Approximately 1 in 1,500 children has a congenital metabolic disorder. These inborn errors of metabolism are caused by deficiencies of different enzymes and result in accumulation of various substances inside cells. These substances affect the function of vital organs, and in many cases are lethal. Transplantation of cells that possess the particular deficient enzyme carries the potential to cure these diseases. Currently, a shortage of human liver cells for transplantation prohibits clinical use of this therapy. The human placenta contains cells that may acquire hepatic function. Following delivery of a baby, these cells can be collected from the placenta which is in most cases is treated as medical waste and discarded. The therapeutic potential of this cell type has been shown in animal models. We propose to first develop a method to separate these cells from non liver like cells, and secondly use these cells to treat multiple mouse models of human inborn errors of metabolism. We will also establish a clinically applicable small-scale preparatory Bio-banking system to provide immunotype-matched cells to patients affected by these diseases. These immunotype-matched cells can replace the missing enzyme function in patients who suffer from congenital liver metabolic disorders, and potentially will be cure the condition. Although this proposal focuses on the congenital liver metabolic disorders, success may lead to the use of these cells in other liver diseases.
We propose to develop a technology to isolate and derive functional hepatic cells from discarded human placentae. The therapeutic cells will be utilized to treat congenital metabolic disorders. Current therapy for congenital metabolic disorders requires life-long treatment. It is easy to imagine how the economical burden afflicts the patients' families and society. If successful, immuotype matched hAEC-derived cell replacement therapy may completely cure some of the congenital metabolic disorders. The benefit of this new regenerative medicine will be tremendous not only for the patients' quality of life but also for our society. Although this proposal focuses on the congenital liver metabolic disorders, the target disease can potentially be extended to other liver diseases. This cell therapy would be the first cell therapy for liver disease and could benefit thousands of patients in California who suffer various liver diseases.
Furthermore, once this therapeutic potential is demonstrated, a placenta collection system, placental stem cell banking system, and a stem cell-derived hepatic cell distribution system might be a novel industry or industries that could provide job opportunities to the citizens of California.
The overall objective of this Development Candidate Feasibility (DCF) proposal is to isolate cells possessing specific liver enzymatic activities from either primary human amniotic epithelial cells (hAEC) or hepatic differentiated hAEC, and then test them in murine models for their ability to treat congenital hepatic metabolic disorders (CMDs). There are six milestones proposed: 1) Identification of cell surface markers that enable enrichment of hepatic enzyme expressing cells from the human placenta; 2) Induction and large-scale enrichment of these placental-derived cells; 3) Validation of the metabolic functions of the enriched cells; 4) Validation of the therapeutic efficacy of the enriched cells in murine models of CMDs; 5) Establishment of a biobanking system to store both unfractionated human placental cells and enriched placental-derived hepatic cells representing a diversity of HLA types; 6) Safety testing of the placental-derived hepatic cells for tumorigenicity.
Objective and Milestones
- The PI adequately addresses the desired safety profile as well as dose, route and regimen. The Target Product Profile (TPP) is scientifically and clinically reasonable and presents the key attributes of the proposed development candidate.
- The aims are focused, complete and logical.
Rationale and Significance
- The rationale for the proposed therapeutic approach is scientifically sound.
- The proposed research leads toward a novel treatment that addresses an unmet medical need.
- The technology could impact individuals with rare inborn errors of metabolism. The full range of such diseases for which the therapy would be appropriate is not clear.
Research Project Feasibility and Design
- The preliminary data are supportive of the proposed research. However, the evidence for functional similarity to hepatocytes is not yet compelling.
- Several of the milestones lack sufficient experimental detail and are underdeveloped. The PI does not discuss potential problems or present alternative approaches.
- The panel questioned the methods described to produce a consistent and robust candidate, given the variability inherent in sourcing cells from multiple donors.
- The applicant indicates plans to identify expressed cell surface markers, but does not describe a complete strategy for development of the desired cell type towards a therapeutic candidate.
- Issues related to biobanking are not addressed in sufficient depth.
- The plan is unlikely to be achieved in three years.
Qualification of the PI (Co-PI and Partner PI, if applicable) and Research Team
- The PI is probably the leading world expert on human amniotic epithelial cells derived from the placenta.
- The PI’s ability to drive a full-scale translational project independently is not clear. However, for this DCF project the PI seems a capable leader.
- The PI has assembled an excellent and appropriate multidisciplinary research team. This is tempered by some concern about the successful and timely completion of the project given that no specific persons are named for the two post doc positions, as well as the minor level of commitment of affiliated consultants.
- The supply budget seems excessive for a project at this stage of development.
Collaborations, Assets, Resources and Environment
- While some reviewers felt that the proposed collaborations and consultants are integral and important to the success of the project, others felt that the level of collaboration proposed was minimal.
- The environment at the PI’s institution is outstanding and conducive to carrying out the proposed studies and enhancing the probability of success. In addition, the institution is committed to supporting translational research, as per its track record.
Responsiveness to the RFA
- The application is responsive to the RFA, as hAEC generally fit the criterion of multipotent adult stem cells, and addresses the RFA’s key objectives.
- A motion was made to move this application into Tier 1, Recommended for Funding. Discussion: There is value to characterizing these cells, but this project is at very early stage, so it doesn’t need such a large budget. The panel recommended a cut in the budget or else a strict requirement to meet the first milestone of cell characterization. Several panelists were unclear as to whether the intended product would be the initial purified cells or if they have to be differentiated. There is a programmatic consideration in that this is a unique cell type not represented in the CIRM portfolio. The motion carried.