Dose-dependent Preservation of beta-cell function in type i diabetes by mesenchymal stromal cells

Abstract

Background & Aim Background Wharton's jelly derived mesenchymal stromal cells (WJMSCs) are a heterogeneous stromal cell population characterized as MSCs as per the ISCT's minimal criteria. This cell source possesses strong immunomodulatory properties, is reliably isolated from easily accessible tissue, and can be expanded in vitro to generate therapeutic doses of cell product (under the classification of an advanced therapeutic medicinal product [ATMP]). Methods, Results & Conclusion Methods ProTrans®, an allogeneic WJMSC product pooled from five donors in each batch, and expanded in vitro for a maximum of three passages, was manufactured under good manufacturing practice conditions, and evaluated for safety and efficacy to preserve beta-cell function in a phase I/IIa clinical trial of adult (18-40 years), newly diagnosed patients with type 1 diabetes (Clinicaltrials.gov identifier: NCT03406585). Under the first phase of the trial, an open, dose-escalating study was performed in 9 male patients, using three different doses of ProTrans®, 25 (low), 100 (medium) and 200 (high) million cells. Cells were delivered in a single intravenous (IV) infusion and patients evaluated 12 months post-treatment. Results No adverse effects related to ProTrans® infusion were observed in any of the treatment groups. No human leukocyte antigen (HLA) immunization occurred. Mixed meal tolerance tests were performed prior to treatment and after one year. C-peptide responses, as measured as area under the curve, decreased in subjects receiving the lowest dose of 25 million cells, while subjects treated with medium or high doses maintained their C-peptide levels during the first year (P=0.014 comparing low to medium doses and P=0.011 comparing low to high doses). No significant difference was seen in C-peptide responses between medium and high dose therapy. Conclusions We conclude that Protrans® MSCs can be safely administered IV in the three tested doses, and that treatment in the two higher doses may exhibit the beneficial effect of preserving C-peptide for at least a year in adult patients newly diagnosed with type 1 diabetes. This study is currently continuing as a blinded phase I/IIa trial including both male and female patients, to further substantiate our safety data and establish efficacy of therapy.