Are Stem Cell-Based Therapies for Parkinson's Disease Ready for the Clinic in 2016?

Recent news of an impending clinical cell transplantation trial in Parkinson's disease using parthenogenetic stem cells as a source of donor tissue have raised hopes in the patient community and sparked discussion in the research community. Based on discussions held by a global collaborative initiative on translation of stem cell therapy in Parkinson's disease, we have identified a set of key questions that we believe should be addressed ahead of every clinical stem cell-based transplantation trial in this disorder. In this article, we first provide a short history of cell therapy in Parkinson's disease and briefly describe the current state-of-art regarding human stem cell-derived dopamine neurons for use in any patient trial. With this background information as a foundation, we then discuss each of the key questions in relation to the upcoming therapeutic trial and critically assess if the time is ripe for clinical translation of parthenogenetic stem cell technology in Parkinson's disease.Some of the work discussed in this commentary was supported by grants from the EU FP 7 programme including TRANSEURO and NeuroStemCellRepair, and the Swedish Research Council. RAB is also supported by an NIHR grant of a Biomedical Research Centre to Addenbrooke’s Hospital and the University of Cambridge.This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by IOP Press

The Biological and Ethical Basis of the Use of Human Embryonic Stem Cells for In Vitro Test Systems or Cell Therapy

Human embryonic stem cells (hESC) are now routinely cultured in many laboratories, and differentiation protocols are available to generate a large variety of cell types. In an ongoing ethical debate opinions of different groups are based on varying sets of religious, historical, cultural and scientific arguments as well as on widely differing levels of general information. We here give an overview of the biological background for non-specialists, and address all issues of the current stem cell debate that are of concern in different cultures and states. Thirty-five chapters address embryo definition, potential killing and the beginning of human life, in addition to matters of human dignity, patenting, commercialisation, and potential alternatives for the future, such as induced pluripotent (reprogrammed) stem cells. All arguments are compiled in a synopsis, and compromise solutions, e.g. for the definition of the beginning of personhood and for assigning dignity to embryos, are suggested. Until recently, the major application of hESC was thought to be transplantation of cells derived from hESC for therapeutic use. We discuss here that the most likely immediate uses will rather be in vitro test systems and disease models. Major and minor pharmaceutical companies have entered this field, and the European Union is sponsoring academic research into hESC-based innovative test systems. This development is supported by new testing strategies in Europe and the USA focussing on human cell-based in vitro systems for safety evaluations, and shifting the focus of toxicology away from classical animal experiments towards a more mechanistic understanding.JRC.I.3-In-vitro method

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

Bringing Advanced Therapies for Parkinson's Disease to the Clinic : The Scientist's Perspective

After many years of preclinical development, cell and gene therapies have advanced from research tools in the lab to clinical-grade products for patients, and today they constitute more than a quarter of all new Phase I clinical trials for Parkinson's disease. Whereas efficacy has been convincingly proven for many of these products in preclinical models, the field is now entering a new phase where the functionality and safety of these products will need to stand the test in clinical trials. If successful, these new products can have the potential to provide patients with a one-time administered treatment which may alleviate them from daily symptomatic dopaminergic medication

Building authentic midbrain dopaminergic neurons from stem cells - lessons from development

The challenge with controlling the differentiation of human pluripotent cells to generate functional dopaminergic neurons for the treatment of Parkinson's disease has undergone significant progress in recent years. Here, we summarize the differences between newer and older protocols for generating midbrain dopaminergic neurons from human pluripotent stem cells, and we highlight the importance of following developmental pathways during differentiation. The field has now developed to a point where it is timely to take human pluripotent stem cells one step closer to clinical use, and cell criteria to be fulfilled for such developments are outlined in this review

Parkinson disease and growth factors — is GDNF good enough?

Previous open-label trials testing glial cell line-derived neurotrophic factor (GDNF) family ligands in Parkinson disease have shown promising clinical effects. However, in placebo-controlled trials, the treatments have failed. A new randomized placebo-controlled trial of intraputamenal delivery of GDNF designed to resolve this conundrum has again failed to do just that

A symphony of stem cells in Vienna - looking to the future

The inaugural 'Symposium for the Next Generation of Stem Cell Research' (SY-Stem) was held on February 22-24 at the Vienna BioCenter in Austria. The meeting focused on having young researchers as speakers, and the program was of an impressively high quality. Here, we summarise key findings from this meeting, which brought together emerging leaders to discuss various topics, including pluripotency, organoids, endogenous regeneration, transcriptional regulation, clinical applications and emerging technologies

The stem cell niche finds its true north

The third ‘Stem Cell Niche’ meeting, supported by The Novo Nordisk Foundation, was held this year on May 22-26 and brought together 185 selected participants from 24 different countries to Hillerød, Denmark. Diverse aspects of embryonic and adult stem cell biology were discussed, including their respective niches in ageing, disease and regeneration. Many presentations focused on emerging technologies, including single-cell analysis, in vitro organogenesis and direct reprogramming. Here, we summarize the data presented at this exciting and highly enjoyable meeting, where speakers as well as kitchen chefs were applauded at every session

Generating regionalized neuronal cells from pluripotency, a step-by-step protocol.

Human pluripotent stem cells possess the potential to generate cells for regenerative therapies in patients with neurodegenerative diseases, and constitute an excellent cell source for studying human neural development and disease modeling. Protocols for neural differentiation of human pluripotent stem cells have undergone significant progress during recent years, allowing for rapid and synchronized neural conversion. Differentiation procedures can further be combined with accurate and efficient positional patterning to yield regionalized neural progenitors and subtype-specific neurons corresponding to different parts of the developing human brain. Here, we present a step-by-step protocol for neuralization and regionalization of human pluripotent cells for transplantation studies or in vitro analysis

Generation of high-purity human ventral midbrain dopaminergic progenitors for in vitro maturation and intracerebral transplantation

Generation of precisely patterned neural cells from human pluripotent stem cells (hPSCs) is instrumental in developing disease models and stem cell therapies. Here, we provide a detailed 16-d protocol for obtaining high-purity ventral midbrain (VM) dopamine (DA) progenitors for intracerebral transplantation into animal models and for in vitro maturation into neurons. We have successfully transplanted such cells into the rat; however, in principle, the cells can be used for transplantation into any animal model, and the protocol is designed to also be compatible with clinical transplantation into humans. We show how to precisely set the balance of patterning factors to obtain specifically the caudal VM progenitors that give rise to DA-rich grafts. By specifying how to perform quality control (QC), troubleshooting and adaptation of the procedure, this protocol will facilitate implementation in different laboratories and with a variety of hPSC lines. To facilitate reproducibility of experiments and enable shipping of cells between centers, we present a method for cryopreservation of the progenitors for subsequent direct transplantation or terminal differentiation into DA neurons. This protocol is free of xeno-derived products and can be performed under good manufacturing practice (GMP) conditions