Assessing the Genome and Sequence Integrity of Cellular Therapeutics

Funding Type: 
Tools and Technologies II
Grant Number: 
ICOC Funds Committed: 
Public Abstract: 

Cellular therapies represent the most advanced technologies in medicine and have a myriad of potential applications. To date, the chromosome and gene composition of cell therapeutics have undergone only minimal evaluation, an oversight that could be of significant detriment to the long-term development of these products. Two major issues need to be addressed during the earliest stages of developing cells for therapy. First, the overall chromosomal integrity of cells must be assured. There are many examples in biology where alterations and mutations in genes can have disastrous effects, most significantly in the development of cancer. Furthermore, an increasing number of studies are documenting large scale alterations in the chromosomes of cell culture populations that mirror several of the changes seen in tumor cells. Secondly, the complete DNA sequence of cell therapy products should be assessed. The number of documented genetic disease with clearly defined gene lesions is over 300, while the number with presently undefined molecular lesion is over 1600. An analogous reasoning holds for disease propensity alleles; shouldn’t we know the satus of genes that are substantially implicated in disease processes? ApoE is one of dozens of genes that can dramatically affect overall health. The above considerations weigh even more heavily on transgenic and genetically modified cell therapeutics. Most cellular therapeutics are intended as permanent grafts and as our discovery and understanding of genetic disease and disease propensity progresses, it will be of considerable importance to be able to review archived genomic data on the products transplanted.

Our proposal will provide important new platforms for ensuring both manufacturing consistency and the long-term safety of cellular therapeutics. We will apply both low (cytogenetic) and high-resolution (complete genome sequencing) methods to thoroughly analyze the DNA content of cell therapeutics and will do this using already available service providers. Our goal is to provide standardized protocols, quality measurements and reports to improve quality assessment and safety of cellular therapeutics.

Statement of Benefit to California: 

California is unquestionably the leading state in the nation for funding and supporting regenerative medicine. Since much of the support provided by CIRM targets the development of expensive and complex cell-based therapeutics, making efficient use of these dollars is crucial. Cell therapeutics represent, in most applications, permanent transplants, and thus it is critical that the overall safety of these products is assessed. DNA-based assessment of cell therapy candidates is a under-utilized quality control step and one where the consequences of unintended mutations or alterations of the genome could have disastrous effect. Our studies will apply the most modern and high resolution methods to thoroughly analyze and document the DNA content of cell therapeutics. In California, we are home to most of the major service companies that provide complete genome sequencing and our study will capitalize on these private industry resources. In addition, applying these methods to the earliest stages of research and development can help optimize the selection of cell therapy candidates and prevent the expenditure of dollars on candidates with unsafe genetic profiles.