scholarly journals Isoprenylcysteine carboxylmethyltransferase-based therapy for Hutchinson–Gilford progeria syndrome

2020 ◽  
Author(s):  
Beatriz Marcos-Ramiro ◽  
Ana Gil-Ordóñez ◽  
Nagore I. Marín-Ramos ◽  
Francisco J. Ortega-Nogales ◽  
Moisés Balabasquer ◽  
...  
Keyword(s):  
Experimental Models ◽  
Premature Aging ◽  
Nuclear Accumulation ◽  
Therapeutic Approaches ◽  
Mouse Cells ◽  
New Treatment ◽  
Isoprenylcysteine Carboxylmethyltransferase ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome ◽  
Potential Use

ABSTRACTProgerin is a mutant prelamin A variant that causes Hutchinson–Gilford progeria syndrome (HGPS, progeria), a rare genetic disease characterized by premature aging and death in childhood. Although several therapeutic approaches have been explored in experimental models, clinical trials have shown very limited benefits in HGPS patients. Here, we describe the development of UCM-13207, a new potent inhibitor of isoprenylcysteine carboxylmethyltransferase (ICMT) that reduces progerin nuclear accumulation and ameliorates the typical alterations in progeroid human and mouse cells. UCM-13207 also improves phenotypic anomalies and extends lifespan in progerin-expressing LmnaG609G/G609G mice. These results support the potential use of UCM-13207 as a new treatment for progeria.

scholarly journals A small-molecule ICMT inhibitor delays senescence of Hutchinson-Gilford progeria syndrome cells

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Xue Chen ◽  
Haidong Yao ◽  
Muhammad Kashif ◽  
Gwladys Revêchon ◽  
Maria Eriksson ◽  
...  
Keyword(s):  
Deficient Mouse ◽  
Wild Type ◽  
Prelamin A ◽  
Cellular Effects ◽  
Late Passage ◽  
Mouse Cells ◽  
Isoprenylcysteine Carboxylmethyltransferase ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome ◽  
Deficient Mice

A farnesylated and methylated form of prelamin A called progerin causes Hutchinson-Gilford progeria syndrome (HGPS). Inhibiting progerin methylation by inactivating the isoprenylcysteine carboxylmethyltransferase (ICMT) gene stimulates proliferation of HGPS cells and improves survival of Zmpste24-deficient mice. However, we don't know whether Icmt inactivation improves phenotypes in an authentic HGPS mouse model. Moreover, it is unknown whether pharmacologic targeting of ICMT would be tolerated by cells and produce similar cellular effects as genetic inactivation. Here, we show that knockout of Icmt improves survival of HGPS mice and restores vascular smooth muscle cell numbers in the aorta. We also synthesized a potent ICMT inhibitor called C75 and found that it delays senescence and stimulates proliferation of late-passage HGPS cells and Zmpste24-deficient mouse fibroblasts. Importantly, C75 did not influence proliferation of wild-type human cells or Zmpste24-deficient mouse cells lacking Icmt, indicating drug specificity. These results raise hopes that ICMT inhibitors could be useful for treating children with HGPS.

Towards a Drosophila model of Hutchinson–Gilford progeria syndrome

2008 ◽  
Vol 36 (6) ◽  
pp. 1389-1392 ◽  
Author(s):  
Gemma S. Beard ◽  
Joanna M. Bridger ◽  
Ian R. Kill ◽  
David R.P. Tree
Keyword(s):  
Drosophila Melanogaster ◽  
Premature Aging ◽  
Lamin A ◽  
Wild Type ◽  
Drosophila Model ◽  
Numerous Cell ◽  
Cellular Abnormalities ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome ◽  
Adult Drosophila

The laminopathy Hutchinson–Gilford progeria syndrome (HGPS) is caused by the mutant lamin A protein progerin and leads to premature aging of affected children. Despite numerous cell biological and biochemical insights into the basis for the cellular abnormalities seen in HGPS, the mechanism linking progerin to the organismal phenotype is not fully understood. To begin to address the mechanism behind HGPS using Drosophila melanogaster, we have ectopically expressed progerin and lamin A. We found that ectopic progerin and lamin A phenocopy several effects of laminopathies in developing and adult Drosophila, but that progerin causes a stronger phenotype than wild-type lamin A.

A genome-wide CRISPR-based screen identifies KAT7 as a driver of cellular senescence

2021 ◽  
Vol 13 (575) ◽  
pp. eabd2655
Author(s):  
Wei Wang ◽  
Yuxuan Zheng ◽  
Shuhui Sun ◽  
Wei Li ◽  
Moshi Song ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Werner Syndrome ◽  
Embryonic Stem ◽  
Accelerated Aging ◽  
Premature Aging ◽  
Mesenchymal Precursor Cells ◽  
Genome Wide ◽  
A Genome ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Understanding the genetic and epigenetic bases of cellular senescence is instrumental in developing interventions to slow aging. We performed genome-wide CRISPR-Cas9–based screens using two types of human mesenchymal precursor cells (hMPCs) exhibiting accelerated senescence. The hMPCs were derived from human embryonic stem cells carrying the pathogenic mutations that cause the accelerated aging diseases Werner syndrome and Hutchinson-Gilford progeria syndrome. Genes whose deficiency alleviated cellular senescence were identified, including KAT7, a histone acetyltransferase, which ranked as a top hit in both progeroid hMPC models. Inactivation of KAT7 decreased histone H3 lysine 14 acetylation, repressed p15INK4b transcription, and alleviated hMPC senescence. Moreover, lentiviral vectors encoding Cas9/sg-Kat7, given intravenously, alleviated hepatocyte senescence and liver aging and extended life span in physiologically aged mice as well as progeroid Zmpste24−/− mice that exhibit a premature aging phenotype. CRISPR-Cas9–based genetic screening is a robust method for systematically uncovering senescence genes such as KAT7, which may represent a therapeutic target for developing aging interventions.

scholarly journals A Very Rare Case of Coronary Artery Bypass Grafting in a Progeria Child

2019 ◽  
Vol 11 (4) ◽  
pp. NP244-NP246
Author(s):  
Rui Pedro Soares Cerejo ◽  
Rui A. N. Rodrigues ◽  
José D. Martins ◽  
Carolina G. E. C. Torres ◽  
Lídia M. Sousa ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery ◽  
Genetic Disorder ◽  
Artery Bypass ◽  
Early Death ◽  
Premature Aging ◽  
Artery Disease ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome ◽  
Vessel Coronary Artery

Hutchinson-Gilford progeria syndrome is a rare genetic disorder, characterized by progressive premature aging and early death in the first or second decade of life, usually secondary to cardiovascular events (myocardial infarction and stroke). We report a case of a 14-year-old boy with progeria syndrome and cardiac arrest due to myocardial infarction, who was submitted to an immediate coronary angiography which revealed left main stem and three-vessel coronary artery disease. A prompt double bypass coronary artery grafting surgery was performed, and, despite successful coronary reperfusion, the patient remained in coma and brain death was declared on fourth day after surgery.

scholarly journals Hutchinson-Gilford Progeria Syndrome: A Rare Genetic Disorder

2013 ◽  
Vol 2013 ◽  
pp. 1-4
Author(s):  
Rajat G. Panigrahi ◽  
Antarmayee Panigrahi ◽  
Poornima Vijayakumar ◽  
Priyadarshini Choudhury ◽  
Sanat K. Bhuyan ◽  
...  
Keyword(s):  
Genetic Disorder ◽  
Premature Aging ◽  
Pectus Carinatum ◽  
Genetic Syndrome ◽  
Live Births ◽  
Follow Up Study ◽  
First Case ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is a rare pediatric genetic syndrome with incidence of one per eight million live births. The disorder is characterised by premature aging, generally leading to death at approximately 13.4 years of age. This is a follow-up study of a 9-year-old male with clinical and radiographic features highly suggestive of HGPS and presented here with description of differential diagnosis and dental consideration. This is the first case report of HGPS which showed pectus carinatum structure of chest.

scholarly journals Neuropeptide Y Enhances Progerin Clearance and Ameliorates the Senescent Phenotype of Human Hutchinson-Gilford Progeria Syndrome Cells

2020 ◽  
Vol 75 (6) ◽  
pp. 1073-1078 ◽  
Author(s):  
Célia A Aveleira ◽  
Marisa Ferreira-Marques ◽  
Luísa Cortes ◽  
Jorge Valero ◽  
Dina Pereira ◽  
...  
Keyword(s):  
Neuropeptide Y ◽  
Caloric Restriction ◽  
Cellular Senescence ◽  
Dermal Fibroblasts ◽  
Cellular Aging ◽  
Premature Aging ◽  
Whole Body ◽  
Lamin A ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Abstract Hutchinson-Gilford progeria syndrome (HGPS, or classical progeria) is a rare genetic disorder, characterized by premature aging, and caused by a de novo point mutation (C608G) within the lamin A/C gene (LMNA), producing an abnormal lamin A protein, termed progerin. Accumulation of progerin causes nuclear abnormalities and cell cycle arrest ultimately leading to cellular senescence. Autophagy impairment is a hallmark of cellular aging, and the rescue of this proteostasis mechanism delays aging progression in HGPS cells. We have previously shown that the endogenous Neuropeptide Y (NPY) increases autophagy in hypothalamus, a brain area already identified as a central regulator of whole-body aging. We also showed that NPY mediates caloric restriction-induced autophagy. These results are in accordance with other studies suggesting that NPY may act as a caloric restriction mimetic and plays a role as a lifespan and aging regulator. The aim of the present study was, therefore, to investigate if NPY could delay HGPS premature aging phenotype. Herein, we report that NPY increases autophagic flux and progerin clearance in primary cultures of human dermal fibroblasts from HGPS patients. NPY also rescues nuclear morphology and decreases the number of dysmorphic nuclei, a hallmark of HGPS cells. In addition, NPY decreases other hallmarks of aging as DNA damage and cellular senescence. Altogether, these results show that NPY rescues several hallmarks of cellular aging in HGPS cells, suggesting that NPY can be considered a promising strategy to delay or block the premature aging of HGPS.

scholarly journals Metabolomic profiling suggests systemic signatures of premature aging induced by Hutchinson–Gilford progeria syndrome

Metabolomics ◽  
2019 ◽  
Vol 15 (7) ◽  
Author(s):  
Gustavo Monnerat ◽  
Geisa Paulino Caprini Evaristo ◽  
Joseph Albert Medeiros Evaristo ◽  
Caleb Guedes Miranda dos Santos ◽  
Gabriel Carneiro ◽  
...  
Keyword(s):  
Premature Aging ◽  
Metabolomic Profiling ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Hutchinson–Gilford Progeria Syndrome (Hgps) And Application Of Gene Therapy Based Crispr/Cas Technology As A Promising Innovative Treatment Approach

2021 ◽  
Vol 15 ◽  
Author(s):  
Mekha Rajeev ◽  
Chameli Ratan ◽  
Karthik Krishnan ◽  
Meenu Vijayan
Keyword(s):  
De Novo ◽  
Treatment Approach ◽  
Genetic Disorder ◽  
Symptomatic Relief ◽  
Dominant Negative ◽  
Premature Aging ◽  
Lamin A ◽  
Promising Therapeutic Approach ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Background: Hutchinson–Gilford progeria syndrome (HGPS) also known as progeria of childhood or progeria is a rare, rapid, autosomal dominant genetic disorder characterized by premature aging which occurs shortly after birth. HGPS occurs as a result of de novo point mutation in the gene recognized as LMNA gene that encodes two proteins Lamin A protein and Lamin C protein which are the structural components of the nuclear envelope. Mutations in the gene trigger abnormal splicing and induce internal deletion of 50 amino acids leading to the development of a truncated form of Lamin A protein known as Progerin. Progerin generation can be considered as the crucial step in HGPS since the protein is highly toxic to human cells, permanently farnesylated, and exhibits variation in several biochemical and structural properties within the individual. HGPS also produces complications such as skin alterations, growth failure, atherosclerosis, hair and fat loss, and bone and joint diseases. We have also revised all relevant patents relating to Hutchinson-gilford progeria syndrome and its therapy in the current article. Method: The goal of the present review article is to provide information about Hutchinson–Gilford progeria syndrome (HGPS) and the use of CRISPR/Cas technology as a promising treatment approach in the treatment of the disease. The review also discusses about different pharmacological and non-pharmacological methods of treatment currently used for HGPS. Results : The main limitation associated with progeria is the lack of a definitive cure. The existing treatment modality provides only symptomatic relief. Therefore, it is high time to develop a therapeutic method that hastens premature aging in such patients. Conclusion: CRISPR/Cas technology is a novel gene-editing tool that allows genome editing at specific loci, and is found to be a promising therapeutic approach for the treatment of genetic disorders such as HGPS where dominant-negative mutations take place.

Emerging candidate treatment strategies for Hutchinson-Gilford progeria syndrome

2017 ◽  
Vol 45 (6) ◽  
pp. 1279-1293 ◽  
Author(s):  
Charlotte Strandgren ◽  
Gwladys Revêchon ◽  
Agustín Sola Carvajal ◽  
Maria Eriksson
Keyword(s):  
De Novo ◽  
Disease Incidence ◽  
Treatment Strategies ◽  
Premature Aging ◽  
Lamin A ◽  
Lmna Gene ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Hutchinson-Gilford progeria syndrome (HGPS, progeria) is an extremely rare premature aging disorder affecting children, with a disease incidence of ∼1 in 18 million individuals. HGPS is usually caused by a de novo point mutation in exon 11 of the LMNA gene (c.1824C>T, p.G608G), resulting in the increased usage of a cryptic splice site and production of a truncated unprocessed lamin A protein named progerin. Since the genetic cause for HGPS was published in 2003, numerous potential treatment options have rapidly emerged. Strategies to interfere with the post-translational processing of lamin A, to enhance progerin clearance, or directly target the HGPS mutation to reduce the progerin-producing alternative splicing of the LMNA gene have been developed. Here, we give an up-to-date resume of the contributions made by our and other research groups to the growing list of different candidate treatment strategies that have been tested, both in vitro, in vivo in mouse models for HGPS and in clinical trials in HGPS patients.

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