A new, rapid urine test to diagnose IC is on the horizon with the award of a $945,142 grant to IC researcher Sonia Planey Ph.D. (Commonwealth Medical College) through the Dept. of Defense office of Congressionally Directed Medical Research Programs (CDMRP). Each year, the CDMRP program awards $50 million dollars to promote the study of conditions which affect military readiness, including interstitial cystitis.
In Fiscal Year 2011, researcher Michael Chancellor received $1.644 million to study a potential new treatment, the use of liposomes to deliver an anti-nerve growth factor into the bladder wall. Dr. Planey is the recipient of funding for Fiscal Year 2012. Fiscal Year 2013 studies are currently in review.
ICN President Jill Osborne has served on the CDRMP research panel for interstitial cystitis for the past three years and recommended Dr. Planey’s study for funding. She offered “CDMRP is a fair and very rigorous review process. Out of the hundreds of applications submitted last year, only eight focused on IC. Dr. Planey’s study was the clear favorite for relevance, innovation and research methodology.”
She continued “I rated it highly because a urine would not only reduce the trauma that many patients experience while undergoing more invasive testing, such as hydrodistention, but will also reduce the cost of testing, a critical need for the majority of patients who struggle to pay for health care in the USA. Just imagine a simple, non-invasive urine test that would identify patients early after onset, allowing for much earlier early intervention and treatment. This is very exciting.”
Dr. Planey will be collaborating with Dr. Susan Keay (University of Maryland), Dr. Phillip Hanno (Univ. of Pennsylvania) and local urologists from Delta Medix, P.C.
Public Abstract
Topic Area and Critical Problem Addressed: The proposed research project addresses the FY12 PRMRP topic area of interstitial cystitis (IC). IC is a chronic, debilitating bladder disease that predominantly affects women. It is frequently undiagnosed or misdiagnosed and as such constitutes a significant and underestimated health burden. IC is not only difficult to diagnose but also complicated to treat, as the etiology of IC remains unknown and no treatment is reliably effective. Most treatments are hypothesized to affect one or more specific abnormalities in IC such as bladder epithelial deficiency, bladder inflammation, bladder mast cell activation, or altered innervations; yet, it is difficult to determine whether any of these processes is occurring in an individual patient. The only well-established information comes from cystoscopy and bladder biopsies, but these procedures are invasive, expensive, and not feasible to repeat over time. Thus, for chronic diseases like IC, whose clinical management may require patients to make multiple lifestyle changes and take medications for years, the need for biomarkers that can facilitate diagnosis and that can be used by clinicians in selecting treatments, evaluating treatment effects, and deciding when and how to modify treatments is critical.
Research Project Overview: Urinary biomarkers, in particular, hold great promise for early detection and accurate diagnosis of IC, as urine collection is non-invasive, painless, and repeatable. Among those biomarkers that have been described, a small peptide named antiproliferative factor (APF) has been shown to be detectable in the urine of 95% to 97% of IC patients vs. healthy controls and, thus, holds the most promise. Not only is APF specifically produced in the bladders of IC patients, but its bioactivities are consistent with IC pathology. Yet, despite its specificity and prevalence in IC patient urine, independent validation of APF as a diagnostic biomarker for IC has been hindered by the absence of specific, sensitive assays to measure its concentration in patient urine. APF’s weak immunogenic properties, including its small size and sequence identity to the protein Frizzled 8, have impeded more common, antibody-based approaches to its detection (i.e., ELISA) and hence likely discouraged more widespread investigation. This proposal seeks to fill that gap by using Surface Plasmon Resonance (SPR) technology, which has emerged as the “gold standard” to measure biomolecular interactions. Taking advantage of the high-affinity interaction of APF with its cellular receptor, cytoskeleton associated protein 4 (CKAP4), our objective is to develop and evaluate an SPR-based assay in which purified CKAP4 protein will be immobilized to a sensor chip as the ligand to detect APF as the analyte in urine samples from patients with IC versus non-IC control groups. We are poised to undertake this project since, in addition to preliminary data demonstrating that our assay works, we have the necessary expertise in CKAP4/APF signaling and on the use of SPR to detect protein-peptide interactions. Further, we have garnered the support of two clinical experts in the IC field, Dr. Phillip Hanno and Dr. Susan Keay, who will be supporting us, both materially, with patient urine specimens, and intellectually, for the proposed study.
Applicability and Impact of the Research: We expect that the proposed SPR-based assay would overcome current barriers associated with validation of APF as a diagnostic biomarker for IC by being able to specifically detect the presence of APF in urine and accurately quantitate its levels for the first time. In the short-term, being able to definitively correlate the concentration of APF to the occurrence of IC as well as to disease severity and progression will validate its utility as a diagnostic and prognostic biomarker for IC. The SPR assay also represents a tangible product that could be developed into an affirmative, point-of-care diagnostic test for IC with the advantages of being rapid, repeatable, and non-invasive. As no such test to diagnose IC exists, this assay could improve clinical practice by obviating the need for more costly, invasive procedures such as cystoscopy and hydrodistension and curtailing misdiagnosis and improper treatment of patients who have symptomological overlap with IC. Certainly, accurate and earlier diagnosis and more appropriate treatment of IC would improve patient care and quality of life and lead to better management (or even prevention) of co-morbidities and reduced healthcare costs. In the long-term, validation of APF as an IC biomarker would foster greater understanding of the relationship between the development of IC and the identification of subgroups that are at increased risk for disease, even in early childhood; further, it could provide a method for homogeneous classification of IC and extend our knowledge base concerning its underlying pathogenesis. These advantages have direct application to all types of clinical investigation, from clinical trials to observational studies in epidemiology and advancement of translational research related not only to earlier and accurate diagnosis, but also to disease prevention, drug target identification, and drug response to therapy.
