The purpose of this project is to develop a commercially viable process to reproducibly grow billions of hESCs for the production of clinically important replacement cells. When completed, it will represent an important FOUNDATION for numerous commercial-scale human embryonic stem cell (hESC)-based treatments.
Tremendous inroads have been made in the past few years in developing cell therapies for many different human diseases from hESCs. For example, scientists have established laboratory-scale procedures for directing hESCs through the developmental pathways to insulin-producing pancreatic beta cells, and these hESC-derived pancreatic cells have been used to correct diabetes in mice. However, in virtually every case, significant TRANSLATIONAL work lies ahead to transform discoveries in the laboratory into real, viable, treatments in the clinic. Two major widely-recognized translational hurdles are reliability and scale-up. Manufacturing processes to generate enough stem cells to constitute a clinically relevant dose, and subsequently a product, will be orders of magnitude greater in scale than those that are currently available. Further, hESC-derived cell products must be manufactured reliably and consistently in order to be safe.
Current estimates indicate that a single dose of cell therapy to treat Type 1 Diabetes could be on the order of billions of cells. The format typically used today for expanding hESCs is adherent static culture. Continuing with this format will literally mean that "football fields" of cells will need to be generated in order to produce significant numbers of human doses of cell therapy. While remarkably the cells have the potential to grow to that scale, the biopharmaceutical industry cannot economically grow hESC in that format.
The proposed project will develop and qualify an improved, efficient, and cost-effective approach -- growth of hESC in suspension culture. Although suspension culture has been used extensively in the biopharmaceutical industry, it has not been well developed for hESCs. The final step of the proposed project is to qualify the use of this new scale-up approach in the manufacturing process for an hESC-derived Type 1 Diabetes product. However, success here will likely be applicable to any hESC-derived cell therapy product.
The proposed research will establish manufacturing procedures that will apply to virtually all human embryonic stem cell (hESC)-based cell therapies. One of the appealing aspects of hESCs is that their numbers can be rapidly expanded in culture. Thus, the number of cells required for pre-clinical testing in animals, clinical testing in human subjects, and eventual commercial manufacture of a cell therapy product can theoretically be generated in a matter of a few weeks. However, the expansion of hESC is limited by current procedures for their cultivation, and a lack of understanding of how to scale hESCs from the laboratory bench to the commercial fermentor. This has led to speculation that hESC-derived products are not practical or commercially viable. Currently, hESC are typically grown in adherent format on plastic surfaces. The proposed research will investigate and develop protocols for growing hESC in a suspension culture format, which is the common practice for most commercially available products made in mammalian cells. This will alleviate the spatial and physical restrictions of the adherent format, allowing for much higher cell yields; the approach also benefits from years of development by the biopharmaceutical industry. This work will benefit the state of California and its citizens in multiple ways. The technology will make hESC-derived cell therapy products more commercially viable, and therefore will allow the numerous research-level approaches to cell therapy to be TRANSLATED into commercial products. Since many of the research-level approaches are being developed in California, all of those laboratories and institutions can benefit from clinical and commercial translation. Having this technology developed in California will continue to attract new talented individuals and their innovations and intellectual property to California. And most importantly, making it feasible for hESCs to actually be TRANSLATED into real treatments for the numerous devastating diseases for which they hold such promise will benefit immeasurably the countless Californians affected directly and indirectly by those conditons.