PR001789 (Project)

Description:SUMMARY This is an open-label, first-in-human, dose-escalation phase I study (NCT03282760, EudraCT2015-004855-37) to determine the feasibility, safety, and tolerability of the transplantation of allogeneic human neural stem/progenitor cells (hNSCs) for the treatment of progressive multiple sclerosis. We report the analysis of 1 year of data from the first cohort of 15 patients from two trial sites that received increasing numbers of allogeneic hNSCs delivered via intracerebroventricular injection in combination with an immunosuppressive regimen. No treatment-related deaths nor serious adverse events (AEs) were observed over the 12-month follow-up. Participants displayed stability of clinical and laboratory parameters, as well as lesion load and activity at the brain MRIs, compared to study entry. Longitudinal metabolomics and lipidomics analyses of cerebrospinal fluid and serum from these patients identified time and dose-dependent responses, with increased levels of free fatty acids and acylcarnitines in the CSF, especially at the highest dose of injected hNSCs at the one-year follow-up time point. Finally, a significant inverse correlation was found between the highest dose of injected hNSCs and the smaller parenchymal brain volume change (PBVC; Spearman’s rho= -0.7, p= 0.03), clinical covariates that correlated with CSF levels of free fatty acids, acyl-carnitines, oxylipins, conjugated bile acids and purine breakdown and deamination products, such as hypoxanthine. The absence of AEs and the stability of functional and structural outcomes is reassuring in terms of risks and represent a main milestone to rigorously address the challenges for the safe translation of key principles of stem cell biology into effective regenerative medicines.