Preclinical quality, safety and efficacy of a human embryonic stem cell-derived product for treatment of people with moderate Parkinson's Disease (STEM-PD) II

Cell replacement therapies for Parkinson's Disease (PD) based on transplantation of dopaminergic neurons generated from pluripotent stem cell sources are now entering clinical trials. Here, we present the quality, safety and efficacy data supporting a first-in-human clinical trial in PD using an embryonic stem cell product STEM-PD, as well as the design of the trial itself. The cryopreserved STEM-PD product was manufactured under Good Manufacturing Practice (GMP) and fully quality-tested in vitro for regulatory compliance. The product was further tested in an extensive 39-week Good Laboratory Practice (GLP) safety study in immunodeficient rats for toxicity, tumourigenicity and biodistribution, as well as in a 24-week non-GLP efficacy study. These studies showed that the transplanted STEM-PD cells could induce full functional recovery in a pre-clinical rat model of PD, and that the treatment did not give rise to any adverse effects. This cell batch will be used for all participants in the STEM-PD Phase I/IIa clinical trial, where the first of 8 patients with moderate PD have now been transplanted. Furthermore, we observed highly comparable in vivo efficacy results between two different GMP batches of STEM-PD cells, verifying that this product has the potential to be serially manufactured for widespread clinical use. Overall design: gDNA from STEM-PD DP batch 3 sample was purified and analysed using the AmpliSeq for Illumina Cancer Hotspot panel v2, which is a targeted sequencing assay for detecting 2,800 COSMIC mutations in 50 cancer and tumour suppressor genes. Libraries were sequenced with an Illumina NextSeq550 instrument. Raw data were pre-processed with the Illumina Local Run Manager and Illumina DNA amplicon analysis module, and further analysed using the Illimuna Variant Studio v3.0. Genetic variants were manually cross-referenced to public databases (dbSNP, ClinVar, COSMIC).