The Impact of SLC7A7 Deficiency on Macrophage Differentiation and Function in Lysinuric Protein Intolerance: Implications for Unraveling Disease Mechanisms and Developing New Therapeutic Strategies

Lysinuric protein intolerance (LPI) is a rare disease caused by mutations in the SLC7A7 gene. This gene mutations impairs the transporter for cationic amino acids in intestinal, renal, and certain immune cells, specifically monocytes and macrophages.s. The defective functioning of this transporter causes intestinal, renal and immunological symptoms. Indeed, LPI patients often present severe, potentially fatal, immunological disorders such as pulmonary alveolar proteinosis (PAP) and hemophagocytic lymphohistiocytosis (HLH), also referred to as macrophage activation syndrome (MAS).  To date, the cellular and molecular mechanisms that underlie the development of LPI associated PAP and HLH/MAS are unknown, making it difficult to find effective treatment. Our preliminary experimental data demonstrated that macrophages from LPI patients have a heightened inflammatory response, linked to the activation of a pathway controlled by a protein called interferon gamma (IFNγ). In this project, we aim to:

1. Confirm that the IFNγ pathway and its associated genes are indeed overactive in macrophages from LPI patients and understand the molecular reasons behind this;

2. Study how changes in the metabolism of these macrophages affect their behavior and function, and 

3. Identify new potential treatment targets beyond IFNγ for LPI-related immune issues.

The ultimate goal is to evalidate IFNγ as a key therapeutic target for LPI. We will test the effectiveness of emapalumab, an antibody neutralizing IFNγ, and ruxolitinib, an anti-inflammatory drug, in reducing the abnormal activation of LPI macrophages. These drugs have already shown success in treating other similar immune disorders, offering hope for new treatments for LPI patients.