Preclinical quality, safety, and efficacy of a human embryonic stem cell-derived product for the treatment of Parkinson's disease, STEM-PD.

Cell replacement therapies for Parkinson's disease (PD) based on transplantation of pluripotent stem cell-derived dopaminergic neurons are now entering clinical trials. Here, we present quality, safety, and efficacy data supporting the first-in-human STEM-PD phase I/IIa clinical trial along with the trial design. The STEM-PD product was manufactured under GMP and quality tested in vitro and in vivo to meet regulatory requirements. Importantly, no adverse effects were observed upon testing of the product in a 39-week rat GLP safety study for toxicity, tumorigenicity, and biodistribution, and a non-GLP efficacy study confirmed that the transplanted cells mediated full functional recovery in a pre-clinical rat model of PD. We further observed highly comparable efficacy results between two different GMP batches, verifying that the product can be serially manufactured. A fully in vivo-tested batch of STEM-PD is now being used in a clinical trial of 8 patients with moderate PD, initiated in 2022.

Donor Variability in Growth Kinetics of Healthy hMSCs Using Manual Processing: Considerations for Manufacture of Cell Therapies.

Human mesenchymal stromal cells (hMSCs) are excellent candidates for cell therapy but their expansion to desired clinical quantities can be compromised by ex vivo processing, due to differences between donor material and process variation. The aim of this article is to characterize growth kinetics of healthy baseline "reference" hMSCs using typical manual processing. Bone-marrow derived hMSCs from ten donors are isolated based on plastic adherence, expanded, and analyzed for their growth kinetics until passage 4. Results indicate that hMSC density decreases with overall time in culture (p < 0.001) but no significant differences are observed between successive passages after passage 1. In addition, fold increase in cell number dropped between passage 1 and 2 for three batches, which correlated to lower performance in total fold increase and expansion potential of these batches, suggesting that proliferative ability of hMSCs can be predicted at an early stage. An indicative bounded operating window is determined between passage 1 and 3 (PDL < 10), despite the high inter-donor variability present under standardized hMSC expansion conditions used. hMSC growth profile analysis will be of benefit to cell therapy manufacturing as a tool to predict culture performance and attainment of clinically-relevant yields, therefore stratifying the patient population based on early observation.

Altered hMSC functional characteristics in short-term culture and when placed in low oxygen environments: implications for cell retention at physiologic sites.

BACKGROUND: It is very difficult to conserve critical cell characteristics during expansion in culture, particularly those of adult mesenchymal stromal cells (MSCs), whose characteristics can change rapidly even within a short period of expansion. AIM: In this study our aim was to measure cell characteristics that are critical for retention at the injury site after therapeutic delivery. Cells were cultured under conditions typical of current standard best practice. The impact of passage number was assessed and assays were performed in low oxygen (2%) as an in vitro model of physiologic oxygen tension at injury sites. The effect of chemokine preconditioning with SDF1 was also assessed. MATERIALS & METHODS: Bone marrow mononuclear cells from patients recruited to the REGENERATE Phase II clinical trials, along with MSCs from healthy volunteers subjected to a short period of expansion, were assessed for attachment and migration ability. Using MSCs from healthy donors, the effect of reduced oxygen was also assessed. RESULTS: Short-term expansion resulted in increased cell attachment but decreased rate of migration, whereas attachment and migration of patient-derived bone marrow mononuclear cells was highly heterogeneous. Reduced oxygen impaired MSC attachment but not migration. Finally, SDF1 did not improve any of the responses. CONCLUSION: The basic functional responses of MSCs required for retention and engraftment alter rapidly even over a relatively short expansion period. This needs careful consideration when expanding cells to achieve clinical quantities for therapy.