Targeting p63 to reactive dormant reserve stem cells in olfactory epithelium for treatment of age-related stem cell exhaustion
Identification of a novel therapeutic target for regeneration of the olfactory epithelium
Lead Inventor: Dr. James E. Schwob
Tufts case T001754
Olfactory dysfunction affects 25% of individuals over the age of 60 and 50% of individuals over the age of 75. One of the underlying causes for this dysfunction is degeneration of the olfactory epithelium, which can lead to anosmia (loss of the sense of smell) and have profound impacts on the nutritional status of these patients (a major problem in the elderly). Dr. James E. Schwob at Tufts Medical Center and his collaborators have recently demonstrated that the transcription factor p63 is required for the formation of a quiescent stem cell in the olfactory epithelium known as horizontal basal cells (HBCs). Furthermore, these researchers have demonstrated in animal models that when stimulated (via olfactory injury), these HBCs downregulate p63 expression to become multipotent progenitor cells, which promote regeneration of the olfactory epithelium. Dr. Schwob and his collaborators have also developed tools to assess p63 knockdown in HBCs in a high-throughput manner in vitro. Dr. Schwob and his collaborators have found that a fall-off in p63 expression in HBCs of about 50% is enough to progress to full activation making it highly amicable to targeting via a miRNA approach. Indeed, other researchers have demonstrated that p63 can successfully be targeted by endogenous host miRNAs. Thus, Tufts researchers have now uncovered a novel therapeutic target for regeneration of the olfactory epithelium that can be targeted by a miRNA approach.
Description of Project:
Dr. James E. Schwob and his collaborators have used elegant in vivo models to demonstrate the role of p63 in the proper generation and regeneration of the olfactory epithelium. Using p63 null animals, they have demonstrated that p63 is not required for the proper architecture of the olfactory epithelium, but is essential for establishing the quiescent stem cell population of HBCs. Furthermore, upon epithelial damage they have demonstrated that p63 expressing HBCs return to the basal most layer of the epithelium, while more apically, cells that express HBC markers but lack p63 expression continue to expand and differentiate until the olfactory epithelium is regenerated. Dr. Schwob and his collaborators have also designed an in vitro cell culture model where the p63 gene is replaced with eGFP, allowing for high-throughput screening of compounds or molecules that knockdown p63 expression. Furthermore, other researchers have validated these findings independently and have demonstrated that conditionally deleting p63 results in spontaneous proliferation and differentiation of HBCs. Together, these data suggest that the downregulation of p63 is required for HBCs to exit from their quiescent state and to proliferate and differentiate to cells that will aid regeneration of the olfactory epithelium. It has previously demonstrated by other researchers that p63 is targeted by miR-203. Thus, the current invention p63 as a novel therapeutic target for epithelial regeneration that can be (i) targeted with existing miRNAs known to act upon p63 and (ii) used to develop better miRNAs to target p63.
Applications: The transcription factor p63 represents a novel therapeutic target for regeneration of the olfactory epithelium. Since a drop-off of p63 activity of ~50% correlates with full activation of HBCs, this target is highly amicable to a miRNA based approach. Additionally, there is a known host miRNA (miR-203) that targets p63, which can inform further development of a miRNA-based therapeutic targeting this transcription factor.
Inventors and Relevant Publications: Lead Inventor is Dr. James E. Schwob of Tufts Medical Center. Achievements relevant to the current invention include the discovery of the role of p63 in HBC development and activation (J Neurosci. 31(24):8748-59, 2011). Additionally, these data were independently verified by another research group (Neuron. 72(5):748-59, 2011).
Intellectual property: Invention is the subject of issued US Patent 9,080,172 and is available for an exclusive license and sponsored research.