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Hideyuki Yoshida, Isao Date, Tetsuro Shingo, Kenjiro Fujiwara, Kazuki Kobayashi, Yasuyuki Miyoshi and Takashi Ohmoto

Object. The PC12 cells are well known for their ability to secrete dopamine and levodopa. In multiple animal models encapsulated PC12 cells have been shown to ameliorate parkinsonian symptoms when transplanted into the striatum; this technique is expected to be effective clinically as well. The present study was performed using nonhuman primates to ensure that the transplantation of encapsulated PC12 cells is likely to be both safe and effective in human clinical trials.

Methods. Unencapsulated or encapsulated PC12 cells were implanted into the brains of Japanese monkeys (Macaca fuscata). Histological and immunocytochemical analyses were performed 1, 2, 4, and 8 weeks posttransplantation on the unencapsulated cells and 2, 4, and 8 weeks after transplantation on the encapsulated cells. The survival of the PC12 cells inside the capsule was determined by measuring the amounts of dopamine and levodopa released from the capsules after removal from the striatum. Magnetic resonance imaging was performed in both unencapsulated and encapsulated PC12 cell—grafted groups.

Due to the immunological reaction of the host brain no unencapsulated PC12 cells remained in the grafted area 8 weeks after transplantation. On the contrary, encapsulated PC12 cells retrieved from the host brain continued to release dopamine and levodopa even 8 weeks after implantation. The host's reaction to the PC12-loaded capsule was much weaker than that to the unencapsulated PC12 cells.

Conclusions. These results suggest that the transplantation of encapsulated PC12 cells could be a safe and effective treatment modality for Parkinson disease in human patients.

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Gary K. Steinberg, Douglas Kondziolka, Lawrence R. Wechsler, L. Dade Lunsford, Anthony S. Kim, Jeremiah N. Johnson, Damien Bates, Gene Poggio, Casey Case, Michael McGrogan, Ernest W. Yankee and Neil E. Schwartz

OBJECTIVE

The aim of this study was to evaluate the safety and clinical outcomes associated with stereotactic surgical implantation of modified bone marrow–derived mesenchymal stem cells (SB623) in patients with stable chronic ischemic stroke.

METHODS

This was a 2-year, open-label, single-arm, phase 1/2a study; the selected patients had chronic motor deficits between 6 and 60 months after nonhemorrhagic stroke. SB623 cells were administered to the target sites surrounding the subcortical stroke region using MRI stereotactic image guidance.

RESULTS

A total of 18 patients were treated with SB623 cells. All experienced at least 1 treatment-emergent adverse event (TEAE). No patients withdrew due to adverse events, and there were no dose-limiting toxicities or deaths. The most frequent TEAE was headache related to the surgical procedure (88.9%). Seven patients experienced 9 serious adverse events, which resolved without sequelae. In 16 patients who completed 24 months of treatment, statistically significant improvements from baseline (mean) at 24 months were reported for the European Stroke Scale (ESS) score, 5.7 (95% CI 1.4–10.1, p < 0.05); National Institutes of Health Stroke Scale (NIHSS) score, −2.1 (95% CI −3.3 to −1.0, p < 0.01), Fugl-Meyer (F-M) total score, 19.4 (95% CI 9.9–29.0, p < 0.01); and F-M motor scale score, 10.4 (95% CI 4.0–16.7, p < 0.01). Measures of efficacy reached plateau by 12 months with no decline thereafter. There were no statistically significant changes in the modified Rankin Scale score. The size of transient lesions detected by T2-weighted FLAIR imaging in the ipsilateral cortex at weeks 1–2 postimplantation significantly correlated with improvement in ESS (0.619, p < 0.05) and NIHSS (−0.735, p < 0.01) scores at 24 months.

CONCLUSIONS

In this completed 2-year phase 1/2a study, implantation of SB623 cells in patients with stable chronic stroke was safe and was accompanied by improvements in clinical outcomes.

Clinical trial registration no.: NCT01287936 (clinicaltrials.gov)

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Mahmud Uzzaman, Ronald J. Benveniste, Gordon Keller and Isabelle M. Germano

Object

For gene therapy strategies currently in clinical trials, viral vectors are used to deliver transgenes directly to normal and tumor cells within the central nervous system (CNS). The use of viral vectors is limited by several factors. The aim of this study was to assess whether embryonic stem cell (ESC)–derived astrocytes expressing a doxycycline-inducible transgene can be used as a vector for gene therapy.

Methods

The authors generated a pure population of ESC-derived astrocytes carrying a transgene, tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), inserted in the chromosome under the control of a highly regulated doxycycline-inducible expression system. Fully differentiated ESC-derived astrocytes were stereotactically transplanted in the mouse brain, and then cell migration and transgene expression were studied.

Results

The ESC-derived astrocytes started to migrate from the transplant site 48 hours after the procedure. They were found to have migrated throughout the brain tissue by 6 weeks. Transplanted ESC-derived astrocytes expressed the TRAIL transgene after doxycycline induction throughout the duration of the experiment. Teratoma formation was not observed in long-term experiments (12 weeks).

Conclusions

These data show that ESC-derived astrocytes can be used as delivery vectors for CNS tumors. This technique might have a major impact on the treatment of patients with malignant gliomas and a wide spectrum of other neurological diseases.

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Grant Sinson, Madhu Voddi and Tracy K. McIntosh

This study was designed to evaluate the histological and behavioral impact of fetal neural transplantation with and without neurotrophin infusion in rats subjected to traumatic brain injury using a clinically relevant model of lateral fluid-percussion brain injury. Adult male Sprague-Dawley rats received lateral fluid-percussion brain injury of moderate severity (2.1-2.3 atm). Twenty-four hours after injury, minced fetal cortical grafts (E16) were stereotactically transplanted into the site of injury cavity formation (in 32 rats). Ten control animals received injections of saline. A third group of 29 animals that received transplants also underwent placement of a miniosmotic pump (immediately after transplantation) to continuously infuse nerve growth factor (NGF) directly into the region of graft placement for the duration of the experiment. A fourth group of eight animals underwent transplantation of fetal cortical cells that had been dissociated and placed in suspension. Animals were evaluated at 72 hours, 1 week, and 2 weeks after injury for cognitive function (using the Morris water maze), posttraumatic motor dysfunction, and transplant survival and morphology (using Nissl and modified Palmgren's silver staining techniques). Robust survival of whole-tissue transplants was seen in 65.6% of animals and was not increased in animals receiving NGF infusion. Animals receiving transplants of cell suspension had no surviving grafts. Brain-injured animals receiving transplants showed significant cognitive improvements compared with controls at the 2-week evaluation. Significantly improved memory scores were seen at all evaluation times in animals receiving both NGF and transplants compared with injured controls and compared with animals receiving transplants alone at the 72-hour and 1-week evaluations. Neurological motor function scores were significantly improved in animals receiving transplants alone and those receiving transplants with NGF infusion. Histological evaluation demonstrated differentiation of grafted cells, decreased glial scarring around transplants when compared with control animals, and the presence of neuronal fibers bridging the interface between graft and host. This study demonstrates that fetal cortical cells transplanted into the injured cortex of the adult rat can improve both posttraumatic cognitive and motor function and interact with the injured host brain.

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Grant Sinson, Madhu Voddi and Tracy K. McIntosh

✓ This study was designed to evaluate the histological and behavioral impact of fetal neural transplantation with and without neurotrophin infusion in rats subjected to traumatic brain injury using a clinically relevant model of lateral fluid-percussion brain injury. Adult male Sprague—Dawley rats received lateral fluid-percussion brain injury of moderate severity (2.1–2.3 atm). Twenty-four hours after injury, minced fetal cortical grafts (E16) were stereotactically transplanted into the site of injury cavity formation (in 32 rats). Ten control animals received injections of saline. A third group of 29 animals that received transplants also underwent placement of a miniosmotic pump (immediately after transplantation) to continuously infuse nerve growth factor (NGF) directly into the region of graft placement for the duration of the experiment. A fourth group of eight animals underwent transplantation of fetal cortical cells that had been dissociated and placed in suspension. Animals were evaluated at 72 hours, 1 week, and 2 weeks after injury for cognitive function (using the Morris water maze), posttraumatic motor dysfunction, and transplant survival and morphology (using Nissl and modified Palmgren's silver staining techniques). Robust survival of whole-tissue transplants was seen in 65.6% of animals and was not increased in animals receiving NGF infusion. Animals receiving transplants of cell suspension had no surviving grafts. Brain-injured animals receiving transplants showed significant cognitive improvements compared with controls at the 2-week evaluation. Significantly improved memory scores were seen at all evaluation times in animals receiving both NGF and transplants compared with injured controls and compared with animals receiving transplants alone at the 72-hour and 1-week evaluations. Neurological motor function scores were significantly improved in animals receiving transplants alone and those receiving transplants with NGF infusion. Histological evaluation demonstrated differentiation of grafted cells, decreased glial scarring around transplants when compared with control animals, and the presence of neuronal fibers bridging the interface between graft and host. This study demonstrates that fetal cortical cells transplanted into the injured cortex of the adult rat can improve both posttraumatic cognitive and motor function and interact with the injured host brain.

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Raphael Guzman, Raymond Choi, Atul Gera, Alejandro De Los Angeles, Robert H. Andres and Gary K. Steinberg

therapies for stroke have been performed to date. 48–50 , 61 , 72 All 3 trials included patients who were treated at least 6 months after their strokes (between 6 months and 4.5 years, 50 between 1 and 6 years, 49 and between 1.5 and 10 years 72 ). In 2 of the trials an hNT was used, 49 , 50 and in the 3rd trial porcine-derived NPCs were utilized. 72 All 3 trials involved stereotactic transplantation of the respective cells into the border zone of the stroke. One patient died of an unrelated cause, and an autopsy was performed. 61 The authors describe a 1-cm 3

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materials without written permission from JNSPG. 2015 Introduction No treatment exists to restore lost brain function after stroke. Animal studies demonstrate that brain transplantation of SB623, a human modified bone marrow derived stromal cell, after experimental stroke can improve neurologic outcome. This clinical study is the first North American trial of intraparenchymal transplantation of bone marrow derived cell therapy for chronic stroke patients. Methods This is a two center open-label safety, dose escalation feasibility study. Stereotactic

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Kenjiro Fujiwara, Isao Date, Tetsuro Shingo, Hideyuki Yoshida, Kazuki Kobayashi, Akira Takeuchi, Akimasa Yano, Takashi Tamiya and Takashi Ohmoto

C , Lindholm D , et al : Post-occlusion treatment with BDNF reduces infarct size in a model of permanent occlusion of the middle cerebral artery in rat. Metab Brain Dis 12 : 271 – 280 , 1997 Yamashita K, Wiessner C, Lindholm D, et al: Post-occlusion treatment with BDNF reduces infarct size in a model of permanent occlusion of the middle cerebral artery in rat. Metab Brain Dis 12: 271–280, 1997 48. Yoshida H , Date I , Shingo T , et al : Stereotactic transplantation of a dopamine-producing capsule

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Takao Yasuhara, Tetsuro Shingo, Kenichiro Muraoka, Kazuki Kobayashi, Akira Takeuchi, Akimasa Yano, Yuan WenJi, Masahiro Kameda, Toshihiro Matsui, Yasuyuki Miyoshi and Isao Date

– 1504 , 2004 Yasuhara T, Shingo T, Kobayashi K, Takeuchi A, Yano A, Muraoka K, et al: Neuroprotective effects of vascular endothelial growth factor (VEGF) upon dopaminergic neurons in a rat model of Parkinson's disease. Eur J Neurosci 19: 1494–1504, 2004 39. Yoshida H , Date I , Shingo T , Fujiwara K , Kobayashi K , Miyoshi Y , et al : Stereotactic transplantation of a dopamine-producing capsule into the striatum for treatment of Parkinson disease: a preclinical primate study. J Neurosurg 98 : 874

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Roberto Pallini, Eduardo Fernandez, Liverana Lauretti, Elisabetta Dell'Anna, Frank La Marca, Carlo Gangitano, Aurora Del Fà, Corrado Olivieri-Sangiacomo, Alessandro Sbriccoli and Gian Franco Rossi

animals, there was an improvement of spontaneous activity that lasted as long as 6 weeks after transplantation. Recently, one parkinsonian patient underwent stereotactic transplantation of the cervical sympathetic ganglion into the right putamen. 22 From 1 to 3 months after surgery, in spite of medication withdrawal, the patient presented the same clinical status as preoperatively under l -Dopa therapy. Survival of the Axotomized SCG Neurons It is known that after direct transplantation of the SCG into the brain, most of the ganglion cells die within a few