Proteomic-guided targeted treatment of leukoencephalopathy with calcification and cysts

Precision therapeutic approaches for rare neurological diseases are often hampered by a limited molecular understanding of the disease. Here, we report the first application of spatially-resolved proteomics to guide targeted treatment in a monogenic leukoencephalopathy. We investigated leukoencephalopathy with calcifications and cysts (LCC), a rare ribosomopathy caused by biallelic mutations in SNORD118 that leads to progressive cerebral white matter degeneration and vascular proliferation. LCC is currently incurable, though understanding the pathogenesis at the proteomic level can offer novel treatment options. We analyzed defined regions of vasculature and white matter from four LCC patients and four healthy controls using laser-capture microdissection followed by label-free mass spectrometry. This spatial proteomic approach revealed distinct, tissue-specific molecular alterations in vasculature and white matter from LCC patients, with dysregulation centered on pathways related to cytoskeleton organisation. Vascular remodeling indicated the primary site of cell proliferation, while leukoencephalopathy appeared driven by ribosomal dysfunction. Notably, VEGFR1/2 and their downstream effectors, including PKC and Ras-MEK-ERK signaling cascades, were consistently upregulated across compartments, highlighting VEGF signaling as a convergent and targetable pathway. In a 53-year-old patient harboring novel compound heterozygous SNORD118 variants, VEGF-targeted treatment with axitinib resulted in sustained radiographic and clinical response for over 35 months, representing the longest therapeutic response reported in LCC to date. This work showcases a proteomics-based framework for mechanism-driven therapy selection in ultra-rare neurological diseases. It further adds to the established genetic drivers of LCC and provides experimental data supporting VEGF pathway modulation as a rational therapeutic strategy in LCC.