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Safety profiling of genetically engineered Pim-1 kinase overexpression for oncogenicity risk in human c-kit+ cardiac interstitial cells

Gene Therapy volume 26, pages 324–337 (2019)Cite this article

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Abstract

Advancement of stem cell-based treatment will involve next-generation approaches to enhance therapeutic efficacy which is often modest, particularly in the context of myocardial regenerative therapy. Our group has previously demonstrated the beneficial effect of genetic modification of cardiac stem cells with Pim-1 kinase overexpression to rejuvenate aged cells as well as potentiate myocardial repair. Despite these encouraging findings, concerns were raised regarding potential for oncogenic risk associated with Pim-1 kinase overexpression. Testing of Pim-1 engineered c-kit+ cardiac interstitial cells (cCIC) derived from heart failure patient samples for indices of oncogenic risk was undertaken using multiple assessments including soft agar colony formation, micronucleation, gamma-Histone 2AX foci, and transcriptome profiling. Collectively, findings demonstrate comparable phenotypic and biological properties of cCIC following Pim-1 overexpression compared with using baseline control cells with no evidence for oncogenic phenotype. Using a highly selective and continuous sensor for quantitative assessment of PIM1 kinase activity revealed a sevenfold increase in Pim-1 engineered vs. control cells. Kinase activity profiling using a panel of sensors for other kinases demonstrates elevation of IKKs), AKT/SGK, CDK1-3, p38, and ERK1/2 in addition to Pim-1 consistent with heightened kinase activity correlating with Pim-1 overexpression that may contribute to Pim-1-mediated effects. Enhancement of cellular survival, proliferation, and other beneficial properties to augment stem cell-mediated repair without oncogenic risk is a feasible, logical, and safe approach to improve efficacy and overcome current limitations inherent to cellular adoptive transfer therapeutic interventions.

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Data availability

RNA-Seq data generated in this study has been uploaded to the Gene Expression Omnibus (GEO) database (GSE124590).

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Acknowledgements

The research in this study was funded by STTR R41HL1377602 to CardioCreate Inc. We thank the staff at Sharp Hospital, in particular Chris Kohlmeyer and Donna Small, for bridging the collaborative arrangement between Sharp Hospital and the Sussman Laboratory. KMB is supported by NIH grant F32HL136196. MAS is also supported by NIH grants: R01HL067245, R37HL091102, R01HL105759, R01HL113647, R01HL117163, P01HL085577, and R01HL122525, as well as an award from the Fondation Leducq.

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  1. Department of Biology and Integrated Regenerative Research Institute, San Diego State University, San Diego, CA, USA

    Kathleen Broughton, Kelli Korski, Oscar Echeagaray & Mark A. Sussman

  2. CardioCreate, Inc., San Diego, CA, USA

    Kathleen Broughton, Kelli Korski & Mark A. Sussman

  3. Division of Cardiology, Sharp Hospital, San Diego, CA, USA

    Robert Adamson & Walter Dembitsky

  4. AssayQuant, Marlborough, MA, USA

    Zhibing Lu & Erik Schaefer

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Correspondence to Mark A. Sussman.

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This study was supported in part through funds awarded to CardioCreate Inc. Authors affiliated with CardioCreate Inc. include MAS (Chief Scientific Officer and co-founder) and KMB (Administrative Official) who both have significant financial interests in the company.

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Broughton, K., Korski, K., Echeagaray, O. et al. Safety profiling of genetically engineered Pim-1 kinase overexpression for oncogenicity risk in human c-kit+ cardiac interstitial cells. Gene Ther 26, 324–337 (2019). https://doi.org/10.1038/s41434-019-0084-5

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