Senior Director of R&D Shanghai UniXell Biotechnology Shanghai
Abstract: Parkinson’s disease (PD) is primarily characterized by the selective loss of midbrain dopaminergic (mDA) neurons in the substantia nigra. Aiming at replacing the lost neurons, cell replacement therapy using human pluripotent stem cell-derived midbrain dopaminergic progenitors (mDAPs) is a promising therapeutic avenue for PD with recent rapid advancements in clinical trials. Here we present the preclinical data supporting the first-in-human phase 1 clinical trial of a personalized autologous cell therapy product, UX-DA001, for PD. We established clinical-grade induced pluripotent stem cells (iPSCs) by reprogramming patients’ peripheral blood mononuclear cells in a GMP facility. The iPSCs from multiple patients were then differentiated into cell products with consistent cellular composition and high mDAP purity using our newly developed 3D cultivation protocol, as confirmed by scRNA-seq analysis, and free from residual iPSCs or genetic aberrations related to cancer- or neurodegenerative diseases. No adverse effects were observed in a mouse GLP-compliant safety study for toxicity, biodistribution, and tumorigenicity. Notably, we achieved high in vivo mDA neuron yields across batches derived from multiple patients, with more than 50% of the human cells in the graft positive for TH (DA neuron marker), accounting for more than 20% of the number of transplanted cells, at 6 months post-grafting. Most of these DA neurons are positive for EN1, a classical midbrain marker These in vivo outcomes demonstrate the high efficiency and robustness of our new differentiation protocol, bolstering the feasibility of personalized cell therapy for numerous patients with PD. An efficacy study confirmed that the transplanted cells mediated full dopamine level restoration in the grafted striatum (by microdialysis coupled with HPLC) and behavioral recovery in a mouse model of PD. Furthermore, the parkinsonian non-human primates receiving mDAP transplantation exhibited behavioral improvements accompanied with strong DA activity in positron emission tomography. Based on these results, the IND application of UX-DA001 has been recently cleared by the National Medical Products Administration in China for a phase 1 clinical trial for PD, and a clinical trial (NCT06778265) for treating patients with PD has been initiated.
