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

> **NIH NIH R41** · RHINO THERAPEUTICS INC · 2024 · $295,662

## Abstract

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.

## Key facts

- **NIH application ID:** 10820948
- **Project number:** 1R41DC021592-01
- **Recipient organization:** RHINO THERAPEUTICS INC
- **Principal Investigator:** JAMES E. SCHWOB
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $295,662
- **Award type:** 1
- **Project period:** 2024-05-16 → 2025-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10820948

## Citation

> US National Institutes of Health, RePORTER application 10820948, Evaluation of siRNA based drugs as pro-regenerative disease-modifying therapeutics for age-related olfactory loss (1R41DC021592-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10820948. Licensed CC0.

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