# Pharmacologic modulation of innate immune dysfunction in heterotopic ossification

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $355,300

## Abstract

PROJECT SUMMARY/ABSTRACT
Heterotopic ossification is a rare but devastating condition of inappropriate bone formation. Although immune
system activity is a critical contributor to heterotopic ossification, we lack a clear understanding of how the
immune system drives bone formation. Fibrodysplasia ossificans progressiva (FOP) is a genetic disease of
massive heterotopic ossification that is associated with inflammatory “flares” that can occur after injury. We
recently found that sera from FOP patients have increased levels of pro-inflammatory cytokines at baseline.
Furthermore, primary FOP monocytes showed increased responsiveness to LPS, a ligand that stimulates the
TLR4 pathway, but not to other ligands that activate other TLR receptors. These preliminary results lead to our
central hypothesis that FOP is an autoimmune disease caused by inappropriate activation of the innate
immune system. Although there are currently no effective treatments for FOP, retinoic acid receptor-γ (RAR-γ)
agonists can inhibit heterotopic ossification in mouse models. UCSF is part of an ongoing multicenter Phase II/III
program sponsored by Clementia Pharmaceuticals to study the efficacy of the RAR-γ agonist palovarotene in
blocking bone formation in FOP. Preliminary results from a completed randomized study (NCT02190747) and
ongoing open label followup study (NCT02279095) indicate that palovarotene can decrease the amount of
heterotopic bone formation in FOP subjects. The ongoing open label PVO-1A-202 (NCT02279095) and Phase
III PVO-1A-301 (NCT03312634) interventional trials will be the parent studies for the proposed unique
and time-sensitive opportunity to elucidate the immune mechanisms in FOP. In Aim 1, we will elucidate
how FOP primary monocytes respond to endogenous TLR4 activation. We will assay FOP sera for known
endogenous TLR4 activators that can be expressed after trauma, and test if FOP monocytes show increased
responsiveness to the TLR4 activators such as HMGB1. In Aim 2, we will test if FOP primary monocytes sensitize
endothelial cells to inflammation. We will use co-cultures to assay if FOP monocytes show increased chemotaxis
towards FOP endothelial cells and if this is dampened by palovarotene. We will also test if FOP endothelial cells
show enhanced pro-inflammatory cytokine expression in the presence of FOP monocytes. These assessments
will also show if palovarotene affects immune cell function. In Aim 3, we will determine how ACVR1 and
palovarotene change innate immune cell activation. We will use single cell RNAseq to elucidate how the ACVR1
R206H mutation changes the composition of peripheral immune cells, if palovarotene can normalize this profile,
and if changes in cytokine production can be linked to inflammation and FOP clinical heterotopic bone formation.
Our results will reveal critical inflammatory mechanisms that may provide the first mechanistic and
diagnostic biomarkers for disease activity in FOP. The results may also improve our treatme...

## Key facts

- **NIH application ID:** 9970196
- **Project number:** 5R01AR073015-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** EDWARD C HSIAO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $355,300
- **Award type:** 5
- **Project period:** 2018-09-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970196

## Citation

> US National Institutes of Health, RePORTER application 9970196, Pharmacologic modulation of innate immune dysfunction in heterotopic ossification (5R01AR073015-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9970196. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*