# Therapeutic Exploitation of IPSE, a Urogenital Parasite-Derived Host Modulatory Protein, for Bladder Hypersensitivity Syndromes

> **NIH NIH R01** · CHILDREN'S RESEARCH INSTITUTE · 2021 · $396,261

## Abstract

We propose to therapeutically exploit Schistosoma haematobium-derived IPSE (Interleukin-4 inducing
Principle from Schistosoma mansoni Eggs) to mitigate bladder hypersensitivity. The incidence of bladder
hypersensitivity (i.e., interstitial cystitis/bladder pain syndromes and overactive bladder) in some patient
populations is over 40%, and existing treatments are ineffective for many. Thus, novel therapeutics are
needed. The S. mansoni homolog of IPSE (M-IPSE) alters host biology by three distinct mechanisms: 1)
translocating into nuclei of target cells to alter gene transcription; 2) binding IgE on basophils and mast cells to
trigger IL-4 secretion; and 3) sequestering chemokines. We have shown that the S. haematobium homolog of
IPSE (H-IPSE) translocates into urothelial cell nuclei and binds IgE on basophils. Our in silico data show H-
IPSE binds CCL2. Collectively, these findings illustrate that H-IPSE and M-IPSE share many host modulatory
features, but their differences are unclear. Immune and non-immune modulation of the bladder may be a new
management approach for bladder hypersensitivity. Blocking CCL2-CCR2 interactions in bladder nerves and
dorsal root ganglia lowers pain in rodent models. IL-4 lessens ifosfamide-induced cystitis in mice and
decreases bladder pain and overactivity. Yet, intravenous IL-4 has adverse side effects in patients. We have
discovered that a single intravenous dose of H-IPSE is superior to both Mesna and recombinant IL-4 in
suppressing ifosfamide-induced bladder hemorrhage, and that it reduces urinary frequency and pain behaviors
through IL-4- and nuclear localization sequence-dependent mechanisms. In conclusion, a single dose of H-
IPSE lessens bladder hypersensitivity in two mouse models through pathways consistent with the known
properties of M-IPSE and H-IPSE. We hypothesize that H-IPSE and M-IPSE variants can be optimized as safe
therapeutics for bladder hypersensitivity by defining and exploiting their nuclear localization signal-, IL-4-, and
chemokine binding-reliant mechanisms. To test this hypothesis, we will, in Aim 1, define and optimize the
mechanisms by which IPSE exerts therapeutic effects in bladder hypersensitivity through the generation of
engineered mutants with: 1) greater nuclear translocation ability to which will dampen transcription of pain-
related genes; 2) increased capacity to induce IL-4 production; and 3) enhanced sequestration of chemokines.
In Aim 2, we will determine the chronic toxicity potential of IPSE. We hypothesize that H-IPSE and M-IPSE
variants and mutants that induce apoptosis of intestinal epithelial cells or dendritic cells upon nuclear
translocation will cause toxicity when given on a chronic basis. Finally, we theorize that IPSE variants/mutants
which do not trigger cancer gene-related transcription upon nuclear translocation into urothelial cells will not
cause bladder cancer. Our work is unique in that it demonstrates that a uropathogen-derived host modulatory
molecule...

## Key facts

- **NIH application ID:** 10168521
- **Project number:** 5R01DK113504-06
- **Recipient organization:** CHILDREN'S RESEARCH INSTITUTE
- **Principal Investigator:** Michael Harrison Hsieh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $396,261
- **Award type:** 5
- **Project period:** 2017-05-05 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10168521

## Citation

> US National Institutes of Health, RePORTER application 10168521, Therapeutic Exploitation of IPSE, a Urogenital Parasite-Derived Host Modulatory Protein, for Bladder Hypersensitivity Syndromes (5R01DK113504-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10168521. Licensed CC0.

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