Development of a platform to generate clinical grade neural progenitors for transplantation in Huntington's disease.
Lead Research Organisation:
CARDIFF UNIVERSITY
Department Name: School of Medicine
Abstract
Human embryonic stem cells (hESCs) have recieved enormous scientific, public and media attention for their potential to develop into all cell types of the body, and thus provide an unparalleled source of cells for regenerative medicines. The neurodegenerative diseases represent a major class of diseases predicted to benefit from emerging stem cell-based therapies. Huntington?s disease (HD) is one such disorder, that in many ways represents a model disorder for the development of cell-based therapies. HD has a defined genetic basis and primarily affects a focal group of cells in the forebrain. It is anticipated that developing technologies and clinical expertise to treat HD will have wider ramifications for the potential treatment of more complex and common neurodegenrative disorders, perhaps including Alzheimer?s disease, Parkinson?s disease and Stroke.
Significant basic research has already been conducted to study the biology and potential of hESCs to generate functional neurons, but while the progress to date rightly generates considerable optimism, many technical and regulatory issues need to be addressed before this research can be considered for clinical trials. This proposal aims to take the first vital step in translating protocols from a research towards a clinical-grade platform. Specifically, we will adapt our protocols that derive neurons from hESCs that are of value to HD, to generate cells with sufficient yield and to meet regulatory standards of safety and reproducibility (i.e. to develop protocols compatible with Good Manufacturing Practice (GMP)), and most importantly cells will be tested for functional efficacy in animal models of HD.
Significant basic research has already been conducted to study the biology and potential of hESCs to generate functional neurons, but while the progress to date rightly generates considerable optimism, many technical and regulatory issues need to be addressed before this research can be considered for clinical trials. This proposal aims to take the first vital step in translating protocols from a research towards a clinical-grade platform. Specifically, we will adapt our protocols that derive neurons from hESCs that are of value to HD, to generate cells with sufficient yield and to meet regulatory standards of safety and reproducibility (i.e. to develop protocols compatible with Good Manufacturing Practice (GMP)), and most importantly cells will be tested for functional efficacy in animal models of HD.
Technical Summary
Transplantation of striatal progenitor cells that reconstitute missing DARPP-32 positive medium spiny projection neurons is a major strategy under assessment and consideration for the treatment of Huntington‘s disease (HD). The greatest single issue for development of this therapy concerns the availability of a renewable source of appropriately specified donor neural progenitor cells.
Currently, directed differentiation of human embryonic stem cells (hESCs) to neural progenitors has the greatest potential of meeting this requirement. This view is supported by key advances in basic research including, (i) progress in developing methodology for the derivation and propagation of hESC lines, and (ii) understanding of underlying mechanisms of forebrain development and neuronal sub-type specification that provide a rationale for the development of directed differentiation protocols. Critically we have now developed protocols for neural differentiation under defined conditions to generate progenitors that express markers of forebrain fate determination, and that differentiate to DARPP-32 positive neurons both in vitro and in vivo in animal models of HD.
This translational project aims to expedite the ultimate goal of bringing stem cell therapies to clinical trial by adapting, and further developing, protocols to generate cells with markedly improved yields and a level of reproducibility and quality control that meet regulatory standards of good manufacturing practice (GMP), while maintaining a high functional efficacy in vivo in animal models of HD.
Currently, directed differentiation of human embryonic stem cells (hESCs) to neural progenitors has the greatest potential of meeting this requirement. This view is supported by key advances in basic research including, (i) progress in developing methodology for the derivation and propagation of hESC lines, and (ii) understanding of underlying mechanisms of forebrain development and neuronal sub-type specification that provide a rationale for the development of directed differentiation protocols. Critically we have now developed protocols for neural differentiation under defined conditions to generate progenitors that express markers of forebrain fate determination, and that differentiate to DARPP-32 positive neurons both in vitro and in vivo in animal models of HD.
This translational project aims to expedite the ultimate goal of bringing stem cell therapies to clinical trial by adapting, and further developing, protocols to generate cells with markedly improved yields and a level of reproducibility and quality control that meet regulatory standards of good manufacturing practice (GMP), while maintaining a high functional efficacy in vivo in animal models of HD.
