First Generation Proteolysis Targeting Chimeras (PROTACs) for the Treatment of Progeria.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by a mutation in the LMNA gene, leading to the production of progerin, an aberrant and toxic form of lamin A. Due to its hydrophobic nature, progerin accumulates at the nuclear membrane, disrupting nuclear architecture, impairing cellular functions, and ultimately resulting in death around adolescence. Reducing progerin levels is considered the most effective strategy to improve disease progression. To date, small-molecule approaches have primarily targeted progerin upstream mechanisms to indirectly reduce its levels. In this study, we report the development of first-generation proteolysis targeting chimeras (PROTACs) designed to directly degrade progerin, establishing a novel therapeutic paradigm for HGPS. We identify UCM-18142 (compound 2) as the first PROTAC capable of selectively degrading progerin. Treatment with UCM-18142 results in significant improvements in cellular phenotype in both HGPS patient-derived cells and a murine model, including enhanced proliferation, reduced senescence markers, and normalization of nuclear and mitochondrial abnormalities. Additionally, transcriptomic analysis of treated human cells reveals the cellular pathways modulated by compound. Remarkably, PROTAC 2 reduces progerin levels in vivo, supporting the therapeutic potential of this direct-targeting approach and opening new avenues for intervention in HGPS and related laminopathies.