Development of a Novel DNA Aptamer-Based IFN-y Targeted Therapy for Chronic Cystitis Pain
Abstract
Our proposed study focuses on Chronification of Pain/Development of mechanistically justified therapies to prevent and treat chronification, one of the Fiscal Year 2022 Chronic Pain Management Research Program Investigator-Initiated Research Award Focus Areas. In this study, we will develop a novel DNA aptamer-based interferon (IFN)-? targeted therapy for chronic cystitis pain seen in human interstitial cystitis/bladder pain syndrome (IC/BPS), one of the most refractory diseases in urology today. IC/BPS is a chronic urologic disorder characterized by persistent pelvic/bladder pain, excessive urinary frequency, and/or urgency. This urologic disorder is significant and severely impacts patients’ quality of life. IC/BPS affects 3-8 million women and 1-4 million men in the U.S. Its financial burden on the U.S. health care system is substantial with estimated costs of $21.1 billion dollars annually. This enigmatic syndrome can be categorized into two subtypes: IC/BPS with Hunner lesions (IC/BPS-HL), characterized by cystoscopic finding of reddish mucosal lesions, and IC/BPS without Hunner lesions (IC/BPS-nonHL). The two IC/BPS subtypes present significantly overlapping symptoms and cannot be clinically identified in the absence of cystoscopic findings. IC/BPS-HL is present in 10%-20% of all IC/BPS patients in North American population, but worldwide prevalence of IC/BPS-HL has varied widely from 5%-57%. At the present time, there is no cure for IC/BPS including the Hunner-type IC/BPS. Treatments are largely aimed at easing symptoms. Accumulating evidence indicates that IC/BPS-HL is a distinct chronic inflammatory disease of the urinary bladder while IC/BPS-nonHL is a non- or minimum inflammatory disorder with no obvious bladder etiologies. In line with published studies, we recently identified prominent expression of IFN-?, an important proinflammatory cytokine, in the IC/BPS-HL bladder. We then tested a novel anti-IFN-? aptamer (mTAGX- 0003), a synthetic oligo DNA sequence containing artificial nucleotides with an unnatural hydrophobic base, to treat chronic cystitis pain in our recently developed murine model of IC/BPS-HL. We observed that bladder instillation of the aptamer effectively prevented the development of chronic cystitis and pain in the animal model, supporting the potential of the IFN-? targeted therapy for treatment of IC/BPS-HL pain in humans. In this study, we will use our novel IC/BPS-HL murine model to further evaluate and optimize the aptamer therapy for chronic cystitis pain in established bladder inflammation, a clinically relevant condition of IC/BPS-HL (Aim 1). We will also use genetically manipulated mice to determine the role of IFN-? in the development of chronic cystitis pain seen in human IC/BPS-HL (Aim 2). Finally, we will perform multifaceted analyses to identify the mechanisms underlying the effect of the aptamer therapy for chronic cystitis pain in the IC/BPS-HL murine model (Aim 3). We anticipate that our study will generate robust preclinical data for future development of clinical strategies to treat IC/BPS-HL pain through IFN-? blockade. Our study will advance the field of IC/BPS research and ultimately impact the clinical care of IC/BPS patients. In the short term, our study will provide an effective anti-IFN-? aptamer therapy for IC/BPS-HL pain in a preclinical setting. The mechanisms of aptamer action will also be identified. In the long term, our results will provide a significant opportunity for the development of a novel, useful and safe IFN-? targeted therapy for IC/BPS-HL pain in humans. We anticipate that at the end of this study, we will be able to translate our preclinical findings into a clinical setting. Since IC/BPS is most prevalent in the age group typical for military Service Members, Veterans, and their Family members or Beneficiaries, our study will greatly benefit U.S. armed forces and both military and civilian public health care.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310979
Entities
People
- Yi Luo
Organizations
- United States Army
- University of Iowa