Funding opportunities

Development of a cell and gene based therapy for hemophilia

Funding Type: 
Early Translational IV
Grant Number: 
Principle Investigator: 
Funds requested: 
$2 322 440
Funding Recommendations: 
Grant approved: 
Public Abstract: 
Hemophilia B is a bleeding disorder caused by the lack of FIX in the plasma and affects 1/30,000 males. Patients suffer from recurrent bleeds in soft tissues leading to physical disability in addition to life threatening bleeds. Current treatment (based on FIX infusion) is transient and plagued by increased risk for blood-borne infections (HCV, HIV), high costs and limited availability. This has fueled a search for gene/cell therapy based alternatives. Being the natural site of FIX synthesis, the liver is expected to provide immune-tolerance and easy circulatory access. Liver transplantation is a successful, long-term therapeutic option but is limited by scarcity of donor livers and chronic immunosuppression; making iPSC-based cell therapy an attractive prospect. As part of this project, we plan to generate iPSCs from hemophilic patients that will then be genetically corrected by inserting DNA capable of making FIX. After validation for correction, we will then differentiate these iPSCs into liver cells that can be transplanted into our mouse model of hemophilia that is capable of accepting human hepatocytes and allowing their proliferation. These mice exhibit disease symptoms similar to human patients and we propose that by injecting our corrected liver cells they will exhibit normal clotting as measured by various biochemical and physiological assays. If successful, this will provide a long-term cure for hemophilia and other liver diseases.
Statement of Benefit to California: 
Generation of iPSCs from adult cells unlocked the potential of tissue engineering, replacement and cell transplant therapies to cure a host of debilitating diseases without the ethical concerns of working with embryos or the practical problems of immune-rejection. We aim to develop a POC for a novel cell- and gene-therapy based approach towards the treatment of hemophilia B. In addition to the obvious and direct benefit to the affected patients and families by providing a potential long-term cure; the successful development of our proposal will serve as a POC for moving other iPSC-based therapies to the clinic. Our proposal also has the potential to treat a host of other hepatic diseases like alpha-1-antitrypsin deficiency, Wilson’s disease, hereditary hypercholesterolemia, etc. These diseases have devastating effects on the patients in addition to the huge financial drain on the State in terms of the healthcare costs. There is a pressing need to find effective solutions to such chronic health problems in the current socio-economic climate. The work proposed here seeks to redress this by developing cures for diseases that, if left untreated, require substantial, prolonged medical expenditures and cause increased suffering to patients. Being global leaders in these technologies, we are ideally suited to this task, which will establish the state of California at the forefront of medical breakthroughs and strengthen its biomedical/biotechnology industries.
Review Summary: 
This Development Candidate Feasibility (DCF) award application proposes to evaluate the feasibility of, and to generate proof of concept for, a development candidate for the treatment of factor IX deficiency (hemophilia B). The applicants plan to generate autologous induced pluripotent cells (iPSC) by reprogramming somatic cells from hemophilia B patients, to correct the genetic defect in these iPSC lines, to differentiate the corrected iPSCs into hepatocytes, and to transplant these cells into the liver in an immunodeficient, hepatocyte engraftment permissive, hemophilia mouse model as proof of concept for this approach. They propose to evaluate tissue engineered delivery methods to improve engraftment. Objective and Milestones - The target product profile (TPP) is scientifically and clinically reasonable. - The milestones were considered feasible and with meaningful parameters to measure outcomes. - The milestones lacked detail on a few points including, how the investigators would determine which method of gene correction would be chosen for Milestone 2 and how to address the universally known challenges with hepatocyte engraftment in the newly generated mouse model, as proposed for Milestone 5. Rationale and Significance - The proposed disease indication in this application is Factor IX deficiency hemophilia, for which there are competitive therapeutic alternatives. However, even if this is not the eventual disease indication for the proposed therapeutic, success in this project could have broad potential applications for other liver and protein deficiency disorders and have a transformative impact on the field. - Their proposed model is clinically relevant in that evaluation of expression of a blood protein is by far the best way to quantify the survival of transplanted cells over time. However, the proposed mouse model raised concerns regarding the ability to predict cell survival and durable engraftment in the human clinical setting. Feasibility and Design - The feasibility of this project and the capabilities of this team are supported by preliminary data included in this application. - The team has generated iPSCs from a wide variety of patient populations, demonstrating directed differentiation of these cells toward mature lineages. They have demonstrated targeted correction of genetic mutations and engraftment of cells in a mouse strain, from which they plan to generate a new immune-compromised, hemophilic strain. - A feasibility issue hinges on maturing iPSC-derived cell lines to fully functional and/or engraftable hepatocytes, a significant unsolved challenge in the field. However this group proposes to use sophisticated in vitro and in vivo engraftment assays to assess stage of maturation and function of the resulting iPSC-derived cells. - The research plan is well written, scientifically sound, and carefully designed to accomplish the proposed milestones. - It is unclear if the proposed mouse model would predict the fate and engraftment of the cell candidate in the human setting where the host liver may be a harsher environment and less permissive to engraftment. - With their collaborator in tissue engineering, they are well positioned to evaluate alternative approaches to cell delivery as a means of improving engraftment. However, the feasibility of the proposed alternative delivery methods would also need to be determined. - Successful generation of iPSC derived functional and engraftable hepatocytes may, in and of itself, provide a liver cell therapeutic candidate that could benefit disease areas other than that specifically proposed such that the project may be successful even in the absence of gene correction Qualification of the PI (Co-PI, Partner PI, if applicable) and Research Team - The PI is an established senior investigator with expertise and an outstanding track record in the areas of gene therapy, stem cell biology, and iPSC technology. The PI and team are well qualified to perform the studies on gene correction of iPSC, hepatocellular differentiation and the in vitro and in vivo functional testing proposed in this application. - The team includes a collaborator who brings expertise in biosynthetic scaffold design and tissue engineering. - The communication plan should be more clearly defined. Collaborations, Assets, Resources and Environment - Institutional support, resources and environment are all considered strengths. - The collaborations are appropriate and, as stated above, includes complementary expertise in tissue engineering, a critical component for the later milestones in the project related to cell delivery. Responsiveness to the RFA - This DCF application was judged to be responsive to the RFA. - The project would build upon other liver projects, which are not currently strongly represented in the CIRM translational portfolio and the approach is novel from any projects currently funded by CIRM.
Programmatic review: 
  • A motion was made and seconded to move this application into Tier 1, Recommended for Funding. With a median of 75, the working group was compelled to discuss the application. One of the key reviewers indicated that he/she had reconsidered his/her thinking and was more supportive. This GWG member stated that success in the targeted correction would have broader impact on other areas and felt that the application was one of the best applications to CIRM related to liver. Notwithstanding the known challenges with obtaining mature, functional hepatocytes from stem cells, the GWG member stated that the hepatocyte candidate characterization plan was strong. The motion carried.

© 2013 California Institute for Regenerative Medicine