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PRBB-CRG Sessions Malin Parmar

PRBB-CRG Sessions Malin Parmar

05/04/2019
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PRBB-CRG Sessions Malin Parmar

MARIE CURIE

05/04/201912:00MARIE CURIEPRBB-CRG SessionsMalin ParmarLund University, SE"Developing a stem cell based therapy for Parkinson’s disease"Host: Laura Batlle (CRG)Abstract:Considerable progress has been made in generating fully functional and transplantable dopamine (DA) neurons from human embryonic stem cells (hESCs). With the aim to use such cells in cell based therapies, we have developed robust and efficient differentiation protocols and performed a comprehensive preclinical assessment of the hESC-derived midbrain DA neurons in a rat model of PD. In these studies, we show long-term survival and functionality using clinically relevant MRI and PET imaging techniques, and demonstrate efficacy in restoration of motor function with a potency comparable to that seen with human fetal DA neurons. Furthermore, we show that hESC-derived DA neurons can project sufficiently long distances for use in humans, integrate into the host brain circuitry, fully regenerate midbrain-to-forebrain projections, and innervate correct target structures. This provides extensive preclinical support for translation of hESC-derived DA neurons.
A major challenge when developing such therapies is that transplantation is performed with immature progenitors that undergo phenotypic and functional maturation after transplantation, and there is a lack of markers reliably predicting yield and functional maturation of the cells in vivo. To tackle this, we took an unbiased approach to identifying markers expressed in DA progenitors that predict successful graft outcome in an animal model of PD through gene expression analysis of >30 batches of grafted hESC-derived progenitors. We found that many commonly used developmental markers did not accurately predict in vivo subtype specific maturation, and identified a novel set of markers associated with the caudal midbrain, which correlated with high dopaminergic yield after transplantation in vivo. Using these markers, we developed a GMP differentiation protocol for highly efficient and reproducible production of transplantable DA progenitors from hESCs.
Here, I will summarize the achievements so far and describe the regulatory process to bring a human embryonic stem cell (hESC)-derived dopamine cell product to clinical trial for PD.