Human neural stem cells sources for cell therapies in the CNS and a synopsis of the experience from phase i clinical trials

Cell-based approaches remain one of the most promising areas of investigation for the development of effective experimental therapies for CNS disorders at large. A wide variety of cell donor sources, spanning from cells from the surrenal gland to primary fetal brain cells have been now tested in clinical settings. Thus, a lot of emphasis goes on the source of donor cells to be used under different therapeutic settings, for many of the cell systems used so fare pose serious procurement, technical or ethical limitations or concerns. Appropriate answers to this situation may be found with stem cells. The inherent functional plasticity of stem cells allows them to carry out a plethora of potential therapeutic actions, spanning the replacement of dead cells, immunomodulation, anti-inflammatory, trophic, homeostatic, scavenging and toxicity-blunting effects. Here we will describe our cGMP protocol and experience with using human fetal brain stem cells (hNSCSs) for the establishment of continuous, stable, plentiful and standardized cell lines that are amenable for certification under clinical good manufacturing practice standards (European Medicine Agencies). We report how such cells successfully obtained cGMP certification (aM 143/2016) and were used in a Phase I clinical trial (EudraCT 2009-014484-39) in which 18 ALS patients received multiple grafts of these cells. The trial was completed successfully, follow up exceeding two years landmark. Safety and efficacy data will be discussed briefly, followed by considerations on the design of an upstarting phase I clinical trial with intracerebroventricular injection of the same cells in secondary progressive multiple sclerosis patients (EudraCt 2015-004855-37). We will also illustrate the establishment of hNSCs from induced pluripotent human cells (hiNSCs) and their comparison to native hNSCs and their perspective cGMP certification for potential use in autologous transplantation upcoming clinical trials. FINANCIAL SUPPORT: Fondazione Cellule Staminali di Terni, Associazione REvert Onlus, Italian Ministry of Health RC1604IT46, Italian Ministry of Health RC1604IS45, Italian Ministry of Health RC1601MI11.