Evaluation of siRNA based drugs as pro-regenerative disease-modifying therapeutics for age-related olfactory loss

PROJECT SUMMARY Age-related smell dysfunction – reduction, absence, and/or distortion – termed presbyosmia, is a major and completely unmet health care need with a prevalence in people over 80 years old of 50%. Presbyosmia is associated with serious consequences including nutritional compromise, increased risks of toxic exposure, diminished quality of life and heightened 5- and 10-year mortality rates. The capacity of the adult olfactory epithelium (OE) to renew and regenerate the population of olfactory sensory neurons (OSNs) depends on the life-long persistence and proper function of stem cells. The pathological changes underlying presbyosmia are due to the disordering and eventual depletion of the normally active olfactory stem and progenitor cells, namely globose basal cells (GBCs), and the disappearance of the OSNs. In this setting of neurogenic exhaustion, the reserve stem cells, namely the horizontal basal cells (HBCs), remain dormant despite the neurogenic exhaustion and disappearance of GBCs. In contrast, if the OE is damaged by an olfactotoxin, the HBCs activate and contribute to the repair of the epithelium. The key to the activation of HBCs and their rejuvenation of the olfactory epithelium is the transcription factor Np63, which is the master switch that controls the cycle of dormancy-activation, such that it is necessary and sufficient to suppress levels of p63 to shift the HBCs out of dormancy and into active mode. This STTR application from Rhino Therapeutics, Inc. and Tufts University School of Medicine seeks to advance the therapeutic strategy of using a p63-targeting siRNA drug to synthetically activate the HBCs and drive their participation in OE repair. Substantial preliminary data suggest this is a viable approach. The three Specific Aims of the project will 1) establish the sequence, dose, and duration of exposure for the optimal siRNA on cultured human and mouse HBCs, and rule out off-target effects; 2) demonstrate the efficacy of the preferred siRNA agent and regimen for activation of the HBCs in vivo in a mouse model of neurogenic exhaustion; 3) engender a preclinical demonstration of compound efficacy by xenotransplanting in vitro siRNA-activated human HBCs into the OE of immunocompromised rats, demomstrating engraftment of the HBCs, and monitoring their differentiation into the constituent cells of the host OE. Completion of the Aims will constitute an important and substantive step towards assembly of a compelling data package on the way to IND-designation and phased clinical trials of a first-in-field drug for treating presbyosmia and potentially other forms of smell dysfunction.