A great deal of attention has recently been focused in the area of stem cells as a possible alternative for the treatment of a variety of diseases. End stage renal disease (ESRD) has reached epidemic proportions in the United States. An estimated 400,00 US residents are in treatment for ESRD and just last year more than 60,000 individuals were awaiting a kidney transplant. Currently, dialysis or kidney transplantation remain the only viable treatments despite significant limitations to both. This situation along with an increasing shortage of donor organs has heightened interest in developing novel therapeutic modalities, especially in the area of chronic kidney disease. Alport Disease is a hereditary glomerulonephritis estimated to affect at least 1 in 20,000 people. It is a chronic kidney disease caused by genetic defects in one of the proteins (type IV collagen) that make up the Glomerular Basement Membrane (GBM), an important component of the kidney’s blood filter. Eventually the kidney is replaced by fibrosis or “scar” which leads to failure of the organ. Herein we focus on the application of a novel source of stem cells from amniotic fluid (AFSC). We have successfully demonstrated that these cells have the potential to differentiate into multiple cell types and when injected into experimental animals they can restore the functionality of multiple organs such us the kidney, lung, and pancreas. In particular, when injected in an animal model of Alport Disease, AFSC have the propensity to lessen inflammation and fibrosis, and restore renal function. Major advantages of AFSC are that they can be easily retrieved through amniocentesis with no injury to the embryo and that they do not form tumors (teratomas) in vivo. We hypothesize that AFSC could represent a readily available source of ethically acceptable, biologically unmodified stem cells that may prove useful as a novel alternative in stem cell therapy for a wide variety of chronic kidney diseases.
Statement of Benefit to California:
The State of California is home to some of the nation's best organ transplant and treatment centers. Having our laboratory next to one of California's busiest pediatric renal transplant programs, at Children’s Hospital Los Angeles, we have been aware of the growing shortage of organs for our patients and the need for good alternative therapies in the field of regenerative medicine. In particular we focused our attention on chronic kidney disease. The need for donor organs continues to rise every year and emerging technologies such as those offered by stem cell research may assist our patients as well as the adult citizens of California with alternative technologies that perhaps can make a significant impact in this field. A novel population of pluripotent stem cells exists within amniotic fluid, which can be easily obtained, stored, and possibly used for future regenerative medicine or clinical purposes without some of the same concerns over clinical compatibility as embryonic stem cells. We intend to characterize the potential of these cells in the treatment of chronic kidney disease for their possible use one day in the clinic. CIRM funding will ensure a competitive advantage for California in this innovative direction.
The goal of this Development Candidate Award proposal is to produce a novel cell therapeutic comprising amniotic fluid stem cells (AFSCs) for treating chronic kidney disease (CKD), particularly the inflammation and fibrosis that is associated with this family of disorders. The applicant proposes to build on his/her previous observations that AFSCs derived from mice can partially restore normal renal function in Alport Syndrome (AS), a representative murine model of CKD. To provide pivotal preclinical data for clinical translation, a series of three aims has been proposed. First, the applicant will determine the optimal dosing regimen, administration route, and biological preparation required to improve renal function as compared to standard therapeutic agents in the murine model of AS. Next, the applicant will characterize the interaction of AFSCs with cells of the immune system and the effects of these interactions on renal repair and inflammation. For the third and final aim, the PI will identify, develop, and characterize GMP reagents, cell banks, and assays for subsequent IND-enabling product development of human AFSCs.
Reviewers agreed that development of a novel therapy for CKD could have very high medical and economic impact, potentially minimizing or lessening the need for dialysis or kidney transplant in a large and growing number of sufferers. However, significant concerns were raised about both the rationale and cell choice for the proposed therapeutic. Importantly, reviewers noted that critical studies proposed in Aims 1 and 2 appeared to be with murine AFSCs as opposed to their human counterparts. There is little evidence presented in the application or literature to suggest that murine and human AFSCs would behave identically, and thus the reviewers questioned whether extrapolation to the human model would be reasonable without further studies to bolster this assumption. The reviewers were also concerned that the applicant did not propose to directly compare AFSCs to mesenchymal stem cells (MSCs), which they felt were likely to have similar efficacy and mechanisms of action in the chronic kidney disease indication. MSCs are easy to obtain and have already been used in many clinical studies, and thus reviewers╒ enthusiasm for the potential impact of the proposed therapeutic was diminished. While acknowledging that the lack of teratoma formation represents an important advantage over pluripotent cell-derived therapies, reviewers nonetheless felt it would be important to demonstrate the safety of undifferentiated allogeneic AFSCs in addition to their superiority over existing pharmacological options and alternative cell-based approaches.
While reviewers appreciated the clear milestones and logical experimental design, a number of questions were raised about the overall feasibility of the research plan. Several reviewers were uncertain whether the chosen routes of administration in the mouse model would be practical in humans. Others questioned the cost and feasibility of obtaining sufficient numbers of cells to use in a clinical setting, a point that was not adequately discussed in the application. It was also unclear to what extent the culturing and growth conditions would be suitable for production within current regulatory guidelines. Beyond these practical considerations, reviewers were greatly concerned that the murine findings would not readily translate to the human system. Despite encouraging preliminary data, it was not clear how the efficacy of AFSC in a syngeneic setting would ultimately translate in the allogeneic context. Furthermore, there was little evidence to demonstrate that human AFSCs would be functionally or behaviorally equivalent to the murine AFSCs in the proposed studies. As a result of these deficiencies, reviewers thought that a three-year timeline to a development candidate suitable for use in humans was not realistic at this stage of the investigation.
The reviewers believed the principal investigator (PI), co-PI, and research team to be eminently qualified to conduct the proposed experiments, although the inclusion of deep immunology expertise would have benefited Aim 2. The research environment and institutional support were considered excellent, and the budget appeared appropriate.
Overall, reviewers raised significant concerns about the rationale, feasibility, and potential impact of the proposed cell therapy for chronic kidney disease. Despite encouraging preliminary studies and a highly qualified research team, the project was considered premature and unlikely to produce a development candidate in three years.