Innovations_in_Molecular_Mechanisms_and_Tissue_Engineering_(Stem_Cell_Biology_and_Regenerative_Medicine)

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Nonetheless, there are several problems that limit the use of NPSCs in clinical

applications. Generally, NPSCs are less proliferative in culture than other stem

cell lines, and as such may be more diffi cult to expand into large cultures as

required for clinical work [ 345 , 346 ]. Further, there is evidence to suggest that the

differentiation potential of NPSCs decreases with time in culture [ 347 ]. Lastly,

direct differentiation of NPSCs into neuronal lineages with high purity is diffi -

cult, although progress has been made in increasing phenotypic purity by using

human NPSCs (hNPSCs) as opposed to murine [ 331 , 335 , 347 , 348 ]. For exam-

ple, Pfeifer et al. demonstrated pre-clinical effi cacy of transplanted adult autolo-

gous NPSCs in murine models of cervical spinal cord lesion [ 335 ]. In this study,

SVZ-derived NPSCs from a single, small biopsy were transplanted with autolo-

gous skin fi broblasts. The authors report that within 8 weeks post-biopsy, over 3

million NPSCs were generated from the single biopsy, and that the culture exhib-

ited very similar differentiation profi les to that of syngeneic neuronal progenitor

cell grafts [ 335 ]. Further, NPSCs within autologous fi broblast co- grafts remained

viable up to 4 weeks post-transplantation and supplanted cystic lesion defects

[ 335 ]. Since these fi ndings, several clinical trials have been conducted in both the

spinal cord and the brain.

Phase I/II trials have been conducted to assess the effi cacy of transplanting

hNPSCs after thoracic SCI [ 344 ]. The study, authorized by SwissMedic regula-

tory authority, enrolled 12 subjects 3–12 months prior to cell transplantation and

administered fi xed doses of 20 million cells directly into the thoracic spinal cord

adjacent to the injury [ 344 ]. The trial reported signifi cant sensory gains in a

majority of the subjects, with two of the seven patients who were enrolled with

complete motor and sensory injuries being converted to incomplete injuries after

the onset of voluntary toe movement [ 344 ]. Further, there is currently a phase I

trial at Emory University investigating the safety of surgically transplanting spi-

nal cord derived NPSCs for the treatment of ALS [ 349 ]. Although this study is

still on going, a completed phase I trial at Oregon Health Sciences University

validated the safety of surgically transplanting hNPSCs into ventricular and

bilateral subcortical sites to treat neuronal ceroid lipofuscinosis (Batten disease)

[ 344 , 350 ]. Subjects of this study received injections of 500 million or 1 billion

cells and immunosuppression for the course of the study. Although some patients

succumbed to the severity of their disease as evidenced by post-mortem exami-

nations, four year follow-up of surviving patients showed no safety concerns

[ 344 , 350 ]. These fi ndings were corroborated in another completed phase I open

label study conducted at the University of California, San Francisco. In this

study, four subjects with severe connatal Pelizaeus-Merzbacher myelin disorder

were given injections of 300 million cells in the frontal white matter of each

hemisphere and received immunosuppression for the fi rst 9 months after injec-

tion [ 344 , 350 ]. MRI assessments did not reveal signs of infl ammation, gliosis,

ischemia, or cystic changes and diffusion tensor imaging verifi ed donor-tissue

myelin development in the patients [ 344 , 350 ]. However, continued testing in

controlled studies will be required to demonstrate clinical effi cacy of hNPSC

transplantation.

A. Roussas et al.