated, with no iNSC-induced abnormal tissue pathology. Overall, this study lays an important foundation as this promising personalized cell therapy advances toward human patient testing.

© 2020 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of The American Institute of Chemical Engineers.

Keywords: glioblastoma; neural stem cells; stem cell delivery

Conflict of interest statement

K. T. S. and S. D. H have an ownership interest in Falcon Therapeutics, Inc., which has licensed aspects of iNSC technology from the University of North Carolina at Chapel Hill. H. N. B., A. V., S. K.

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