# Role of PAPP-A in Graves' Ophthalmopathy

> **NIH NIH R03** · MAYO CLINIC ROCHESTER · 2024 · $79,500

## Abstract

PROJECT SUMMARY
Graves’ Ophthalmopathy (GO) is the most serious extra-thyroidal complication that develops in patients with
autoimmune Graves’ hyperthyroidism. It is characterized by increased orbital fat volume and extra-ocular
muscle within the unyielding bony orbit, which can have deleterious consequences on eye function. Orbital
decompression surgery is an effective but invasive treatment used for severe GO. A better understanding of
the pathological mechanisms underlying GO may identify novel targets to inhibit the development and
progression of GO before any clinical manifestation.
 Insulin-like growth factor-I receptor (IGF-IR) signaling has been found to be essential in promoting GO
pathogenesis. A monoclonal antibody that binds to and blocks IGF-IR signaling, was recently FDA-approved
for treatment of GO. However, adverse events have been documented, all likely due to the ubiquitous nature of
IGF-IR. A better understanding of IGF signaling and its regulation in orbital tissue is needed to fully understand
mechanism and avoid/reduce off-target consequences. One approach would be to target modifiers of IGF-IR
signaling, instead of the IGF-IR per se. We propose PAPP-A as such a target.
 PAPP-A is a novel zinc metalloprotease that can increase pericellular IGF bioavailability through cleavage of
inhibitory IGF binding proteins, in particular IGFBP-4. Conversely, inhibition of PAPP-A expression or its
proteolytic activity represents an innovative approach to decrease IGF availability with resultant attenuation of
IGF-IR signaling. Interestingly, the most potent stimulators of PAPP-A expression are pro-inflammatory
cytokines, which are increased in orbital tissue from GO patients.
 We hypothesize that PAPP-A is a key modulator of IGF-R signaling in GO. Our Specific Aims are to:
 1) Determine PAPP-A expression (basal and pro-inflammatory cytokine-induced) in orbital
 fibroblasts from GO patients and control subjects.
 2) Determine the effect of a neutralizing monoclonal antibody that specifically inhibits PAPP-A-
 mediated IGFBP-4 proteolysis on IGF-I stimulated proliferation and differentiation in orbital
 fibroblasts from GO patients.
 We have primary fibroblasts from retro-orbital fat of GO patients at early passage in-hand and the experience
with culture and analyses to establish feasibility. Preliminary results support a role for PAPP-A in GO. We
anticipate outcomes from the proposed experiments that could ultimately lead to a novel targeted therapy for
patients with GO.

## Key facts

- **NIH application ID:** 10765697
- **Project number:** 5R03AI170571-02
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Cheryl A. Conover
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $79,500
- **Award type:** 5
- **Project period:** 2023-01-18 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765697

## Citation

> US National Institutes of Health, RePORTER application 10765697, Role of PAPP-A in Graves' Ophthalmopathy (5R03AI170571-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10765697. Licensed CC0.

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