A flexible system for the safe, rapid, and efficient isolation and sensitive biosafety testing of hESC derivatives, leading to FDA-approved products for cellular therapies

Funding Type: 
Tools and Technologies I
Grant Number: 
RT1-01123
Investigator: 
ICOC Funds Committed: 
$0
oldStatus: 
Closed
Public Abstract: 
In embryonic stem cellsí path from the bench to the bedside, there are several very important safety studies that must be done before therapies can be brought to patients in safe and effective clinical trials. Our application focuses on two key areas recently identified by the FDA: the ability to cleanly sort hESC derivatives away from primitive cells that can form teratomas, and the ability to test the safety of hESC derivatives in extremely sensitive assays. Our technologies will allow the field to mov forward through these current bottlenecks in the minimal amount of time, because we use methods and reagents that we have had previously approved by the FDA for cellular therapy trials. They are now modified to fit uniquely to the specialized problems of hESC selection and safety testing. We also have 20 years experience in developing and conducting clinical cellular therapy trials and in demonstrating to the FDA that safety comes first. We are developing clean and effective sorting strategies using immunomagnetic isolation technology with cell surface markers currently in use in clinical trials of adult stem cell therapies. This isolation strategy is more realistic for hESC isolation than flow cytometer-based sorting, the other alternative, because it is gentler on the cells, takes only two hours for a clinical dose, and gives a higher viable cell yield. The isolation marker is transiently produced on the surface of the specific derivatie cell type of interest, just long enough to allow the sorting (without manipulation of the genome). The cells are also safety modified to allow better levels of confidence by the ability to eradicate primitive cells. Our sorting systems are highly flexible, and are developed in conjunction with 20 disease teams, 14 at our University and 6 at collaborating sites. The methods developed in the current proposal will benefit all teams, plus others who would like to cross-reference our Standard Operating Procedures and investigational New Drug applications (INDs) in the future. Our flexible technology development is a good value since it will have wide-spread utility for hESC-based clinical trials. We also have a novel, most sensitive model available for validating the safety of the isolated products for cellular therapy, and have just completed a decade-long safety study examining adult stem cells. These models, which detect injected cells with single cell sensitivity and can allow dynamic in vivo visualization for tumor surveillance, will be available to all disease teams for teratoma testing. All previous cellular therapy trials have used adult stem cells. Our mission in the current proposal is to continue to bring our tools and techniques that have led to previous approvals by the FDA now to the field of hESC therapy. We will perform safe and effective hESC-based therapies in our [REDACTED] GMP facility after the proposed scale-up process is conducted at the level of ìgood laboratory practice”.
Statement of Benefit to California: 
California is leading the way in human embryonic stem cell research, due to CIRM funding, allocated by taxpayers via proposition 71. But several bottlenecks exist in our efforts to safely and effectively bring exciting advances to the clinic, to bring cures to our community members. The present application addresses two such bottlenecks recently identified by the FDA: the ability to cleanly sort hESC derivatives away from the primitive cells, which retain the potential to form teratoma, and the ability to test the safety in extremely sensitive in vivo assays. The PI and co-Director have each had two decades of experience in human stem cell sorting and manipulation at the clinical level, and testing biosafety of the cellular therapy products to obtain approvals by the FDA. All previous cellular therapy trials have used adult stem cells. Our mission in the current proposal is to continue to bring our tools and techniques that have led to previous approvals by the FDA to the field of hESC therapy. We are unable to advance further in our goals without funding from the CIRM, since this type of scale-up technology development with new hESC lines cannot be funded by federal allocations. CIRM has generously funded renovation of our good manufacturing practice facility, where these clinical trials will take place after the proposed scale-up and validation process. We are collaborating with 20 disease teams, 14 at our University and 6 at collaborating sites in California, and the flexible methods that we are developing in the current proposal will benefit all teams, plus others who would like to cross-reference our Standard Operating Procedures and Investigational New Drug applications (INDs) in the future, for their own therapies. Our technologies use methods and reagents that we have had previously approved by the FDA for cellular therapy trials. They are now modified to fit uniquely to the specialized problems of hESC selection and safety testing. Our flexible technology development is a good value since it will have wide-spread utility for hESC-based clinical trials throughout California, and for our affiliated collaborators.

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