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Regulatory Wire
NIH To Hold Workshop on Cell Therapy for Pediatric Diseases
The National Heart, Lung, and Blood Institute (NHLBI) is supporting an initiative that includes a Coordinating Center and five facilities for the production and testing of novel cell therapies. The facilities are the Baylor College of Medicine, Center for Cell and Gene Therapy (CAGT); Center for Human Cell Therapy Boston (CHCT); City of Hope, Center for Applied Technology Development (CATD); University of Minnesota, Molecular and Cellular Therapeutics facility (MCT); and the University of Wisconsin, Madison, Waisman Clinical Biomanufacturing Facility (WCBF). These institutions form the Production Assistance for Cellular Therapies (PACT) group.
The PACT program is designed to develop novel cellular therapies that will aid investigators by providing production assistance in areas ranging from translational development to the scale-up of a product that is intended for use in human clinical trials. The cell-processing facilities are charged with implementing the rapid and safe transition of innovative treatment concepts to clinical investigation as well as supplying clinical grade products produced in a manner that complies with applicable regulatory requirements. The facilities are committed to providing the investigator the data needed to support an Investigational New Drug (IND) application.
As part of its ongoing educational outreach efforts to investigators and other parties involved in the production of cellular therapies, the PACT group will be conducting a 2-day public workshop entitled “Cell Therapy for Pediatric Diseases: A Growing Frontier.” The workshop will be held September 14–15, 2011, and will address strategies to overcome the barriers in advancing the development and delivery of cell-based therapies for pediatric patients, in particular those with rare and life-threatening diseases. The clinical applications of cellular therapies and regenerative medicine, including the ethical considerations and models of clinical trial design, will be examined with intent to optimize overall processes for the future. Registration information can be found here:
FDA Public Meeting on Cellular and Gene Therapy for Retinal Disorders
The Food and Drug Administration's Cellular, Tissue and Gene Therapies Advisory Committee will be convening a 1-day public meeting on June 29, 2011, to discuss cellular and gene therapy products for the treatment of retinal disorders. Topics to be considered include the following: (1) efficacy endpoints in pediatric and adult populations, (2) potential safety issues related to repeat administration or second eye administration, and (3) evaluation of product delivery into target site. More information can be found here:
Tissue Reference Group Releases Annual Report
The Tissue Reference Group (TRG) was created as specified in the “Proposed Approach to the Regulation of Cellular and Tissue-Based Products” published by FDA in February of 1997. The purpose of the TRG is to provide a single reference point for product specific questions received by FDA (either through the Centers, or from the Office of Combination Products) concerning jurisdiction and applicable regulation of human cells, tissues, and cellular and tissue-based products (HCT/Ps). TRG has just released its most recent annual report for the year 2010. The report can be accessed here:
Science Wire
How to Convert Mouse Tails to Functional Liver Cells
A recent report in the May 11, 2011 issue of Nature by the group of Dr. Lijian Hui of the Shanghai Institutes for Biological Sciences in China demonstrates that cells taken from the tips of mouse tails and genetically reprogrammed to mimic mature liver cells can repair damaged livers of diseased mice. In this month's issue of the Science Wire, Dr. Karl-Dimiter Bissig and Dr. Stephen Strom summarize the findings by the Hui group and provide context for the relevance of this study to the fields of cell therapy and regenerative medicine (sk).
Dr. Karl-Dimiter Bissig Baylor College of Medicine's Stem Cells and Regenerative Medicine Center
Although pluripotent stem cell derived tissue engineering holds therapeutic promise, many potential problems, such as formation of teratoma, must first be solved. These challenges might be circumvented when using differentiated cells as a source for tissue engineering. Motivated by the general concept of ‘overwriting’ a cell signature as shown by the generation of induced pluripotent stem (iPS) cells, many investigators are re-exploring the possibility of transdifferentiation. Huang et al. now show that mouse tail-tip fibroblasts can be converted into hepatocyte like cells following expression of three transcription factors (Gata4, HNF1alpha and Foxa3) and inactivation of p19Arf (Huang et al., 2011).
The transcription factors FOXA and GATA can decompact chromatin (Bossard and Zaret, 1998), while HNF1alpha is a key transcription factor in hepatocytes. It binds to >1000 genes, including HNF4alpha and other master regulators of the hepatocyte signature (Kyrmizi et al., 2006; Odom et al., 2006). While the utilized transcription factors harbor no surprises, it is unexpected that p19ARF inactivation is also required to convert fibroblasts into hepatocyte like cells (iHep). Although p19ARF inhibits reprogramming of fibroblasts into iPS cells its inactivation is not necessary. Moreover, transdifferentiation of fibroblasts into neurons (Vierbuchen et al.), cardiomyocytes (Ieda et al., 2010) and blood cells (Szabo et al., 2010) did not require the silencing or knockout of p19ARF. The authors used p19ARF-/- fibroblasts to overcome cellular senescence; however, there might be more to it when transdifferentiating fibroblasts to hepatocytes.
In contrast to other organ systems, amenable to transdifferentiation the study of Huang et al. provides a complete and convincing set of in vivo data. They show that their fibroblast derived hepatocyte like cells (iHep) do not fuse with endogenous hepatocytes and, secondly and more importantly, they rescue 5 of 12 fumarylacetoacetate-hydrolase-deficient (Fah-/-) mice from fulminant liver failure with iHeps. It would have been interesting to see a longer-term analysis (>8wks) of safety and efficacy following administration of their iHeps. Removing the tumor suppressor p19ARF might result in the formation of tumor cells, which are typically AFP positive like the iHeps but unlike hepatocytes. It is conceivable that tumor cells (or iHeps) can rescue a fulminant liver failure; however, the long-term benefit of such a therapy is questionable. Nevertheless, this concern should not impact the significance of present study that is the first step of a long journey.
Dr. Stephen Strom University of Pittsburgh's Institute for Regenerative Medicine
This Nature paper is exciting. It is well-controlled. These investigators read all of the same literature and make most of the mistakes that are made in the previous paper with PAS, ICG and ac-LDL; however, they have additional information that is interesting, albeit preliminary. Huang et al. can show actual drug metabolism, that is metabolism of testosterone, diclofenac and phenacetin. I find this very compelling. It is hard to believe that the metabolism is as close to authentic liver as they report, but this is what is presented. The most exciting part of the paper is the transplantation and repopulation of the liver of Fah-deficient animals. These data seems to suggest that they have real hepatocytes following transplantation of the cells, in vivo.
The down side, and it is large, is that they need P19 knockout cells for these experiments so that the cells do not show proliferation arrest (senescence). Normal cells do not function in this manner. One will have to find a way around the need for P19 knockout cells before it will become useful in the clinic, but that will likely happen with additional experimentation or reversible inhibition.