Targeting CRM1 for Progeria Syndrome Therapy

Area of Science:

• Cell Biology
• Genetics
• Pharmacology

Background:

• Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease caused by progerin, a mutant lamin A variant, leading to nuclear envelope abnormalities and cellular senescence.
• Overexpression of chromosomal region maintenance 1 (CRM1) enhances nuclear export in HGPS fibroblasts, and its inhibition with leptomycin B rescues senescence.
• CRM1 is identified as a potential therapeutic target for HGPS.

Purpose of the Study:

• To investigate the therapeutic potential of selinexor, a selective CRM1 inhibitor, in HGPS.
• To evaluate the effects of selinexor on progerin clearance, cellular senescence, and gene expression in HGPS patient-derived cells.
• To assess the in vivo efficacy of selinexor in a mouse model of progeria.

Main Methods:

• Treatment of HGPS patient-derived dermal fibroblasts and LMNA^G609G/G609G mice with selinexor.
• Analysis of cellular senescence, progerin levels (immunostaining, immunoblotting), gene expression, and aortic histopathology.
• Pharmacological modulation of CRM1 activity.

Main Results:

• Selinexor treatment mitigated senescence and promoted progerin clearance via autophagy in HGPS fibroblasts.
• Transcriptional analysis revealed restoration of numerous differentially-expressed genes and rescued aging-associated cellular processes.
• In vivo, selinexor decreased progerin levels and improved aortic histopathology in progeric mice.

Conclusions:

• Selinexor demonstrates geroprotective effects in HGPS by normalizing nucleocytoplasmic protein distribution and reducing progerin levels.
• Selinexor acts through at least two mechanisms: modulating the aging-associated transcriptome and decreasing progerin.
• Further research into selinexor's effects on cardiovascular function in progeric mice is warranted for HGPS and aging disorder therapeutics.