Intracranial Delivery of Stem Cells
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CELL-BASED THERAPIES FOR STROKE
Intracranial Delivery of Stem Cells Keith W. Muir & John Sinden & Erik Miljan & Laurence Dunn
Received: 27 June 2011 / Revised: 13 July 2011 / Accepted: 13 July 2011 / Published online: 26 July 2011 # Springer Science+Business Media, LLC 2011
Abstract The method of delivery of stem cells is a major factor to consider in the design of clinical trials of cell therapy. Different methods of delivery will be associated with different risks to the patient, and may also be associated with different potential for benefit. Current approaches are partly informed by the routes selected for study in animal models of focal ischaemia and CNS transplantation, but there has been little work comparing the efficacy of different routes of administration. Direct intraparenchymal delivery of cells has been employed in several preliminary clinical trials, and data on the safety of this approach are reviewed. Keywords Stem cell . Stroke . Intracranial injection . Clinical trial . Safety
Background Clinical trials of cell therapies face a large number of design issues, for most of which there are presently only limited data—and frequently none at all—to inform investigators. These include patient factors (age range, interval since stroke, stroke type), factors related to measurement of K. W. Muir (*) Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, UK e-mail: [email protected] J. Sinden : E. Miljan ReNeuron, Guildford, Surrey, UK K. W. Muir : L. Dunn Institute of Neurological Sciences, Southern General Hospital, Glasgow G51 4TF, UK
efficacy (nature and severity of neurological deficit, adjunctive use of brain imaging or clinical assessment tools), the validity of different control groups (historical, concurrent ineligible, sham) and issues that primarily relate to mode of delivery [1]. The small number of clinical studies that have been undertaken to date have employed either direct intracranial delivery of cells via stereotaxic neurosurgery (including teratocarcinoma-derived NT2 cells [2, 3] and the current trial of the CTX0E03 neural stem cell line—the PISCES trial—http://www.clinicaltrials.gov/ct2/show/ NCT01151124?term=PISCES&rank=2) or intravascular delivery of bone marrow-derived cells (cells with surface markers of mesenchymal stem cells selected and expanded ex vivo given intravenously [4] or current trials of CD34+ cells delivered by the intra-arterial route). The former studies using direct intracranial delivery have been safety evaluations in patients late after stroke (minimum of 6 months after the incident event), while the latter have delivered cells in the early subacute phase within weeks of the event. These trial designs do not follow logically from the cell types involved, since allogeneic cell grafts should permit “off the shelf” use in patients without delay, while the need for ex vivo expansion of autologous cells derived from bone marrow necessarily entails a delay of several weeks before administration is possible. Rather, the trial designs have been
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