Translating a Stem Cell-Based Therapy for Epidermolysis Bullosa into the Clinic
Abstract
Current therapy for patients with epidermolysis bullosa (EB), a group of rare inherited skin blistering diseases, is primarily limited to wound care. EB derives from genetic mutations in structural proteins of the skin and sentences those afflicted to a life of severe pain and disability due to constant blistering and scaring, and in some cases, early death. The technological breakthrough that allows adult skin cells to be reprogrammed into immature induced pluripotent stem cells (iPSC) now offers the possibility of developing a permanent corrective therapy for EB without the risk of immune rejection. Specifically, skin cells can be biopsied from a patient suffering from EB and then “reprogrammed” into iPSCs. The iPSCs can then be grown outside the body, genetically corrected, differentiated into new skin stem cells, and then administered back to the same patient as an autograft. The promise but attendant complexity and novelty of iPSC-based therapies to heal and cure EB led to the creation of a unique consortium between the University of Colorado (Dr. Dennis Roop, main Principal Investigator [PI] on this application), Stanford (Dr. Anthony Oro, subrecipient PI), and Columbia (Dr. Angela Christiano, subrecipient PI) Universities. The Consortium was established in May 2016, with the goal to develop an iPSC-based therapy for the most severe form of EB, recessive dystrophic EB (RDEB), and advance this therapy toward a clinical trial. The “EB iPS Cell Consortium” is currently supported by the EB Research Partnership, the EB Medical Research Foundation, and the SOHANA Research Fund. Since its inception, the Consortium has already validated approaches with which to move forward in clinical development and is now requesting support for the generation of preclinical data necessary for the approval of a clinical trial. Specifically, we propose to develop an optimal manufacturing protocol for genetically corrected iPSC-derived skin grafts as a potential therapeutic product for an iPSC-based therapy for RDEB and to generate a set of safety and efficacy data to fulfill regulatory requirements for cell therapy production. Therefore, this application addresses Fiscal Year 2017 Peer Review Medical Research Program (PRMRP) Topic Area, Epidermolysis Bullosa and satisfies criteria for a Technology/Therapeutic Development Award. IPSC-based strategies similar to the one proposed in this application, whereby patient-specific iPSCs undergo genetic modifications for subsequent differentiation into target cell types for transplantation, can be applied to virtually any other currently incurable monogenic disease, including cystic fibrosis, Fanconi anemia, beta thalassemia, etc. However, unlike other monogenic diseases, EB, and especially RDEB, may represent an ideal platform to initially test an iPSC-based therapy due to the orphan nature of EB and its severity. Furthermore, the skin is an ideal target tissue to initially test an iPSC-based therapy: it is readily accessible, easy to monitor, and if an adverse event should occur, the affected cells could be easily excised. Therefore, if successful and proven to be safe in a clinical trial for EB, the iPSC-based therapy could then be easily expanded to monogenic diseases affecting internal organs, where the difficulty in monitoring adverse effects of an iPSC-based therapy would make them unlikely first targets. We also predict that the iPSC-based therapy for EB could be used to treat military Service members who develop severe blistering following exposure to vesicants, such as sulfur mustard or who suffer from burns over a large portion of their body. In addition, iPSC-based therapies could also be applied to accelerate wound repair in military personnel who experience acute injuries or in older Veterans with chronic wounds that do not heal.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810706
Entities
People
- Dennis Roop
Organizations
- United States Army
- University of Colorado Denver