5.1.4. Human ES-derived motor neurons

SCIs. After preclinical success, the uses of hESCs-ODPs are being evaluated into clinical trials on patients with SCIs. The hESCs-ODPs are currently known as ASTOPC1, while previously it was known as GRNOPC1. It was permitted for clinical trials by US FDA in 2009; however, the proper trials begin in 2010 after being evaluated for safety reason in patients as it developed cysts in animal models [42, 43]. While for some unknown reasons Geron-Corporation ceases the trials, another corporation Asterias Biotherapeutics begin the same trials in phase 1 (NCT01217008) on individuals suffering from subacute thoracic SCIs. The trial was concluded in year 2013 with positive results where safety and tolerability was achieved with no serious fallouts [44, 45]. A year after, Asterias Biotherapeutics initiated a new clinical trial of phase I/IIa (NCT02302157) involving the use of hESCs-ODPs for treatments of sensorimotor complete cervical SCIs, which is expected to complete in year 2018 [44]. Since direct transplantation of hESCs poses a risk of forming teratomas and problem of differentiating into exact cells progeny within a body [41], the highly purified ODPs that are freshly derived from hESCs will offer

a best treatment option for patients with SCIs.

130 Essentials of Spinal Cord Injury Medicine

absolutely no safety issues have been documented [52].

5.1.3. Umbilical cord blood-derived mononuclear cells

5.1.2. Fetal brain-derived human central nervous system stem cell/neural precursors

The skill of isolation, proliferation and genetic manipulation of ESCs is one of the most important accomplishments in experimental stem cells biology [46]. An isolation of ESCs and their controlled proliferation into neural precursors population has been achieved in variety of preclinical models. After transplantation of ESC-derived neural precursors into the CNS of animal models, the cells have been observed to assimilate well into the recipient tissue and have also shown to improve locomotional recovery in injured rat spinal cord [46, 47]. To evaluate in vivo differentiation of hESC-derived neural precursors, a study has shown that these cells were able to integrate, migrate and differentiate into a host tissue [40]. After the preclinical validations and successful outcomes from ESC-derived neural precursors, they are being evaluated in clinical trials with a name HuCNS-SC. The HuCNS-SCs are highly purified fetal brain-derived human CNS stem cells, which have been shown to promote neuroprotection after SCIs [48]. In addition to its use for SCIs, HuCNS-SCs have been used in clinical trials for other disorders including neuronal ceroid lipofuscinosis, age-related macular degeneration and Pelizaeus-Merzbacher disease [48–51]. Following transplantation, HuCNS-SCs are shown to differentiate into neurons and glia and also retained semipermanent survival ability in host tissues. They have been recently evaluated in phase I/II clinical trials (NCT01321333) for safety and preliminary efficacy in patients with subacute SCI via intramedullary transplantation into thoracic spinal cord region [44]. In the clinical outcome from this trial (NCT01321333) that involved 5-year follow-up period,

Transplantation of human umbilical cord blood-derived stem cells has been reported to migrate well and promote therapeutic recovery from neurological injuries such as stroke and SCIs [53]. Following intravenous administration of human umbilical cord blood-derived stem cells, a study has demonstrated that the transplanted cells were able to improve behavioral properties of induced SCI [53]. Another preclinical study has reported functional locomotory effect following the administration of human umbilical cord blood cells in combination with It has been reported that growth signaling pathway-related factors are able to prompt mouse ESCs differentiation into vertebral progenitor cells, followed by subsequent differentiation into motor neurons [58]. These ESC-derived motor neurons have been recognized with a potential to occupy the embryonic medulla spinalis, lengthen axons and develop synaptic connections with respective muscle tissues [58]. Another study has reported that earlier neuroectodermal cells derived from hESCs population, which expressed Pax6 but not Sox1, were able to differentiate into spinal motor neurons in the presence of retinoic acid and sonic hedgehog. Whereas the neuroectodermal cells in later stages that were expressing both Pax6 and Sox1 were unable to differentiate into spinal motor neurons [59]. Following transplantation, these motoneurons have the ability to quickly engraft, maintain proper phenotype and project axonal elongation into peripheral regions in recipient's tissues [60]. These evidences of in vivo subsistence of hESC-derived motoneurons are a major way forward to treat SCIs via cellular therapy using motoneurons' transplantation.
