The pursuit of therapy for progeria.
Ontology highlight
ABSTRACT:
SUBMITTER: Saxena S
PROVIDER: S-EPMC8266361 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Hutchinson-Gilford progeria syndrome (HGPS, progeria) is a rare genetic disease characterized by premature aging and death in childhood for which there were no approved drugs for its treatment until last November, when lonafarnib obtained long-sought FDA approval. However, the benefits of lonafarnib in patients are limited, highlighting the need for new therapeutic strategies. Here, we validate the enzyme isoprenylcysteine carboxylmethyltransferase (ICMT) as a new therapeutic target for progeria with the development of a new series of potent inhibitors of this enzyme that exhibit an excellent antiprogeroid profile. Among them, compound UCM-13207 significantly improved the main hallmarks of progeria. Specifically, treatment of fibroblasts from progeroid mice with UCM-13207 delocalized progerin from the nuclear membrane, diminished its total protein levels, resulting in decreased DNA damage, and increased cellular viability. Importantly, these effects were also observed in patient-derived cells. Using the Lmna G609G/G609G progeroid mouse model, UCM-13207 showed an excellent in vivo efficacy by increasing body weight, enhancing grip strength, extending lifespan by 20%, and decreasing tissue senescence in multiple organs. Furthermore, UCM-13207 treatment led to an improvement of key cardiovascular hallmarks such as reduced progerin levels in aortic and endocardial tissue and increased number of vascular smooth muscle cells (VSMCs). The beneficial effects go well beyond the effects induced by other therapeutic strategies previously reported in the field, thus supporting the use of UCM-13207 as a new treatment for progeria.
| S-EPMC8393201 | biostudies-literature
Project description:AimsHutchinson-Gilford progeria syndrome (HGPS) is an accelerated ageing syndrome associated with premature vascular disease and death due to heart attack and stroke. In HGPS a mutation in lamin A (progerin) alters nuclear morphology and gene expression. Current therapy increases the lifespan of these children only modestly. Thus, greater understanding of the underlying mechanisms of HGPS is required to improve therapy. Endothelial cells (ECs) differentiated from induced pluripotent stem cells (iPSCs) derived from these patients exhibit hallmarks of senescence including replication arrest, increased expression of inflammatory markers, DNA damage, and telomere erosion. We hypothesized that correction of shortened telomeres may reverse these measures of vascular ageing.Methods and resultsWe generated ECs from iPSCs belonging to children with HGPS and their unaffected parents. Telomerase mRNA (hTERT) was used to treat HGPS ECs. Endothelial morphology and functions were assessed, as well as proteomic and transcriptional profiles with attention to inflammatory markers, DNA damage, and EC identity genes. In a mouse model of HGPS, we assessed the effects of lentiviral transfection of mTERT on measures of senescence, focusing on the EC phenotype in various organs. hTERT treatment of human HGPS ECs improved replicative capacity; restored endothelial functions such as nitric oxide generation, acetylated low-density lipoprotein uptake and angiogenesis; and reduced the elaboration of inflammatory cytokines. In addition, hTERT treatment improved cellular and nuclear morphology, in association with a normalization of the transcriptional profile, effects that may be mediated in part by a reduction in progerin expression and an increase in sirtuin 1 (SIRT1). Progeria mice treated with mTERT lentivirus manifested similar improvements, with a reduction in inflammatory and DNA damage markers and increased SIRT1 in their vasculature and other organs. Furthermore, mTERT therapy increased the lifespan of HGPS mice.ConclusionVascular rejuvenation using telomerase mRNA is a promising approach for progeria and other age-related diseases.
| S-EPMC8603239 | biostudies-literature
Project description:Hutchinson-Gilford progeria syndrome (HGPS) is one of the most severe disorders among laminopathies-a heterogeneous group of genetic diseases with a molecular background based on mutations in the LMNA gene and genes coding for interacting proteins. HGPS is characterized by the presence of aging-associated symptoms, including lack of subcutaneous fat, alopecia, swollen veins, growth retardation, age spots, joint contractures, osteoporosis, cardiovascular pathology, and death due to heart attacks and strokes in childhood. LMNA codes for two major, alternatively spliced transcripts, give rise to lamin A and lamin C proteins. Mutations in the LMNA gene alone, depending on the nature and location, may result in the expression of abnormal protein or loss of protein expression and cause at least 11 disease phenotypes, differing in severity and affected tissue. LMNA gene-related HGPS is caused by a single mutation in the LMNA gene in exon 11. The mutation c.1824C > T results in activation of the cryptic donor splice site, which leads to the synthesis of progerin protein lacking 50 amino acids. The accumulation of progerin is the reason for appearance of the phenotype. In this review, we discuss current knowledge on the molecular mechanisms underlying the development of HGPS and provide a critical analysis of current research trends in this field. We also discuss the mouse models available so far, the current status of treatment of the disease, and future prospects for the development of efficient therapies, including gene therapy for HGPS.
| S-EPMC6406247 | biostudies-literature
Project description:CRISPR/Cas9-based therapies hold considerable promise for the treatment of genetic diseases. Among these, Hutchinson-Gilford progeria syndrome, caused by a point mutation in the LMNA gene, stands out as a potential candidate. Here, we explore the efficacy of a CRISPR/Cas9-based approach that reverts several alterations in Hutchinson-Gilford progeria syndrome cells and mice by introducing frameshift mutations in the LMNA gene.
| S-EPMC6546610 | biostudies-literature
Project description:This paper explores the homogeneity of coefficients in high-dimensional regression, which extends the sparsity concept and is more general and suitable for many applications. Homogeneity arises when regression coefficients corresponding to neighboring geographical regions or a similar cluster of covariates are expected to be approximately the same. Sparsity corresponds to a special case of homogeneity with a large cluster of known atom zero. In this article, we propose a new method called clustering algorithm in regression via data-driven segmentation (CARDS) to explore homogeneity. New mathematics are provided on the gain that can be achieved by exploring homogeneity. Statistical properties of two versions of CARDS are analyzed. In particular, the asymptotic normality of our proposed CARDS estimator is established, which reveals better estimation accuracy for homogeneous parameters than that without homogeneity exploration. When our methods are combined with sparsity exploration, further efficiency can be achieved beyond the exploration of sparsity alone. This provides additional insights into the power of exploring low-dimensional structures in high-dimensional regression: homogeneity and sparsity. Our results also shed lights on the properties of the fussed Lasso. The newly developed method is further illustrated by simulation studies and applications to real data. Supplementary materials for this article are available online.
| S-EPMC4465377 | biostudies-literature
Project description:Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare premature aging disorder characterized by short stature and atherosclerosis-induced death within teenage years. A 13-year-old male diagnosed with HGPS was administered three intravenous infusions of allogeneic cord blood (CB) cells from unrelated donors at four-month intervals to evaluate the safety and its therapeutic efficacy. Adverse events were monitored in addition to height, weight, laboratory blood tests, joint range of motion (ROM), and carotid Doppler. Cytokine and receptor assays were also performed. The patient exhibited an increase in growth rate for both height and weight. One year after therapy initiation, evident amelioration in pulse wave velocity, bilateral maximal intima-media thickness, and dyslipidemic status were observed, which were in abrupt aggravation prior to treatment. Further, an increase in flexibility occurred in some joints of the upper extremities. No serious adverse events were observed throughout the study period and one year beyond. A molecular assay revealed downregulation of proinflammatory and atherosclerosis, representing cytokine expressions following the administration of CB cells. This is the first reported case of an allogeneic CB trial in a patient with HGPS showing therapeutic effects of CB with improvements in anthropometric measures, joint ROM with amelioration of atherosclerosis, and dyslipidemia induced by anti-inflammatory and anti-atherosclerotic responses.
| S-EPMC8619635 | biostudies-literature
Project description:Hutchinson-Gilford progeria syndrome (HGPS) is a rare lethal genetic disorder characterized by symptoms reminiscent of accelerated aging. The major underlying genetic cause is a substitution mutation in the gene coding for lamin A, causing the production of a toxic isoform called progerin. Here we show that reduction of lamin A/progerin by a single-dose systemic administration of adeno-associated virus-delivered CRISPR-Cas9 components suppresses HGPS in a mouse model.
| S-EPMC6541418 | biostudies-literature
Project description:Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare lethal genetic disorder characterized with symptoms reminiscent of accelerated aging. The major underlying genetic cause is a substitution mutation in the gene coding for lamin A, causing the production of a toxic isoform called progerin. Here we show the RNA sequencing analyses performed on primary mouse fibroblasts of different genotypes (in terms of Progeria; Cas9 background) treated with Cas9 guide RNAs targeting Lmna/Progerin. The mouse genetic background in (1) Pro/Pro;Cas9/+: homozygous for Progeria and heterozygous for transgenic Cas9 The mouse genetic background in (2) Pro/+; +/+: heterozygous for Progeria and no transgenic Cas9 (wild type) The mouse genetic background in (3) +/+;Cas9/+: no Progeria (wild type) and heterozygous for transgenic Cas9
2019-02-15 | GSE122865 | GEO
Project description:Hutchinson-Gilford progeria syndrome (HGPS) is an important model disease for premature ageing. Affected children appear healthy at birth, but develop the first symptoms during their first year of life. They die at an average age of 13 years, mostly because of myocardial infarction or stroke. Classical progeria is caused by the heterozygous point mutation c.1824C>T in the LMNA gene, which activates a cryptic splice site. The affected protein cannot be processed correctly to mature lamin A, but is modified into a farnesylated protein truncated by 50 amino acids (progerin). Three more variations in LMNA result in the same mutant protein, but different grades of disease severity. We describe a patient with the heterozygous LMNA mutation c.1821G>A, leading to neonatal progeria with death in the first year of life. Intracellular lamin A was downregulated in the patient's fibroblasts and the ratio of progerin to lamin A was increased when compared with HGPS. It is suggestive that the ratio of farnesylated protein to mature lamin A determines the disease severity in progeria.
| S-EPMC3421121 | biostudies-literature