Neural Stem Cell Tumorigenicity and Biodistribution Assessment for Phase I Clinical Trial in Parkinson’s Disease

Garitaonandia, Ibon; Gonzalez, Rodolfo; Christiansen-Weber, Trudy; Abramihina, Tatiana; Poustovoitov, Maxim; Noskov, Alexander; Sherman, Glenn; Semechkin, Andrey; Snyder, Evan Y.; Kern, Russell

doi:10.1038/srep34478

Cited by 55 publications

(40 citation statements)

References 48 publications

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“…In fact, Hentze et al could demonstrate that as few as 245 pluripotent stem cells can lead to teratoma formation ( 39 ). Conversely, human pSC-derived neural stem cells did not induce teratomas in immune deficient athymic nude rats ( 40 ). This is in line with own data on the implantation of human embryonic stem cell derived EHM in nude rats ( 41 ).…”

Section: Discussionmentioning

confidence: 99%

Immunological Properties of Murine Parthenogenetic Stem Cell-Derived Cardiomyocytes and Engineered Heart Muscle

et al. 2017

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Pluripotent parthenogenetic stem cells (pSCs) can be derived by pharmacological activation of unfertilized oocytes. Homozygosity of the major histocompatibility complex (MHC) in pSCs makes them an attractive cell source for applications in allogeneic tissue repair. This was recently demonstrated for pSC-based tissue-engineered heart repair. A detailed analysis of immunological properties of pSC-derived cardiomyocytes and engineered heart muscle (EHM) thereof is, however, lacking. The aim of this study was to determine baseline and cytokine-inducible MHC class I and MHC class II as well as programmed death ligand-1 (PDL-1) and co-stimulatory protein (CD40, CD80, CD86) expression in pSC-derived cardiomyocytes and pSC-EHM in vitro and in vivo. Cardiomyocytes from an MHC-homologous (H2d/d) pSC-line were enriched to ~90% by making use of a recently developed cardiomyocyte-specific genetic selection protocol. MHC class I and MHC class II expression in cardiomyocytes could only be observed after stimulation with interferon gamma (IFN-γ). PDL-1 was markedly upregulated under IFN-γ. CD40, CD80, and CD86 were expressed at low levels and not upregulated by IFN-γ. EHM constructed from H2d/d cardiomyocytes expressed similarly low levels of MHC class I, MHC class II, and costimulatory molecules under basal conditions. However, in EHM only MHC class I, but not MHC class II, molecules were upregulated after IFN-γ-stimulation. We next employed a cocultivation system with MHC-matched and MHC-mismatched splenocytes and T-cells to analyze the immune stimulatory properties of EHMs. Despite MHC-mismatched conditions, EHM did not induce splenocyte or T-cell proliferation in vitro. To evaluate the immunogenicity of pSC-derived cardiomyocytes in vivo, we implanted pSC-derived embryoid bodies after elimination of non-cardiomyocytes (cardiac bodies) under the kidney capsules of MHC-matched and -mismatched mice. Spontaneous beating of cardiac bodies could be observed for 28 days in the matched and for 7 days in the mismatched conditions. Teratomas formed after 28 days only in the MHC-matched conditions. Immunohistochemistry revealed single clusters of CD3-positive cells in the border zone of the implant in the mismatched conditions with few CD3-positive cells infiltrating the implant. Taken together, MHC-matched pSC-cardiomyocyte allografts show little immune cell activation, offering an explanation for the observed long-term retention of pSC-EHM allografts in the absence of immunosuppression.

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Section: Discussionmentioning

confidence: 99%

Immunological Properties of Murine Parthenogenetic Stem Cell-Derived Cardiomyocytes and Engineered Heart Muscle

et al. 2017

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“…Besides direct tissue replacement, stem cells can form synapses, modulate inflammation, and provide sustained enrichment of neuronal microenvironments via paracrine factor delivery. Direct central nervous system (CNS) stem cell injections are in clinical trials for stroke and Parkinson’s disease 5 – 7 , and our own laboratory has unique experience translating a cellular therapy to the clinic for amyotrophic lateral sclerosis (ALS) 8 – 13 . In AD, several preclinical studies have shown the short-term benefit of stem cell transplantation in murine models and indicate that efficacy is frequently associated with the delivery of neurotrophic factors 14 – 20 .…”

Section: Introductionmentioning

confidence: 99%

Human neural stem cell transplantation improves cognition in a murine model of Alzheimer’s disease

McGinley

Kashlan

Bruno

et al. 2018

Sci Rep

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Stem cell transplantation offers a potentially transformative approach to treating neurodegenerative disorders. The safety of cellular therapies is established in multiple clinical trials, including our own in amyotrophic lateral sclerosis. To initiate similar trials in Alzheimer’s disease, efficacious cell lines must be identified. Here, we completed a preclinical proof-of-concept study in the APP/PS1 murine model of Alzheimer’s disease. Human neural stem cell transplantation targeted to the fimbria fornix significantly improved cognition in two hippocampal-dependent memory tasks at 4 and 16 weeks post-transplantation. While levels of synapse-related proteins and cholinergic neurons were unaffected, amyloid plaque load was significantly reduced in stem cell transplanted mice and associated with increased recruitment of activated microglia. In vitro, these same neural stem cells induced microglial activation and amyloid phagocytosis, suggesting an immunomodulatory capacity. Although long-term transplantation resulted in significant functional and pathological improvements in APP/PS1 mice, stem cells were not identified by immunohistochemistry or PCR at the study endpoint. These data suggest integration into native tissue or the idea that transient engraftment may be adequate for therapeutic efficacy, reducing the need for continued immunosuppression. Overall, our results support further preclinical development of human neural stem cells as a safe and effective therapy for Alzheimer’s disease.

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“…This assay is highly sensitive, and Tano et al [23] reported that the LOD was 0.001% when a 10-cm dish was used as a culture vessel. Indeed, this assay was employed in the tumorigenicity assessment of an hPSC-derived cell therapy product, human parthenogenetic stem cell-derived neural stem cells (ISC-hpNSCs) prior to conducting a phase 1 clinical trial under the requirements of the US Food and Drug Administration and the Australian Therapeutic Goods Administration (clinicaltrials.gov identifier NCT02452723) [28]. Briefly, ISC-hpNSCs were grown either as a pure population (100% ISC-hpNSCs) or spiked with 0.1%, 0.01% or 0.001% hPSCs.…”

Section: Discussionmentioning

confidence: 99%

Multisite studies for validation and improvement of a highly efficient culture assay for detection of undifferentiated human pluripotent stem cells intermingled in cell therapy products

et al. 2021

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Background aims: The Multisite Evaluation Study on Analytical Methods for Non-Clinical Safety Assessment of Human-Derived Regenerative Medical Products (MEASURE) is a Japanese experimental pub-licÀprivate partnership initiative, which aims to standardize methodology for tumorigenicity evaluation of human pluripotent stem cell (hPSC)-derived cell therapy products (CTPs). Undifferentiated hPSCs possess tumorigenic potential, and thus residual undifferentiated hPSCs are one of the major hazards for the risk of tumor formation from hPSC-derived CTPs. Among currently available assays, a highly efficient culture (HEC) assay is reported to be one of the most sensitive for the detection of residual undifferentiated hPSCs. Methods: MEASURE first validated the detection sensitivity of HEC assay and then investigated the feasibility of magnetic-activated cell sorting (MACS) to improve sensitivity. Results: The multisite experiments confirmed that the lower limit of detection under various conditions to which the human induced pluripotent stem cell lines and culture medium/substrate were subjected was 0.001%. In addition, MACS concentrated cells expressing undifferentiated cell markers and consequently achieved a detection sensitivity of 0.00002%. Conclusions: These results indicate that HEC assay is highly sensitive and robust and that the application of MACS on this assay is a promising tool for further mitigation of the potential tumorigenicity risk of hPSCderived CTPs.

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Neural Stem Cell Tumorigenicity and Biodistribution Assessment for Phase I Clinical Trial in Parkinson’s Disease

Cited by 55 publications

References 48 publications

Immunological Properties of Murine Parthenogenetic Stem Cell-Derived Cardiomyocytes and Engineered Heart Muscle

Immunological Properties of Murine Parthenogenetic Stem Cell-Derived Cardiomyocytes and Engineered Heart Muscle

Human neural stem cell transplantation improves cognition in a murine model of Alzheimer’s disease

Multisite studies for validation and improvement of a highly efficient culture assay for detection of undifferentiated human pluripotent stem cells intermingled in cell therapy products

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