stem cells in their environment
King's College London Stroke Forum – Professor Jack Price: "Developing a stem cell therapeutic for stroke”
14 October 2013
By Gernot Walko
Professor Jack PriceStroke is the third major cause of death and the single major source of disability in developed countries. Most cases of stroke are caused by ischemia (a restriction of blood supply to the brain), with debilitating consequences ranging from motor function impairments to complete paralysis.
Professor Price's King's College London-based research group is primarily interested in neural stem cells (NSCs) and their capacity to repair stroke-damaged brains. NSCs are multipotent and can generate all neural cell types, both neurons and glia, making them intriguing candidates for stem cell transplantation therapy.
In the last King's College London Stroke Forum lecture (02/10/2013), Professor Price presented a new promising therapeutic approach based on NSCs. The Price lab, in collaboration with the UK-based company ReNeuron, developed a stem cell therapy based on transplantation of a human immortalised neural stem cell line (CTX0E03, derived from human fetal brain cortical cells) into stroke patients. These CTX0E03 cells have been genetically modified to achieve conditional growth control. For this they used the c-mycER(TAM) technology, which is based on a fusion protein comprising the growth promoting gene c-myc and the estrogen hormone receptor (ER), which can be regulated by the synthetic drug, 4-hydroxy-tamoxifen (4-OHT) [Pollock et al., Exp Neurol., 2006].
In a first study it could be shown that transplantation of the CTX0E03 cells into brains of ischemic rats promoted robust recovery of motor function in a dose-dependent manner [Stroemer et al., Neurorehabil. Neural Repair, 2009]. Interestingly, whereas the CTX0E03 cells were unable to regenerate the lost tissue in stroke-damaged rat brains, a significantly greater endogenous cell proliferation was observed in the striatum (an important part of the forebrain) of ischemic brains receiving a CTX0E03 graft compared to vehicle-treated ischemic brains. A significant proportion of these proliferative cells were found to be striatal neuroblasts. The preservation of neuronal proliferative activity upon CTX0E03 transplantation was preceded and accompanied by a high rate of proliferating microglia, suggesting that microglia might mediate in part the effect of CTX0E03 transplantation on neuronal proliferation in ischemic stroke conditions [Hassani et al., PLoS One, 2012]. Thus, the potential of CTX0E03 transplantation appears not to be to repair the severely damaged brain of disabled stroke patients, but to promote the recovery of brain function sufficiently to give them an improved quality of life. Extensive pre-clinical testing of CTX0E03 cells indicated that the therapy appears to be safe, with no adverse safety effects having arisen from the administration of the cells.
A first-in-man clinical trial using the CTX0E03 cells-based therapy called ReN001 is now underway in the UK. The PISCES study (Pilot Investigation of Stem Cells in Stroke) is the world's first fully regulated clinical trial of a neural stem cell therapy for disabled stroke patients. ReNeuron is the first company that received regulatory approval for a stem cell-based clinical trial in the UK. Following the progress made in the PISCES study, an application has been submitted to the UK regulatory authority to commence a multi-site Phase II clinical trial to examine the efficacy of the ReN001 stem cell therapy in patients disabled by ischemic stroke.
The entire stem cell community will follow the outcomes of this clinical trial with great interest.
• Hassani Z, O'Reilly J, Pearse Y, Stroemer P, Tang E, Sinden J, Price J, Thuret S. Human neural progenitor cell engraftment increases neurogenesis and microglial recruitment in the brain of rats with stroke. PLoS One. 2012;7(11):e50444. doi: 10.1371/journal.pone.0050444. Epub 2012 Nov 21.
• Pollock K, Stroemer P, Patel S, Stevanato L, Hope A, Miljan E, Dong Z, Hodges H, Price J, Sinden JD. A conditionally immortal clonal stem cell line from human cortical neuroepithelium for the treatment of ischemic stroke. Exp Neurol. 2006 May;199(1):143-55. Epub 2006 Feb 7.
• Stroemer P, Patel S, Hope A, Oliveira C, Pollock K, Sinden J. The neural stem cell line CTX0E03 promotes behavioral recovery and endogenous neurogenesis after experimental stroke in a dose-dependent fashion. Neurorehabil Neural Repair. 2009 Nov;23(9):895-909. doi: 10.1177/1545968309335978. Epub 2009 Jul 24.