European stem cell consortium for neural cell replacement, reprogramming and functional brain repair
|Title||European stem cell consortium for neural cell replacement, reprogramming and functional brain repair|
|Sponsor||European Union's Seventh Framework Programme (FP7)|
Neurostemcellrepair aims at creating a world-leading Consortium that can take stem cells through the final pre-clinical steps necessary before their clinical use in trials for Parkinson’s Disease (PD), as well as achieve substantial advancements in their adoption as cell replacement strategies for Huntington’s Disease (HD). These two disorders are at different stages in their clinical translation for stem cell treatment, yet they have common paths and requirements that need to be fulfilled. Addressing one condition will benefit the other and will also be useful for establishing a platform by which we can treat a wider spectrum of neurodegenerative disorders. PD is taken as the prototypical disease because it has been successfully treated with dopamine cell therapies and, in addition, recent developments have provided cells and protocols ready for optimization for GMP compatibility and translation to the clinic. At the same time, we aim to further advance the field by implementing emerging stem cell programming tools and methods for enhanced tissue integration of grafted cells in order to develop new approaches, validated at pre-clinical stages, for the treatment of PD and HD. Experience gained from clinical trials using grafts of fetal mesencephalic dopaminergic (DA) and striatal GABAergic progenitors have shown that effective repair can be achieved by neural transplantation. Notably, transplanted DA neurons, derived from the ventral mesencephalon (VM), can functionally reinnervate the denervated striatum, restore dopamine release and, at least in some PD patients, induce substantial long-term clinical improvement (Politis, Sci Transl Med, 2010; Barker, Lancet Neurology, 2013). Similarly, fetal striatal tissue grafted into mild HD patients has, in some cases, produced long-term amelioration of motor, behavioural and cognitive dysfunction (Reuter, J Neurol Neurosur Psychiatry, 2008). On the basis of these observations a new clinical trial has been initiated (Transeuro, http://www.transeuro.org.uk), aimed at developing efficacious and safe conditions for fetal VM-based therapies for PD. However, to move to large-scale applications, readily available, renewable, and bankable cells are needed. Recent discoveries, stemming from members of this Consortium, have identified morphogens and transcription factors (TF) critical for successful phenotype specification and differentiation of therapeutically relevant DA neurons from human pluripotent stem cells. These findings have led to cell differentiation protocols that currently represent the gold standard for cell therapy with ventral mesencephalic (mes) DA neurons (Kriks, Nature, 2011; Kirkeby, Cell Reports, 2012) and, very recently, to novel ontogenetic factors that promote the dopaminergic phenotype (Theofilopoulos, Nat Chem Biol, 2012; Andersson, PNAS, 2013). Inspired by this work, a protocol to generate authentic striatal GABAergic medium spiny neurons (MSNs) has also been recently published by other members of this Consortium (Delli Carri, Development, 2013). Furthermore, partners in this Consortium have identified a scalable source of neural progenitors able to mature into functional neurons (Koch, PNAS, 2009). With the advent of induced pluripotent stem (iPS) cell technologies and direct reprogramming of somatic cells, further sources of transplantable cells have become available. One partner in this Consortium was one of the first groups to report on the reprogramming of fibroblasts into DA neurons (Pfisterer, PNAS, 2011), while work by another partner has identified small molecules that increase efficiency of neuronal conversion (Ladewig, Nat Methods, 2012). Hence, this Consortium brings together several groups that are leaders in the world and are capable of moving this field forward, towards a safe clinical translation of stem cell-based interventions, especially for PD. In particular, the project aims at fulfilling the final requirements for progressing stem cells towards clinical translation for dopamine cell replacement in PD, while addressing crucial issues on the way to future applications also in HD. Thus, our main goal will be to optimise and standardise the current cell-generating protocols and incorporate tools, methods and technologies to ensure efficient, accurate and safe integration and functional efficacy of human stem cell-derived neurons, to promote brain repair and functional recovery in PD and HD.