Spatially resolved transcriptomic analysis of cardiac architecture in Anderson-Fabry disease: identification of novel pathogenetic mechanisms

Anderson-Fabry disease (AFD) is a lysosomal storage disorder caused by mutations in the GLA gene, which encodes the enzyme alpha-galactosidase A. Deficiency of this enzyme leads to progressive intracellular lipid accumulation, resulting in tissue damage primarily affecting the heart, kidneys, and brain. The pattern of organ involvement is highly heterogeneous among affected individuals. Currently, the only available treatments for AFD are enzyme replacement therapy and, more recently, chaperone therapy for patients with amenable GLA mutations. These therapies can slow disease progression but are not curative. The main objective of our study is to investigate the molecular mechanisms underlying AFD by examining changes in cardiac tissue using advanced spatial transcriptomics technologies. These methods enable the characterization of gene expression profiles at the single-cell level while preserving the spatial localization of each cell within the tissue. Spatial transcriptomics allows for comprehensive profiling of all resident cell populations, including inflammatory cells, which may play a key role in disease progression. The preservation of spatial context also provides insights into potential cell-to-cell interactions. This approach is expected to reveal novel therapeutic targets, related both to primary pathological alterations and to secondary changes associated with heart failure progression.