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

Area of Science:

• Genetics
• Molecular Biology
• Drug Discovery

Background:

• Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by LMNA gene mutations.
• These mutations lead to toxic progerin accumulation at the nuclear membrane, causing cellular dysfunction and premature aging.
• Current treatments indirectly target progerin production, but direct degradation offers a more effective strategy.

Purpose of the Study:

• To develop and evaluate the first-generation proteolysis targeting chimeras (PROTACs) for direct progerin degradation in HGPS.
• To establish a novel therapeutic paradigm for HGPS by targeting progerin directly.
• To assess the efficacy of PROTACs in cellular and animal models of HGPS.

Main Methods:

• Development of novel PROTACs designed to induce progerin degradation.
• In vitro testing of PROTACs in HGPS patient-derived cells.
• In vivo studies using a murine model of HGPS.
• Cellular phenotype analysis, including proliferation and senescence markers.
• Transcriptomic analysis to identify modulated cellular pathways.

Main Results:

• Identified UCM-18142 (compound 2) as the first PROTAC to selectively degrade progerin.
• Demonstrated significant improvements in cellular phenotypes in HGPS cells and a murine model.
• Observed enhanced proliferation, reduced senescence, and normalized nuclear/mitochondrial structures.
• Confirmed in vivo reduction of progerin levels by PROTAC 2.
• Transcriptomic analysis revealed pathways modulated by the PROTAC treatment.

Conclusions:

• First-generation PROTACs offer a novel therapeutic strategy for directly degrading progerin in HGPS.
• UCM-18142 demonstrates significant therapeutic potential in cellular and in vivo models.
• This direct-targeting approach opens new avenues for treating HGPS and related laminopathies.