Problem

Idiopathic pulmonary fibrosis (IPF) is a chronic disease where activated fibroblasts mediate the abnormal accumulation of extracellular matrix (ECM) in the lung interstitial space, leading to progressive impairment of pulmonary function. Current IPF therapies are associated with significant side effects and offer only palliative benefits. With a median survival of three years if left untreated, there is a critical need for new therapies that can reverse the progression of IPF.

Solution

We developed a new platform where synthetic lysophosphatidic acid receptor 1 (LPA1) antagonist-derived amino lipids (LA-lipids) were formulated into LNPs encapsulating the A20 mRNA. As LPA1 is highly expressed on activated fibroblasts, LA-lipids enhance mRNA uptake in lung fibroblasts while reducing chemotaxis and proliferation upon LPA1 blockade. The A20 protein negatively regulates NF-кB activation and inflammation, slows migration, and reduces collagen synthesis in primary mouse lung fibroblasts both in vitro and ex vivo. The invention provides a fibroblast-specific delivery platform and a promising anti-fibrotic A20 mRNA therapy to treat IPF

Advantages

• Enhanced delivery specificity to lung fibroblasts: The use of LPA1 antagonist-derived lipid nanoparticles provides specific delivery to lung fibroblasts, improving drug efficacy and minimizing off-target effects
• Dual mechanisms with synergistic anti-fibrotic action: LPA1 antagonism with A20 mRNA delivery are combined to target both fibrotic and inflammatory pathways
• Reduced side effects: Potentially fewer side effects compared to current FDA-approved drugs (pirfenidone and nintedanib)
• Offering a modular delivery platform for mRNA-based therapies

Applications

• Therapy for treating idiopathic pulmonary fibrosis

Fibroblast-targeted drug delivery: The delivery platform can be adapted to target other molecules to fibroblasts or other cell types involved in fibrotic diseases