Results from Phase I Clinical Trial with Intraspinal Injection of Neural Stem Cells in Amyotrophic Lateral Sclerosis: A Long-Term Outcome

Abstract

The main objective of this phase I trial was to assess the feasibility and safety of microtransplanting human neural stem cell (hNSC) lines into the spinal cord of patients with amyotrophic lateral sclerosis (ALS). Eighteen patients with a definite diagnosis of ALS received microinjections of hNSCs into the gray matter tracts of the lumbar or cervical spinal cord. Patients were monitored before and after transplantation by clinical, psychological, neuroradiological, and neurophysiological assessment. For up to 60 months after surgery, none of the patients manifested severe adverse effects or increased disease progression because of the treatment. Eleven patients died, and two underwent tracheotomy as a result of the natural history of the disease. We detected a transitory decrease in progression of ALS Functional Rating Scale Revised, starting within the first month after surgery and up to 4 months after transplantation. Our results show that transplantation of hNSC is a safe procedure that causes no major deleterious effects over the short or long term. This study is the first example of medical transplantation of a highly standardized cell drug product, which can be reproducibly and stably expanded ex vivo, comprising hNSC that are not immortalized, and are derived from the forebrain of the same two donors throughout this entire study as well as across future trials. Our experimental design provides benefits in terms of enhancing both intra- and interstudy reproducibility and homogeneity. Given the potential therapeutic effects of the hNSCs, our observations support undertaking future phase II clinical studies in which increased cell dosages are studied in larger cohorts of patients. Stem Cells Translational Medicine 2019;8:887&897.

Keywords: Adult stem cells; Cellular therapy; Clinical trials; Fetal stem cells.

Figure 1

Magnetic resonance imaging follow‐up in patient ISS‐799. Turbo Spine Echo T2‐weighted sequences acquired on sagittal plane before and 1, 3, 6, 12, 18, 24, and 30 months after cervical stem cell implant showing no consequences on spinal cord of cervical laminectomy.

Figure 2

Spinal cord fibre Tracking (A): Whole cervical spinal cord fiber tracking reconstruction; the arrow indicates the laminectomy and implant site. (B) Magnetic resonance imaging (MRI) 15 days after stem cell graft. Directional color‐coded fractional anisotropy map at the implant site level, obtained from diffusion tensor imaging acquisition, with evidence of apparent diffusion coefficient map. (C–E): Follow‐up MRI with directional fractional anisotropy map and apparent diffusion coefficient map, respectively, at 12 months, 24 months, and 30 months.

Figure 3

Longitudinal progression of ALS‐FRS‐R score in the 3‐month period of natural history observation and 12 months after transplantation in the three groups of patients. Group A (upper left panel) group B (upper right panel), and group C (lower left panel). Mean values (lower right panel). Abbreviation: ALS‐FRS‐R, amyotrophic lateral sclerosis‐functional rating scale revised.

Figure 4

Longitudinal progression of FVC (%) score in the 3‐month period of natural history observation and 12 months after transplantation in the three groups of patients. Group A (upper left panel) group B (upper right panel), and group C (lower left panel). Mean values (lower right panel). Abbreviation: FVC, forced vital capacity.

Figure 5

Cytokines production evaluation (A): VEGF quantification in conditioned media during differentiation process modulated by saline or CSF derived from patients with amyotrophic lateral sclerosis (ALS) or healthy volunteers. (B): OPN quantification in conditioned media during differentiation process modulated by saline or cerebrospinal fluid derived from patients with ALS or healthy volunteers. Abbreviations: OPN, osteopontin; VEGF, vascular endothelial growth factor.