Human neural fetal stem cell transplantation in Amyotrophic Lateral Sclerosis: a safety and feasibility study

Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive, invariably fatal, degenerative disorder of the central nervous system, which predominantly targets motor neurons in the primary motor cortex, brainstem and spinal cord. Although classified as a rare condition from an epidemiological point of view, ALS carries a substantial emotional, social and economic burden, being a devastating illness, as far as disease progression and life expectancy are concerned, with still undisclosed mutually interdependent pathogenic and pathophysiological mechanisms. Unfortunately, the increasing knowledge on the molecular basis of ALS has not yet been translated into new therapeutics and riluzole is the only currently available drug, with modest efficacy in increasing patients’ survival. Stem Cells (SCs) clinical trials have been recently proposed as a novel therapeutic approach. The rationale propelling this growing field of research is related to capability of these cells to potentially interfere with deranged pathways at the core of motor neurons degeneration and disease progression. Specific SC populations have been shown to undergo differentiation both into motor neurons in vitro, even though this process seems unlikely and largely ineffective in studies in vivo, and into glial cells, extensively reviewed for their role in disease onset and progression. Cell-replacement strategy could positively affect neurons’ microenvironment, promoting CNS repair and delivering neurotrophic factors. Neuroinflammation would also be a main target, since SCs are able to release soluble molecules to promote “bystander” immunomodulation. In this study we analyzed GMP-grade, fetal human neural stem cells (hNSCs) from natural in utero death, transplanted into the anterior horns of the spinal cord at lumbar or cervical level of 18 ALS patients. The trial was approved by the Istituto Superiore di Sanità and the Ethics Committees and monitored by an external Safety Board (Trial EU Registration: EudraCT:2009-014484-39). Patients were recruited using a risk-escalation paradigm. Under this paradigm, risk to patients receiving human spinal cord SCs transplants escalates across the different cohorts (designated A–C with cohort A being the lowest-risk and cohort C being the highest-risk group) according to disease severity and the number and placement of injections. The focal delivery of cells was performed using a stabilized, stereotaxic frame, upon laminectomy. Tacrolimus was administered at 0.1 mg/kg orally twice a day, beginning on post-operative day 1 for six months. Primary outcome measures were mortality from any cause and serious adverse event, both in the short and long term; the secondary outcome measures were he difference in functional outcomes measured by the ALS-FRS-R scale, MRC and forced vital capacity (FVC). A database of historical controls was built taking into consideration 13 patients who were previously enrolled in other clinical trials (Lithium, Acetyl-L-Carnitine, Erythropoietin), receiving placebo, or patients excluded from this current trial because of undercurrent causes. No patients manifested severe treatment-related adverse events. The most common side effect was mild post-surgical pain disappearing in an average of 4 days. In 10 patients serial MRI revealed an extradural fluid collection at the site of surgery which resolved spontaneously after 3 to 6 months. No structural changes (including tumor or syrinx formation) were detected also in the long term. Clinical assessments after transplantation demonstrated no evidence of acceleration of disease progression due to the treatment. This study confirms the procedural safety of this surgical procedure and shows no evidence of immediate or delayed toxicity related to human NSC lines from the brain tissue of single fetuses. Our results support future phase II trials examining therapeutic efficacy.