A Novel Skin-Based Approach to Treat Lupus Nephritis

Repurposing topical MC903, an FDA-approved vitamin D analog, to trigger skin-derived bile acid synthesis and generate systemic anti-inflammatory effects in lupus nephritis.
Ongoing Systemic Diseases Systemic Lupus Erythematosus (SLE) Animal Models Biological & Mechanistic Cytokine Signaling Drug Repurposing Experimental Platforms & Models Immunometabolism Therapeutic Development Translational & Clinical

Funding Year: 2025

Project Overview

Lupus nephritis is a severe and treatment-resistant manifestation of SLE with no safe, effective long-term therapies. This project explores a novel approach: applying topical MC903 — a vitamin D analog already FDA-approved for psoriasis — to induce protective systemic effects against lupus nephritis via the skin. Preliminary data reveal that MC903-treated skin produces bile acids previously thought to be synthesized only in the liver. These skin-derived bile acids enter circulation and act through the farnesoid X receptor (FXR), which has known anti-inflammatory effects in immune and kidney cells. Using multiple lupus mouse models, the team will investigate how MC903 affects immune activation and kidney pathology, and whether bile acid synthesis and FXR signaling are required for therapeutic benefit.

Impact & Innovation

The skin as an untapped source of systemic immune regulation.

 

By demonstrating that MC903-treated skin produces bile acids that circulate and act through FXR, this project upends conventional biology and opens a repurposable, non-immunosuppressive path to treating lupus nephritis topically.

  • Challenges the liver-centric model of bile acid synthesis, establishing the skin as a novel endocrine-like organ capable of generating systemic anti-inflammatory signals
  • Generates IP potential through Penn Center for Innovation, with a patent filing planned for topical MC903 use in LN and industry collaborations envisioned for formulation and clinical advancement
  • Advances the Consortium’s From Mechanistic Insight to Translation pillar by repurposing an FDA-approved topical compound toward a low-barrier clinical trial pathway for lupus nephritis
Research Approach

A framework designed for discovery

This project combines preclinical lupus modeling with mechanistic investigation of skin-derived bile acid synthesis and FXR signaling to evaluate topical MC903 as a non-immunosuppressive therapeutic strategy for lupus nephritis. The work moves from mechanistic validation through preclinical efficacy testing toward clinical translation.

Topical MC903 application in multiple lupus mouse models to assess effects on immune activation and kidney pathology; investigation of skin-derived bile acid synthesis and FXR signaling as required mediators of therapeutic benefit; and mechanistic studies of FXR anti-inflammatory activity in immune and kidney cells.

Multiple lupus mouse model datasets measuring immune activation, kidney pathology, and systemic bile acid levels following topical MC903 treatment; preliminary data confirming skin bile acid synthesis in MC903-treated skin; and FXR signaling datasets in immune and kidney cell contexts.

Validation of skin-derived bile acid synthesis and FXR signaling as a novel, targetable mechanism for systemic immune modulation in lupus nephritis, with a translational path leveraging MC903’s existing FDA approval for psoriasis to minimize barriers to clinical trials. A patent filing is planned through Penn Center for Innovation, with industry collaborations envisioned for formulation testing and clinical advancement.

Investigators & Institutions

Powering the science

Principal Investigator

Taku Kambayashi, MD, PhD, Colton Consortium Member

Professor, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania

Colton Centers & Institutions

Colton Center for Autoimmunity at the University of Pennsylvania

Perelman School of Medicine