2025-10-14 ウィスコンシン大学マディソン校(UW-Madison)
<関連情報>
- https://news.wisc.edu/parkinsons-treatment-tested-at-uw-showing-promise-in-first-clinical-trial/
- https://thejns.org/view/journals/j-neurosurg/141/6/article-p1554.xml
- https://www.nature.com/articles/s41591-021-01257-1
パーキンソン病における移植細胞の分布促進を目的とした体軸内軌道の前臨床評価 Preclinical evaluation of transaxial intraputaminal trajectory for enhanced distribution of grafted cells in Parkinson’s disease
Marina E. Emborg MD, PhD,Anthony Mancinelli BS,Julia C. Colwell BS,Alexandra D. Zinnen BS,…
Journal of Neurosurgery Published:26 Jul 2024
DOI:https://doi.org/10.3171/2024.4.JNS24367
Abstract
OBJECTIVE
The objective of this study was to develop and evaluate the feasibility and safety of a novel transaxial surgical approach for the delivery of human induced pluripotent stem cell–derived dopaminergic neuroprogenitor cells (DANPCs) into the putamen nucleus using nonhuman primates and surgical techniques and tools relevant to human clinical translation.
METHODS
Nine immunosuppressed, unlesioned adult cynomolgus macaques (4 females, 5 males) received intraputaminal injections of vehicle or DANPCs (0.9 × 105 to 1.1 × 105 cells/µL) under real-time intraoperative MRI guidance. The infusates were combined with 1-mM gadoteridol (for intraoperative MRI visualization) and delivered via two tracks per hemisphere (ventral and dorsal) using a transaxial approach. The total volumes of infusion were 25 µL and 50 µL for the right and left putamen, respectively (infusion rate 2.5 µL/min). Animals were evaluated with a battery of clinical and behavioral outcome measures and euthanized 7 or 30 days postsurgery; full necropsies were performed by a board-certified veterinary pathologist. Brain tissues were collected and processed for immunohistochemistry, including against the human-specific marker STEM121.
RESULTS
The optimized surgical technique and tools produced successful targeting of the putamen via the transaxial approach. Intraoperative MR images confirmed on-target intraputaminal injections in all animals. All animals survived to scheduled termination without clinical evidence of neurological deficits. The first 4 animals to undergo surgery had mild brain swelling noted at the end of surgery, of which 3 had transient reduced vision; administration of mannitol therapy and reduced intravenous fluid during the surgical procedure addressed these complications. Immunostaining against STEM121 confirmed the presence of grafted cells along the injection track within the targeted putamen area of DANPC-treated animals. All adverse histological findings were limited in scope and consistent with surgical manipulation, injection procedure, and postsurgical inflammatory response to the mechanical disruption caused by the cannula insertion.
CONCLUSIONS
The delivery system, injection procedure, and DANPCs were well tolerated in all animals. Prevention of mild brain swelling by mannitol dosing and reduction of intravenous fluids during surgery allowed visual effects to be avoided. The results of the study established that this novel transaxial approach can be used to correctly and safely target cell injections to the postcommissural putamen and support clinical investigation.
自家移植療法はパーキンソン病サルの運動行動と抑うつ行動を軽減する Autologous transplant therapy alleviates motor and depressive behaviors in parkinsonian monkeys
Yunlong Tao,Scott C. Vermilyea,Matthew Zammit,Jianfeng Lu,Miles Olsen,Jeanette M. Metzger,Lin Yao,Yuejun Chen,Sean Phillips,James E. Holden,Viktoriya Bondarenko,Walter F. Block,Todd E. Barnhart,Nancy Schultz-Darken,Kevin Brunner,Heather Simmons,Bradley T. Christian,Marina E. Emborg &Su-Chun Zhang
Nature Medicine
Abstract
Degeneration of dopamine (DA) neurons in the midbrain underlies the pathogenesis of Parkinson’s disease (PD). Supplement of DA via L-DOPA alleviates motor symptoms but does not prevent the progressive loss of DA neurons. A large body of experimental studies, including those in nonhuman primates, demonstrates that transplantation of fetal mesencephalic tissues improves motor symptoms in animals, which culminated in open-label and double-blinded clinical trials of fetal tissue transplantation for PD1. Unfortunately, the outcomes are mixed, primarily due to the undefined and unstandardized donor tissues1,2. Generation of induced pluripotent stem cells enables standardized and autologous transplantation therapy for PD. However, its efficacy, especially in primates, remains unclear. Here we show that over a 2-year period without immunosuppression, PD monkeys receiving autologous, but not allogenic, transplantation exhibited recovery from motor and depressive signs. These behavioral improvements were accompanied by robust grafts with extensive DA neuron axon growth as well as strong DA activity in positron emission tomography (PET). Mathematical modeling reveals correlations between the number of surviving DA neurons with PET signal intensity and behavior recovery regardless autologous or allogeneic transplant, suggesting a predictive power of PET and motor behaviors for surviving DA neuron number.
