Atps-29intranasal Delivery of Therapeutic Neural Stem Cells to Target Intracerebral Glioma

Gutova, Margarita; Davit, Shahmanyan; Oganesyan, Diana; Abramyants, Yelena; Danielyan, Lusine; Frey, William H.; Khankaldyyan, Vazgen; Najbauer, Joseph; Balyasnikova, Irina; Moats, Rex; Lesniak, Maciej S.; Barish, Michael E.; Aboody, Karen S.

doi:10.1093/neuonc/nov204.29

Cited by 7 publications

(10 citation statements)

References 27 publications

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“…Although this modality has been successfully utilized for delivering a variety of growth factors, hormones, and neuropeptides ( Chapman et al., 2013 ) to the CNS, the efficacy of this route to deliver cell-based carriers is still in its early phase of exploration. As the tropism of NSCs to intracranial glioma and other malignancies is well validated ( Aboody et al., 2000 , Gutova et al., 2015 , Kanojia et al., 2015 ), the intranasal delivery imposes strict requirements for fast migration of therapeutic cell carriers from the nasal cavity to prevent rapid clearance from the nasal cavity. In this respect, MSCs genetically modified to overexpress CXCR4 have been shown to possess higher migratory properties and therapeutic potential in an acute lung injury model ( Yang et al., 2015 ), better homing capacity to bone marrow in irradiated mice ( Chen et al., 2013 ), and mobilization and enhanced neuroprotection in a rat cerebral ischemia model ( Yu et al., 2012 ).…”

Section: Discussionmentioning

confidence: 99%

“…(2012) demonstrated that intranasally delivered neural stem cells (NSCs) localize to the intracranial human or murine glioma xenografts in mouse models. Furthermore, our group has shown that therapeutic MSCs and NSCs when delivered to the nasal cavity not only travel to intracranial tumors in mice, but also prolong the animals' survival ( Balyasnikova et al., 2014 , Gutova et al., 2015 ). Further validation of intranasal delivery of various therapeutics to the brain is of particular interest in the context of MG.…”

Section: Introductionmentioning

confidence: 99%

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Intranasal Oncolytic Virotherapy with CXCR4-Enhanced Stem Cells Extends Survival in Mouse Model of Glioma

Dey

Kanojia

et al. 2016

Stem Cell Reports

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SummaryThe challenges to effective drug delivery to brain tumors are twofold: (1) there is a lack of non-invasive methods of local delivery and (2) the blood-brain barrier limits systemic delivery. Intranasal delivery of therapeutics to the brain overcomes both challenges. In mouse model of malignant glioma, we observed that a small fraction of intranasally delivered neural stem cells (NSCs) can migrate to the brain tumor site. Here, we demonstrate that hypoxic preconditioning or overexpression of CXCR4 significantly enhances the tumor-targeting ability of NSCs, but without altering their phenotype only in genetically modified NSCs. Modified NSCs deliver oncolytic virus to glioma more efficiently and extend survival of experimental animals in the context of radiotherapy. Our findings indicate that intranasal delivery of stem cell-based therapeutics could be optimized for future clinical applications, and allow for safe and repeated administration of biological therapies to brain tumors and other CNS disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Intranasal Oncolytic Virotherapy with CXCR4-Enhanced Stem Cells Extends Survival in Mouse Model of Glioma

Dey

Kanojia

et al. 2016

Stem Cell Reports

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“…Sham-operated mice (without TBI) were used as controls. The LM-NSC008 and HB1.F3.CD NSCs ( Kim et al., 2008 ) were administered intranasally on days 9 and 11 following generation of moderate TBI or a sham operation (n = 5 per group), as described previously ( Gutova et al., 2015 ). Mice received intranasal drops of hNSCs (5 × 10 5 cells in 12 μL of PBS), equally divided and administered into both nostrils.…”

Section: Resultsmentioning

confidence: 99%

L- MYC Expression Maintains Self-Renewal and Prolongs Multipotency of Primary Human Neural Stem Cells

Oganesyan

Mooney

et al. 2016

Stem Cell Reports

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SummaryPre-clinical studies indicate that neural stem cells (NSCs) can limit or reverse CNS damage through direct cell replacement, promotion of regeneration, or delivery of therapeutic agents. Immortalized NSC lines are in growing demand due to the inherent limitations of adult patient-derived NSCs, including availability, expandability, potential for genetic modifications, and costs. Here, we describe the generation and characterization of a new human fetal NSC line, immortalized by transduction with L-MYC (LM-NSC008) that in vitro displays both self-renewal and multipotent differentiation into neurons, oligodendrocytes, and astrocytes. These LM-NSC008 cells were non-tumorigenic in vivo, and migrated to orthotopic glioma xenografts in immunodeficient mice. When administered intranasally, LM-NSC008 distributed specifically to sites of traumatic brain injury (TBI). These data support the therapeutic development of immortalized LM-NSC008 cells for allogeneic use in TBI and other CNS diseases.

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“…Although it has not been directly demonstrated, results may also be affected by the volume of therapeutic delivered. The fast clearance of therapeutic agents observed following IND should be taken into account when developing preclinical experiments [5,13,44]. Additionally, how stem cells utilize the olfactory and trigeminal nerve, the vasculature, and the lymphatic pathways for brain entry remains to be delineated [6,20,22,101–103].…”

Section: Experimental Considerations For Ind In Preclinical Studiesmentioning

confidence: 99%

“…Fluorescent microscopy, [H3]-thymidine, and near-infrared live imaging have previously been utilized to track MSCs following IND; florescent microscopy has also been used to image NSCs following IND [2,16,44,112,113]. …”

Section: Imaging To Track Intranasally Delivered Stem Cellsmentioning

confidence: 99%

Intranasal delivery of stem cell-based therapies for the treatment of brain malignancies

Bonamici

Dey

et al. 2017

Expert Opinion on Drug Delivery

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Introduction Glioblastoma (GBM) is the most aggressive malignant brain cancer in adults, and its poor prognosis and resistance to the existing standard of care require the development of innovative therapeutic modalities. The local delivery of stem cells as therapeutic carriers against glioma has produced encouraging results, but encounters obstacles with regards to the repeatability and invasiveness of administration. Intranasal delivery of therapeutic stem cells could overcome these obstacles, among others, as a noninvasive and easily repeatable mode of administration. Areas covered This review describes nasal anatomy, routes of stem cell migration, and factors affecting stem cell delivery to hard-to-reach tumors. Furthermore, this review discusses the molecular mechanisms underlying stem cell migration following delivery, as well as possible stem cell effector functions to be considered in combination with intranasal delivery. Expert opinion Further research is necessary to elucidate the dynamics of stem cell effector functions in the context of intranasal delivery and optimize their therapeutic potency. Nonetheless, the technique represents a promising tool against brain cancer and has the potential to be expanded for use against other brain pathologies.

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Atps-29intranasal Delivery of Therapeutic Neural Stem Cells to Target Intracerebral Glioma

Cited by 7 publications

References 27 publications

Intranasal Oncolytic Virotherapy with CXCR4-Enhanced Stem Cells Extends Survival in Mouse Model of Glioma

Intranasal Oncolytic Virotherapy with CXCR4-Enhanced Stem Cells Extends Survival in Mouse Model of Glioma

L- MYC Expression Maintains Self-Renewal and Prolongs Multipotency of Primary Human Neural Stem Cells

Intranasal delivery of stem cell-based therapies for the treatment of brain malignancies

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