The clinical application of cell replacement therapy in the US is dependent on the FDA's approval, and the primary objective of the FDA is to protect patients from unsafe drugs and procedures. The FDA has a specific mandate for human gene and cell therapy and since the unexpected deaths in early trials of gene therapy trials the bar for safety in these areas is unusually high.
This is a summary of the key findings from the FDA's report on human embryonic stem cell therapy (April 2008): "From the perspective of toxicology, the proliferative potential of undifferentiated human embryonic and embryonic germ cells evokes the greatest level of concern. A characteristic of hESCs is their capacity to generate teratomas when transplanted into immunologically incompetent strains of mice. Undifferentiated hESCs are not considered as suitable for transplantation due to the risk of unregulated growth. Before clinical trials are begun in humans, the issue of unregulated growth potential and its relationship to stem cell differentiation must be evaluated".
In order to overcome the concerns about the safety of pluripotent stem cell therapy, we have designed a pipeline of quality control measures that can be applied to any cell type that is being considered for Investigational New Drug (IND) approval by the FDA. The technologies that we will develop under this award will allow rigorous selection and characterization of cells before they are tested as transplants. By reducing the possibility that stem cell therapies will be toxic or cause cancer in patients, we will remove the major barriers to advancement of these therapies to the clinic.
Californians are a large and diverse population that poses unique challenges for the future of medical care. Fortunately, California has a tradition of taking the lead in technology and medical breakthroughs and following through from the first idea to the final product. Almost 20,000 Californians await organ transplants, and more than a million suffer from progressive degenerative diseases and injuries such as Alzheimer disease, Parkinson’s disease, nerve-muscle disease such as amyotrophic lateral sclerosis (ALS) and muscular dystrophy, liver disease, diabetes, and spinal cord injury. The possibility of applying cell replacement therapy to these problems could drastically improve the outlook for treatment for the victims. A major goal for California's supporters of stem cell research is development of stem cell-based products that have medical use, and the mandate for the research community is to provide the best possible fundamental information to help guide clinical applications to make these cells as safe as is possible for cell therapy, by ensuring that they retain normal, noncancerous qualities.
California scientists have taken the first steps to clinical applications of pluripotent stem cells through their cutting edge research in developing new ways to derive these cells and to differentiate them into cell types that can be used to replace damaged tissues. We propose to take this research to the next step, to prepare the cells for clinical trials. We propose to develop a comprehensive pipeline of quality control technologies that will ensure the safety and purity of cells used first for preclinical testing and later for obtaining IND approval from the FDA for initiating human trials. These technologies can be used for any cell therapy, and will considerably reduce the barriers to development of safe, effective new treatments for incurable disease. This will have a positive effect on the health care of all Californians, reduce the cost of development of cell therapies, and create new opportunities for jobs and industry in the state.
Potential teratoma formation resulting from residual human pluripotent stem cells (hPSC) in human embryonic stem cell- (hESC) or hiPSC-derived products is a bottleneck to the development of pluripotent cell-derived therapies. The applicant proposes to address this bottleneck by developing a toolbox and a process that would detect and remove hPSC from hPSC-derived cell therapy candidates prior to treatment of patients. The investigators will develop new antibody tools and cell purity assays with the goals of removing undesired cell types by antibody based methods and enriching for the desired cell type. There are four aims: 1) to develop monoclonal antibody- (mAb-) based methods to generate homogenous pluripotent stem cells; 2) to develop mAb-based methods to eliminate undesired pluripotent or differentiated cells from desired cell population; 3) to develop biomarker panels to evaluate the purity of pluripotent and differentiated cell types; and 4) to test the process using a well-studied hESC-derived cell population as a proof-of principle. The project involves collaboration between laboratories with expertise in human pluripotent stem cells (hPSC), molecular profiling, high throughput screening and antibody development.
This proposal was well written and its translational focus was considered responsive to the RFA. Reviewers praised its detailed flow diagrams, well stated rationale, and clearly developed antibody development. Concern was expressed about the level of experimental co-ordination required of the collaborators to meet the ambitious proposed timelines; although the flow diagrams demonstrated that this difficulty and potential impact on the timelines had been considered. Recognition of the importance of removing potentially deleterious more differentiated cell types in addition to undifferentiated cells strengthens the proposal. This work has potential to generate a valuable toolbox that will benefit the stem cell community, including needed antibodies specific to pluripotent cell surface markers. The work will build upon and exploit the Principal Investigator’s (PI’s) unique database of cell type specific gene expression profiles to develop antibodies. Reviewers did comment that no tumorgenicity study appeared to be part of the proof of principle study to validate that the proposed process for removal of undesirable cells
The PI is well established, familiar with translational and safety issues and capable of managing this large, multicenter project. The sponsoring institute has a rich, interactive environment. The co-PI has expertise in mAb generation. This multidisciplinary team brings appropriate expertise and facilities including antibody manufacture, stem cell culture, molecular profiling, assay development and screening to successfully pursue the project. The inclusion of a consultant on the team who has experience in interacting with the FDA was noted as an expertise that should have been included by many more of the applicants .
All reviewers expressed concern at the inappropriate size of the proposal’s “enormous” budget. Given the scope and nature of the work, the overall budget was judged to be excessive, and not sufficiently justified. Reviewers pointed out the large number of requested personnel with little articulated justification for their roles on the project. Additionally, the consumables expense category was noted to be very high.
In summary, this proposal addresses the teratoma bottleneck to hPSC cell therapy development by establishing a toolbox and a workflow to remove residual pluirpotent stem cells from differentiated cell products for therapy . In addressing the teratoma bottleneck, reviewers felt that this program will result in needed tools that will benefit the entire stem cell community but had reservations about the cost of the program given the proposed deliverables.