New York State Stem Cell Science Consortia

Project Details

Developing a good manufacturing practice (GMP) qualified source of hESC-derived DA neurons

Isabelle Rivière, PhD
Direction, Cell Therapy and Cell Engineering Facility
Memorial Sloan Kettering

Mark Tomishima, PhD
Director, Sloan Kettering Institute Stem Cell Facility
Associate Member, Center for Stem Cell Biology
Memorial Sloan Kettering

Any new therapy has to meet several requirements to be considered by the US Food and Drug Administration (FDA). These regulations are designed to protect patients, doctors, and hospitals. They require researchers to have the facilities and reagents as well as the protocols to produce a reliable and safe product.

This project focuses on the identification of cells and reagents that will allow for the production of clinical-grade DA neurons under good manufacturing practice (GMP) conditions. Under the leadership of Isabelle Rivière and Mark Tomishima, whose expertise encompasses translational research and stem cell biology, respectively, the group will identify the right pluripotent stem cell — one that can fulfill the stringent requirements for cellular therapies by the FDA — and source media and other reagents that are GMP compliant. In addition, they will establish production standards for a large-scale bank of frozen (cryopreserved) DA neurons to be used in the transplantation studies.

The team will also provide materials to advance studies performed by the other groups of the consortium.

Transplantation and behavioral studies in murine hosts

Viviane Tabar, MD
Member, Center for Stem Cell Biology
Member, Center for Cell Engineering
Memorial Sloan Kettering

Experiments can be carried out in vitro in a cell culture dish or in vivo in living organisms. These two approaches are neither redundant nor competing, but rather act in concert to better our understanding of the physiology and biology of hESC-derived DA neurons and Parkinson’s disease. Neurodegenerative diseases are often characterized by changes in behavior and changes in functions of daily life — both virtually impossible to model in a laboratory cell culture dish.

Under the guidance of Viviane Tabar, the team will develop standard operating procedures that will allow us to test the impact of transplanted, hESC-derived DA neurons on the health and behavior of parkinsonian animals. Not only will we gain insights into the safety and function of these cells, we will also learn about potential variability of the preparations. Furthermore, these models will be used to evaluate additional projects — “Cell purification and enrichment of A9 type DA neurons” and “Use of engineered cell surface polysialic acid (PSA) to promote in vivo integration and fiber outgrowth of grafted DA neuron.”

Cell purification and enrichment of A9 type DA neurons

Lorenz Studer, MD
Director, Center for Stem Cell Biology
Member, Center for Cell Engineering
Memorial Sloan Kettering

Fetal tissue transplantation studies for Parkinson’s disease have had mixed outcomes in double-blinded clinical trials. One possible explanation for this is the heterogeneity of the transplant (graft). A mixed population may be desired in some cases, but the more knowledge about the graft composition we have, the more reliable the product should be.

For this project, Lorenz Studer’s team uses directed differentiation of hESCs, which allows for the routine production of large quantities of DA neurons. Although the cultures are already largely positive for DA markers, further purification especially of A9 DA neurons may be desirable. A9 DA neurons are the specific cell type lost in Parkinson’s disease. Using monoclonal antibodies against cell surface markers specifically expressed on A9 DA neurons, this project is targeted at the specific isolation of transplantable A9 DA neurons.

Clinical Trial Development Team

Claire Henchcliffe, MD
Weill Cornell Medical College

Flint Beal, MD
Weil Cornell Medical College

While scientists in the lab are busy finding the right conditions to make the best possible transplant product, our team is active in designing the clinical trial.

This task is not trivial. Prior to the first transplant, we need to identify the most suitable patients, carefully weighing the risks and benefits for this group.

We also need to consider the best strategy to evaluate the outcome of the trial. How can we measure improvement? How can we ensure safety for the patient and the clinician? How long will it take to see an improvement and when will we know how long the therapy will last?

All these questions and more are discussed by our team of experts, encompassing clinicians, physician-scientists, ethicists, trial experts, and statisticians.