Progeria: a new therapeutic avenue?

#Progeria  #PrematureAging  #CRM1  #Selinexor  #Senescence  #TargetedTherapy


Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic disorder that causes premature aging. It is triggered by a mutation in the LMNA gene, leading to the abnormal production of progerin. This protein accumulates in the cell nucleus, disrupting cellular function and accelerating aging. Affected children develop severe cardiovascular complications, leading to early death, usually before the age of 15.

Currently, no curative treatment exists for progeria. Lonafarnib, a drug that limits progerin’s anchoring to the nuclear membrane, slows disease progression, but its effectiveness remains partial. Other approaches, such as rapamycin, show promise but are still limited.

Recent research has revealed that CRM1, a protein involved in nuclear export, is overexpressed in HGPS cells. This hyperactivity contributes to the cellular dysfunctions observed in progeria. Selinexor, a drug used in cancer treatment, inhibits CRM1 and may help restore nuclear function while promoting progerin clearance.

The aim of this study is to evaluate the efficacy of selinexor in progeria. This treatment could offer a new therapeutic option for children affected by this disease.

Selinexor: The key to slowing down Progeria?

The effects of selinexor were studied on fibroblasts derived from HGPS patients and a progeroid mouse model (LmnaG609G/G609G). The study analyzed drug toxicity, cellular senescence markers, gene expression regulation, and progerin degradation. experiments also assessed the impact of selinexor on progerin levels and cardiovascular tissue health.

Results showed that selinexor effectively inhibits CRM1 with lower toxicity than leptomycin B. It reduces several markers of senescence by restoring normal nuclear morphology, decreasing mitochondrial damage and oxidative stress, and downregulating proteins associated with cellular aging. Additionally, selinexor promotes progerin clearance by stimulating autophagy without altering its gene expression. Transcriptomic analysis revealed normalization of numerous genes involved in cellular aging. Finally, experiments conducted on progeroid mice demonstrated a reduction in progerin levels in the liver and aorta, along with improved aortic histopathology, suggesting a beneficial in vivo effect.

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Selinexor: A hope against accelerated aging!

Hutchinson-Gilford Progeria Syndrome is a rare genetic disease characterized by accelerated aging due to the accumulation of progerin, a toxic protein that disrupts nuclear structure and promotes cellular senescence. Despite therapeutic advancements, current treatments remain limited and only slow disease progression without effectively addressing its underlying causes.

This study aimed to assess the potential of selinexor, a CRM1 inhibitor, in restoring nuclear balance and promoting progerin clearance. The results demonstrate that selinexor effectively inhibits CRM1, reduces cellular senescence markers, and facilitates progerin degradation through autophagy. Moreover, in vivo tests on progeroid mice revealed decreased progerin levels in the liver and aorta, accompanied by vascular tissue improvement.

However, uncertainties remain, including the lack of long-term data and the need to evaluate its safety and efficacy across different tissues and physiological functions. Further research is necessary to better understand its overall impact and explore its potential application in other aging-related diseases.