Moving Stem Cells to the Clinic: Potential and Limitations for Brain Repair

Steinbeck, Julius A.; Studer, Lorenz

doi:10.1016/j.neuron.2015.03.002

Cited by 121 publications

(104 citation statements)

References 225 publications

(278 reference statements)

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“…However, the general consensus is that therapeutic outcomes attained by current NPC transplantation techniques do not reach a level that is satisfactory for the treatment of patients (reviewed in ref. 1,2). To overcome this limitation, studies have mainly centered on the improvement of intrinsic donor cell qualities.…”

Section: Introductionmentioning

confidence: 99%

Cografting astrocytes improves cell therapeutic outcomes in a Parkinson’s disease model

Song¹,

Oh²,

Kwon³

et al. 2017

Journal of Clinical Investigation

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In this study, we have attempted to exploit the neurotrophic actions of astrocytes and Nurr1+Foxa2 functions in this cell type to improve the therapeutic outcomes of NPC transplantation using an animal model of PD. Our in vitro assays using a coculture system and conditioned media treatment revealed that astrocytes, especially those cultured from the ventral midbrain (VM), where HNF3β) is a potent cofactor that synergizes the Nurr1-mediated antiinflammatory roles in glia (16). Furthermore, forced coexpression of Nurr1 and Foxa2 (Nurr1+Foxa2) in glia promotes the synthesis and release of various neurotrophic factors, indicating that engineering of Nurr1 and Foxa2 in glia could become a powerful strategy for treating CNS disorders. Representative images of TH + DA neurons differentiated from VM-NPCs in the presence of Ctx-NPCs (control), Ctx-Ast, or VM-Ast. Scale bar: 100 μm. Insets, enlarged images of the boxed areas (original magnification, ×400). (C) DA neuronal yields at differentiation day 6 (D6). (D-H) Morphometric measurement of DA neuron maturity assessed by neurite outgrowth lengths (D), soma size (E), and by the Sholl test (F and G). In the Sholl analysis, the total number of neurite crossings was counted in each circle with the radius increasing in steps of 15 μm (F). The critical value (G) is the radius at which there was a maximum number of neurite crossings. *P < 0.05, significantly different from the control; # P < 0.05, significantly different from Ctx-Ast, 1-way ANOVA. n = 3-5 wells (C) and 100 (D and E) and 25-30 (F and G) TH + cells in each group.(H) Representative TH + neuronal morphologies reconstructed in 3D by Neurolucida. (I-L) Synaptic densities on TH + fibers. (I) Representative confocal images of synapsin + TH + fibers. Scale bar: 25 μm. Puncta positive for the synaptic vesicle-specific markers SV2 (J), synapsin (K), and bassoon (L) on TH + fibers were counted. *P < 0.05, significantly different from the control; # P < 0.05, significantly different from Ctx-Ast. n = 20 TH + fibers for each group. (M) Presynaptic DA release. n = 3 independent cultures. DA levels were measured in the media conditioned in the differentiated cultures for 24 hours (D13-D15) and in cultures evoked by KCl-mediated depolarization for 30 minutes. *P < 0.05; # P < 0.05, 1-way ANOVA. The Journal of Clinical Investigation R E S E A R C H A R T I C L E4 6 5 jci.org Volume 128 Number 1 January 2018 (Supplemental Figure 1B; supplemental material available online with this article; https://doi.org/10.1172/JCI93924DS1), immunocytochemical analyses revealed that major cell populations in the Ctx-and VM-astroglial cultures at day in vitro (DIV) 14 were positive for GFAP (85% and 82%), CD44 (79% and 76 %), GLT-1 (58% and 71 %), and GLAST protein (71% and 77%), respectively (Supplemental Figure 1A), except S100β (20% and 32%), a soluble protein associated with harmful reactivation of astrocytes (22). A few (0.24% ± 0.35% in Ctx-Ast and 0.43% ± 0.39% in VM-Ast, where Ast indicates astrocytes) and none of the cells in these c...

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Section: Introductionmentioning

confidence: 99%

Cografting astrocytes improves cell therapeutic outcomes in a Parkinson’s disease model

Song¹,

Oh²,

Kwon³

et al. 2017

Journal of Clinical Investigation

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“…Information gathered through in vitro tests should be correlated to in vivo preclinical functional assays on relevant animal models, performed to obtain complementary data on the biological activity of the product. Results from preclinical studies of hESC-based therapies for brain repair show that further research is needed to validate the correlation between functional properties of transplanted cells in vitro and in vivo [49]. For example, in the context of hESC-based products for the therapy of PD, the stage of differentiation of hESC-derived dopamine progenitors is crucial.…”

Section: Potency: "How Strong Is This Stuff?"mentioning

confidence: 99%

Adapting Preclinical Benchmarks for First-in-Human Trials of Human Embryonic Stem Cell-Based Therapies

Barazzetti

Hurst

Mauron

2016

Stem Cells Translational Medicine

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As research on human embryonic stem cell (hESC)-based therapies is moving from the laboratory to the clinic, there is an urgent need to assess when it can be ethically justified to make the step from preclinical studies to the first protocols involving human subjects. We examined existing regulatory frameworks stating preclinical requirements relevant to the move to first-in-human (FIH) trials and assessed how they may be applied in the context of hESC-based interventions to best protect research participants. Our findings show that some preclinical benchmarks require rethinking (i.e., identity, purity), while others need to be specified (i.e., potency, viability), owing to the distinctive dynamic heterogeneity of hESC-based products, which increases uncertainty and persistence of safety risks and allows for limited predictions of effects in vivo. Rethinking or adaptation of how to apply preclinical benchmarks in specific cases will be required repeatedly for different hESC-based products. This process would benefit from mutual learning if researchers included these components in the description of their methods in publications. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:1058-1066 SIGNIFICANCETo design translational research with an eye to protecting human participants in early trials, researchers and regulators need to start their efforts at the preclinical stage. Existing regulatory frameworks for preclinical research, however, are not really adapted to this in the case of stem cell translational medicine. This article reviews existing regulatory frameworks for preclinical requirements and assesses how their underlying principles may best be applied in the context of human embryonic stem cell-based interventions for the therapy of Parkinson's disease. This research will help to address the question of when it is ethically justified to start first-in-human trials in stem cell translational medicine.

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“…1,[23][24][25] Several preclinical studies have evaluated the efficacy of rodent neural precursor cells in TBI rodent models. 22,[26][27][28][29][30] The culturing NSCs in vitro started as an attempt to grow multipotent embryonic cortical tissue (the word neural stem cells was not yet coined) and successfully accomplished in 1989 at the University of Miami. 31 This work evolved when Martin Raff, a Canadian born Boston neurologist decided to move to England and chose to leave the United States (US) than fight in Vietnam War and to pursue immunology.…”

Section: Step 1 Cell Therapy Candidatementioning

confidence: 99%

“…1,55 Further the experts in the field recommended that 8-week survival period prior to assessments would allow sufficient time for differentiation and integration of human neural stem cells with the host and possibly validate the presumed mechanism of action. 1,26 The successful preclinical ALS, SCI and stroke studies. 40,41,44,56 have employed a different immunosuppression technique that was pioneered by Hefferan et al 40 This technique relies on three agents namely: mycophenylate mofetil, tacrolimus and methyl prednisolone.…”

Section: Step 2 Immunosuppressionmentioning

confidence: 99%

One Step at a Time, Stem Cell Therapy for Traumatic Brain Injury Needs Two More Breakthroughs

Gajavelli¹

2016

JSRT

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26As of 2015, a total of 49 ALS patients have received NSI-566 cells. Both the cells and surgery were well tolerated and the ALS studies reported a 47% responder rate with decline in disease progression and improved grip strength. Stem cells inc., on the other hand lost a patent dispute to NSI and recently closed operations.J Stem Cell Res Ther. 2016;1(4):160-164. 160© 2016 Shyam. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and build upon your work non-commercially.One step at a time, stem cell therapy for traumatic brain injury needs two more breakthroughs Step 2 ImmunosuppressionTransplantation of the cells conferred benefits such as restoration of injured neuronal morphology 45 and cognitive function. 46 even without immunosuppression. Transient immunosuppression was shown to be sufficient to support engraftment and transplanted derived neurons were reportedly present 6 months post transplantation. 47 However, no data quantifying either engraftment or behavior modification were presented. Such studies were limited by cyclosporine mediated immunosuppression which resulted in persistence of barriers to engraftment and demonstration of effectiveness of the approach. 48-50The initial optimism was replaced by skepticism if the therapeutic potential of neural stem cells: greater in people's perception than in their brains. 51,52 The US Food and Drug Administration (FDA; Rockville, MD) guidelines on preclinical assessment of cell therapies in the publication "Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products".53,54 A review of literature shows human cell therapy in rat TBI that measure cognitive benefit have not addressed donor cell fate past one-month posttransplantation. 1,55 Further the experts in the field recommended that 8-week survival period prior to assessments would allow sufficient time for differentiation and integration of human neural stem cells with the host and possibly validate the presumed mechanism of action. 1,26The successful preclinical ALS, SCI and stroke studies. 40,41,44,56 have employed a different immunosuppression technique that was pioneered by Hefferan et al. 40 This technique relies on three agents namely: mycophenylate mofetil, tacrolimus and methyl prednisolone. The combination has been found to be superior to cyclosporine, a standard immunosuppressant between 1999-2012. Step 3 Mechanism of actionHowever, due to the lack of exact mechanism of action still precludes attempts to move neural stem cell therapy to the clinic. 26Paul Lu et al. 41 demonstrated the mechanism of regeneration in spinal cord injury models. 41 Axonal growth was partially dependent on mammalian target of rapamycin (mTOR), but not Nogo signaling. Grafted neurons supported formation of electrophysiological relays across sites of complete spinal transection, resulting in functional recovery. The recovery was lost subsequent to re-transection of the spinal cord....

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Moving Stem Cells to the Clinic: Potential and Limitations for Brain Repair

Cited by 121 publications

References 225 publications

Cografting astrocytes improves cell therapeutic outcomes in a Parkinson’s disease model

Cografting astrocytes improves cell therapeutic outcomes in a Parkinson’s disease model

Adapting Preclinical Benchmarks for First-in-Human Trials of Human Embryonic Stem Cell-Based Therapies

One Step at a Time, Stem Cell Therapy for Traumatic Brain Injury Needs Two More Breakthroughs

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