Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.1.4-1 | Award Amount: 7.82M | Year: 2013
This project will tackle the huge complexity of taking stem cell therapies to clinical application for neurodegenerative disease by focusing on selective differentiation of a single neuronal phenotype (medium spiny striatal neuron: MSN) for a single well-defined disease (Huntingtons: HD). Our consortium contains expertise in all elements required to drive this technology to the point of clinical delivery, including expertise in stem cell differentiation and control of proliferation; in vitro genetic, molecular, cellular and functional characterisation; preclinical assessment in both rodents and primates models of HD; GMP knowledge, development and production; and clinical translation. Our clinical team includes world leaders in HD clinical trials, including fetal neural transplants and is well placed to design the translation process. We focus on human embryonic stem (hES) cells as our primary target for first-in-man proof-of-concept studies, as they are closest to clinical readiness. HD is the target disease as it provides both an excellent model relevant to a wide range of neurodegenerative conditions, and is a stringent test of the capacity of selectively differentiated stem cells to repair neural circuits. The starting point for the work is the existence within the consortium of three of the most advanced protocols to date for MSN differentiation, and a feature of our consortium is that the specificity of stem cell differentiation will be tested against primary fetal MSNs (current gold standard) at all stages of both in vitro and in vivo assessment. In order to maintain flexibility in an emerging ethical environment, we will develop induced pluripotent (hiPS) cells to the point of GMP validation as a second generation target to hESCs. This will build European infrastructure and capacity to deliver emergent stem cell therapies through the highest quality clinical trials into clinical practice in a broad range of human neurodegenerative diseases.
Murdoch A.,Newcastle University |
Braude P.,King's College London |
Courtney A.,Roslin Cells Ltd |
Brison D.,University of Manchester |
And 5 more authors.
Stem Cell Reviews and Reports | Year: 2012
The donation of human embryos for the derivation of embryonic stem cell lines that may be used in the development of therapeutic products raises more complex ethical, practical and regulatory problems than the donation of embryos for non-clinical research. This review considers these issues and offers recommendations for good practice. © 2011 Springer Science+Business Media, LLC.
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.1.4-1 | Award Amount: 7.97M | Year: 2013
Neurostemcellrepair aims at taking human stem cells through the final steps toward clinical application in cell replacement therapy for neurological disorders. PD will be taken as the prototypical disease because stem cell therapy is now close to clinical translation. Moreover, we will tackle next generation issues pertaining to stem cells at a basic level and develop new approaches and novel cell sources, validated at pre-clinical stages, for both PD and HD. The project teams represent a wide range of competences, including stem cell specialists, developmental neurobiologists, experts in neurodegeneration, scientists with links to the clinic and stem cell manufacturing/clinical validation. The research plan is constructed on exchange of tools, sharing of protocols and expertise and joint deliverables among the participants. We will address issues related to the control of progenitor proliferation and differentiation into authentic, functional and phenotypically stable dopaminergic or striatal neurons, and exploit new technology for cell reprogramming. We will develop strategies to obtain endurable donor cell engraftment in the host, including acquisition of specific neuronal identities and functional integration in the recipient brain. The therapeutic effect will be evaluated following transplantation in animal models of PD and HD. Cutting edge technologies will be guaranteed by the involvement of three SMEs, one industry and partners experienced in bioengineering, who will collectively provide a toolbox to deliver ontogenetic and reprogramming factors, small molecules and miRNA, immunoseparation strategies, in vivo monitoring of donor cell behaviour, scale up and GMP-compliant protocols. Ultimately, Neurostemcellrepair is expected to develop new cell sources based on cellular reprogramming, make significant advance towards stem cell therapy in HD, and close the gap between development and clinical implementation of stem cell replacement therapies for PD.
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2007-1.4-7 | Award Amount: 3.98M | Year: 2009
Current technology to control embryonic and adult stem cell behaviour is dependent on conventional in vitro culture systems and crude factors such as serum and purified proteins, often sourced from vertebrate animal tissue. These factors contribute to variations in cell properties and differentiation potential which impact on the efficacy of cell culture. More worryingly these factors are potential avenues for the introduction of unknown or known pathogens with the capacity to infect transplant recipients thereby becoming communicable to the general population. Especially concerning is the opportunity for transmission of potentially lethal diseases across vertebrate species for which there are no known cures. The propensity of primitive stem cell populations to spontaneously differentiate is an added challenge which generally necessitates cumbersome manipulation of cells by skilled operators involving daily assessment, media replenishment and or cell passaging by physical dissociation. Realising the promise of stem cells and their derivatives for clinical and industrial applications therefore requires the evolution of new paradigms for cell culture which maximise chemical definition, minimise the involvement of skilled operators, and offer non-invasive modulation of cells by biocompatible means. The aim of this proposal is to discover and integrate with established and new cell culture technology, synthetic and non-vertebrate derived purified molecules with a capacity to mimic the functional properties of crude biological reagents currently used to control the behaviour of embryonic and adult stem cells, most notably affecting self-renewal, pluripotency, lineage specification and stability following cryopreservation. These will be validated to deliver new culture paradigms designed for compliance with Good Manufacturing Practice Standards necessary for the delivery of clinical grade cells for therapeutic use.
Anderson R.A.,University of Edinburgh |
Bayne R.A.L.,University of Edinburgh |
Gardner J.,University of Edinburgh |
De Sousa P.A.,University of Edinburgh |
De Sousa P.A.,Roslin Cells Ltd.
Fertility and Sterility | Year: 2010
Objective: To investigate a role for brain-derived neurotrophic factor (BDNF) in human oocyte maturation. Design: Prospective study. Setting: Research institute. Patients: Women undergoing laparoscopic sterilization. Intervention(s): Small antral follicle cumulus-oocyte complexes (COCs) were matured in vitro (IVM) to metaphase II (MII) in media with hormones (H; FSH, LH, E2), serum replacement (SR), BDNF, or blocking antibodies to BDNF (BDNF/AB and TrkB/Fc), and activated. Main Outcome Measure(s): The COCs were analyzed for expression of neurotrophin ligands/receptors and cumulus genes (HAS2, TNFAlP6, PTGS2, GREM1) by reverse transcription-polymerase chain reaction (RT-PCR), cumulus expansion, maturation to MII, and parthenogenetic embryo development. Result(s): The BDNF and truncated TrkB receptor were expressed in cumulus and mature oocytes. There was no difference in MII yields after IVM in control (H + SR) versus H + BDNF, H + SR + BDNF, or BDNF + SR media. However, both BDNF/AB and TrkB/Fc improved MII yields. After activation, normal cleavage was highest in H + SR (38%), whereas blocking antibodies yielded the highest abnormal cleavage (BDNF/AB 68%; TrkB/Fc 57%). Failure to cleave was highest in H + BDNF + SR (92%). Only H + SR yielded morulae/blastocysts (6%). Expression of GREM1 in cumulus increased after IVM in H + BDNF versus H + SR or in vivo maturation. Conclusion(s): The BDNF signaling within COCs influences oocyte maturation and early embryogenesis. © 2010 American Society for Reproductive Medicine.
Courtney A.,Roslin Cells Ltd.
Regenerative Medicine | Year: 2011
Scotland is shaping up as Europe's 'go-to' place to translate cell therapy research from the laboratory into the clinic. While continuing to punch above its weight in fundamental research, the resources for translating research to clinical application are perhaps its main attraction for the international stem cell research community. © 2011 Future Medicine Ltd.
Kaupisch A.,University of Glasgow |
Kennedy L.,Roslin Cells Ltd. |
Stelmanis V.,Roslin Cells Ltd. |
Tye B.,Roslin Cells Ltd. |
And 4 more authors.
Journal of Cardiovascular Translational Research | Year: 2012
Revascularisation of ischaemic tissue remains an area of substantial unmet clinical need in cardiovascular disease. Strategies to induce therapeutic angiogenesis are therefore attractive. Our recent focus has been on human embryonic stem cell (hESC) strategies since hESC can be maintained in a pluripotent state or differentiated into any desired cell type, including endothelial cells (EC), under defined differentiation culture conditions. We recently published a protocol for non-good manufacturing practice (GMP) feeder- and serum-free hESC-EC-directed monolayer differentiation to vascular EC demonstrating the potential to generate hESC-derived EC in a GMP-compliant manner suitable for use in clinical trials. In this study we modified that laboratory protocol to GMP compliance. EC production was confirmed by flow cytometry, qRT-PCR and production of vascular structures in Matrigel®, yielding approximately 30 % mature VE-cadherin+/PECAM-1+ cells using the GMP-compliant hESC line RC13. In conclusion, we have successfully demonstrated the production of vascular EC under GMP-compliant conditions suitable for clinical evaluation. © 2012 Springer Science+Business Media, LLC.
Agency: GTR | Branch: Innovate UK | Program: | Phase: Feasibility Study | Award Amount: 124.15K | Year: 2012
This project will assess the feasibility of improving the clinical utility of umbilical cord blood (UCB) through ex vivo expansion mediated by co-culture with mesenchymal stromal cells (MSCs). We have patented technology for the production pluripotent stem cell derived MSCs, which means that we can supply these cells in almost limitless quantities. The haematopoietic stem and progenitor cells found in UCB are of immense clinical value and our MSCs exhibit several advantages over bone marrow derived MSCs. Over half of all UCB units cannot be used clinically as they lack sufficient quantities of haematopoietic stem or progenitor cells. This feasibility project will build on patented and other prior work and create the opportunity to establish a significant business with important clinical impact.
PubMed | University of Edinburgh and Roslin Cells Ltd
Type: Journal Article | Journal: Stem cell research | Year: 2016
The human embryonic stem cell line RCe021-A (RC-17) was derived under quality assured compliance with UK regulation, European Union Directives and International guidance for tissue procurement, processing and storage according to Good Manufacturing Practice (GMP) standards. The cell line was derived from a day 3 embryo voluntarily donated as unsuitable or surplus to fertility requirements following informed consent. RCe021-A (RC-17) shows normal pluripotency marker expression and differentiation to the three germ layers in vitro. It has a normal 46XX female karyotype and microsatellite PCR identity, HLA and blood group typing data are available.
PubMed | University of Edinburgh and Roslin Cells Ltd
Type: Journal Article | Journal: Stem cell research | Year: 2016
The human embryonic stem cell line RCe015-A (RC-11) was derived under quality assured compliance with UK regulation, European Union Directives and International guidance for tissue procurement, processing and storage according to Good Manufacturing Practice (GMP) standards. The cell line was derived from a fragmented cleavage stage embryo voluntarily donated as unsuitable or surplus to fertility requirements following informed consent. RCe015-A (RC-11) shows normal pluripotency marker expression and differentiation to the three germ layers in vitro and in vivo. It has a normal 46XX female karyotype and microsatellite PCR identity, HLA and blood group typing data are available.