RARE DISEASE
Hutchinson-Gilford progeria syndrome
Hutchinson-Gilford progeria syndrome
Hutchinson-Gilford progeria syndrome
Synonyms: HGPS, Progeria
Synonyms: HGPS, Progeria
Synonyms: HGPS, Progeria
Drug discovery
8
drugs
With orphan designations
Overview
Hutchinson-Gilford Progeria Syndrome (HGPS) is an ultra-rare, autosomal dominant genetic disorder caused by a LMNA gene mutation, leading to accumulation of progerin, a toxic protein. This results in accelerated aging, growth failure, alopecia, lipodystrophy, and severe atherosclerosis. Cardiovascular complications (myocardial infarction, stroke) drive early mortality, with median survival of ~14.5 years [1][5][7][10]. Diagnosis is clinical and confirmed via genetic testing [6][16].
Therapies
Lonafarnib (farnesyltransferase inhibitor): FDA-approved, extends lifespan by ~2.5 years [8][9].
Combination therapies: Triple therapy (lonafarnib + pravastatin + zoledronate) improves cardiovascular outcomes [3][9].
Investigational approaches: CRISPR-based gene editing, rapamycin, vitamin D supplementation, and microbiome modulation [3][5][12].
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare skin diseases
Research Papers
652 drug discovery papers about Hutchinson-Gilford progeria syndrome, with 6 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
652 drug discovery papers about Hutchinson-Gilford progeria syndrome, with 6 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-09-17 | HMGA1-HP1β axis regulates premature aging in Hutchinson-Gilford progeria syndrome through chromatin remodeling.
Hutchinson‑Gilford progeria syndrome (HGPS) is a rare premature aging disorder caused by mutations in the LMNA gene. High mobility group A1 (HMGA1) exhibits differential expression patterns across aging models. However, its roles and mechanisms in aging remain unclear. Here, we show a positive correlation between HMGA1 and the heterochromatin protein HP1β in multiple tissues of LmnaG609G/G609G, a classic genetic mouse model of HGPS to recapitulate typical premature aging features, and naturally aging mice, and HP1β was decreased in Hmga1-/- mice. We further demonstrate that HMGA1 mitigates HGPS cellular senescence in a HP1β-dependent manner. Multi-omics reveals that HP1β downregulates angiopoietin-like protein 2 (ANGPTL2) by reducing chromatin accessibility, thereby suppressing SASP factors, and thus, alleviating senescence. Furthermore, HMGA1 stabilizes HP1β by recruiting de-ubiquitinating enzyme USP7. Based on the binding region of HMGA1 with HP1β and USP7, we develop a unique HMGA1 peptide (UHP) that prevents HP1β degradation, thereby ameliorating HGPS cellular senescence and significantly extending the lifespan of LmnaG609G/G609G mice. Our findings elucidate a critical HMGA1-HP1β axis in premature aging and suggest that therapeutic strategies based on UHP may hold promise for HGPS.
2026-04-10 | The senescence-inhibitory p53 isoform Δ133p53α represses the proinflammatory chemokine CXCL10 in progeria model mice and naturally aged mice.
Δ133p53α is a naturally occurring isoform of the human p53 protein that inhibits p53-mediated cellular senescence. We previously reported that transgenic expression of this senescence-inhibitory p53 isoform counteracts aging-associated pathological changes in progeria model mice (heterozygous Lmna G609G/+ ). The anti-aging effect of Δ133p53α was attributed in part to reduced levels of the proinflammatory cytokine IL-6. This study aims to comprehensively profile Δ133p53α-induced changes in cytokines and chemokines. A Luminex-based multiplex quantitative assay was performed using mouse serum samples from transgenic Δ133p53α-expressing Lmna G609G/+ mice and non-expressing controls. Quantitative RT-PCR and RNA in situ hybridization assays were used to assess Cxcl10 expression in mouse tissues. In addition, gene expression datasets from human tissues were analyzed. We confirmed Δ133p53α-mediated repression of serum IL-6 levels. We also found that Δ133p53α reduced serum levels of CXCL1, IL-1α, and CXCL10. We further characterized CXCL10, which has not previously been associated with progeria in mice or humans. Consistent with reduced serum CXCL10 levels, both young (15-week-old) and old (10-month-old) Δ133p53α-expressing Lmna G609G/+ mice showed reduced Cxcl10 expression in the liver, spleen, and brain, major organs that produce CXCL10, compared with age-matched non-expressing controls. In naturally aged wild-type mice (2 years old), transgenic Δ133p53α expression also significantly repressed Cxcl10 expression in the spleen and brain. An inverse association between CXCL10 and Δ133p53α levels was observed in human spleen tissues, suggesting physiological relevance to human aging. CXCL10, a proinflammatory chemokine elevated in both accelerated and natural aging, is a potential target of the anti-inflammatory activity of Δ133p53α.
2026-04-03 | Abstract 6001: Senescence-inhibitory Δ133p53α mitigates accelerated ageing in mice
Abstract Hutchinson-Gilford progeria syndrome (HGPS), a premature aging disorder caused by a de novo LMNA G608G mutation, is characterized by the accumulation of DNA damage and persistent inflammation, which drive accelerated aging and lead to severe clinical manifestations, including skin atrophy, alopecia, and progressive deterioration of the aortic wall due to loss of vascular smooth muscle cells, resulting in severely shortened lifespan. Mouse models of HGPS recapitulate these pathological aging phenotypes, including cardiovascular defects, increased cellular senescence, DNA damage accumulation, systemic inflammation, and shortened lifespan.The human p53 isoform Δ133p53α, which lacks the N-terminal 133 amino acids, is a naturally occurring truncated variant with distinct biological functions. In HGPS patient-derived fibroblasts, Δ133p53α suppresses cellular senescence, reduces pro-inflammatory IL-6 production, limits DNA-damage accumulation, and extends replicative lifespan. These findings suggest that Δ133p53α selectively attenuates p53-mediated cell-cycle arrest and senescence while preserving DNA-repair functions.Here, in a heterozygous HGPS mouse model, we show that transgenic expression of Δ133p53α reproduces these in vitro-observed effects across multiple organs in vivo and extends median lifespan by approximately 10% (387 vs. 358 days, P = 0.0235). In the aorta and skin, Δ133p53α mitigates progeria-associated pathological changes and preserves tissue integrity. Δ133p53α also mitigates spinal kyphosis characteristic of the HGPS mouse phenotype. RNA-sequencing analysis suggests that Δ133p53α promotes mitochondrial function and metabolic fitness. The effects of Δ133p53α in naturally aging mice are under investigation. Our human expression database analysis shows an age-associated downregulation of Δ133p53α in multiple human tissues, including aorta and skin.This study suggests not only a Δ133p53α-based therapeutic approach for HGPS but also broader interventions for preventing or delaying aging. Citation Format: Leo Yamada, Huaitian Liu, Natalia Von Muhlinen, Curtis C. Harris, Izumi Horikawa, . Senescence-inhibitory Δ133p53α mitigates accelerated ageing in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6001.
2026-01-09 | Senescence-inhibitory Δ133p53α counteracts accelerated ageing and mortality.
Research on progeria not only contributes to treatments for the disease but also enhances our understanding of physiological ageing1. Mouse models of progeria recapitulate pathological ageing phenotypes seen in patients, including cardiovascular defects, increased cellular senescence, systemic inflammation, DNA damage accumulation, and shortened lifespan2. In cultured cells from Hutchinson-Gilford progeria syndrome (HGPS) patients, the human p53 isoform Δ133p53α was previously shown to inhibit p53-mediated cellular senescence, proinflammatory IL-6 production, and DNA damage accumulation, and to extend cellular replicative lifespan3. Here we show that, in a heterozygous HGPS mouse model4, transgenic expression of Δ133p53α reproduces these in vitro-observed effects across multiple organs in vivo and extends median lifespan by 11% (387 versus 349 days, P = 0.0379). In the aorta and skin, Δ133p53α abrogates progeria-characteristic pathological changes and preserves tissue integrity. Our data further suggest that Δ133p53α may promote a broad spectrum of ageing-counteracting mechanisms, including bone homeostasis, metabolic fitness, antioxidant defense, youthful epigenome, and tissue stemness. Together with the anti-inflammatory and tissue-preserving effects of Δ133p53α in naturally aged mice and its age-associated downregulation in human tissues, this study suggests that Δ133p53α-based therapeutic strategies may be applicable not only to HGPS but also as broader interventions for preventing or delaying ageing.
2025-12-24 | Why and How Are Infants with Hutchinson-Gilford Progeria Syndrome Born Without Severe Manifestations?
Children with Hutchinson-Gilford progeria syndrome (HGPS) are born without height and weight abnormalities, and postnatal development is delayed from two months of age. The pathophysiological manifestations of HGPS can be categorized into the three tissue systems that are primarily affected: bone and cartilage, the smooth muscular layer of the vasculature, and the dermis layer. To understand the biology of the syndrome's complications resulting from the inherited dominant mutation of the LMNA gene, HGPS has to be considered in embryogenesis. Since the development of the primarily affected HGPS tissues involves a simultaneous contribution of mesodermal and neural crest cells, we hypothesized that the stochastic and heterogeneous coexistence of mesoderm and neural crest cells might be crucial for the onset and manifestation of HGPS. In addition, the expression of Lamin A and/or progerin during embryonic development tends to accumulate in the cell nucleus, causing the syndrome manifestation. Then, how and why are infants with the LMNA gene mutation born without severe deviations? Migration is a distinguishing property of mesoderm and neural crest cells, so that they are continuously subjected to mechanical stimuli throughout development and require normal lamina function. However, the viscoelastic property and the mechanosensor capability to respond to mechanical stress of the HGPS cell nucleus are disturbed. Despite the presence of progerin in development, we assume that high levels of Lamin B1 in cells determine the delayed onset of HGPS after birth. We also hypothesized that progerin toxicity could be managed and prevented, potentially allowing for rescue by the presence of Lamin B1.
small molecules
2026-09-17 | CK2α restriction of STING accumulation underlies systemic aging.
Chronic activation of the cGAS-STING pathway drives inflammaging and cellular senescence. Although nuclear envelope (NE) barrier failure leading to cytoplasmic chromatin leakage is a key trigger, the molecular mechanisms governing STING activity at the NE during aging remain poorly understood. Here, we identify lamin A/C (LMNA) as a critical NE scaffold that orchestrates STING regulation by recruiting both STING and Casein Kinase 2 (CK2α). We demonstrate that LMNA facilitates the phosphorylation of STING at Ser366 by CK2α, which promotes STING turnover and restricts its accumulation, thereby attenuating pathway activation and mitigating senescence in myeloid cells as well as systemic aging. Strikingly, pharmacologic STING inhibition in vivo robustly rescues progeroid phenotypes-including loss of bone density and multi-tissue senescence-and extends lifespan in progeroid mouse models. Moreover, H-151 treatment also ameliorates the premature aging phenotypes induced by myeloid-specific CK2α ablation. In contrast, constitutive STING ablation yields limited survival benefits, revealing that controlled attenuation of STING signaling, rather than complete elimination, drives therapeutic efficacy. Our findings establish the LMNA-CK2-STING axis as a key biochemical mechanism that suppresses innate immune activation at the NE, offering a promising strategy for ameliorating aging and progeroid pathologies.
2026-09-17 | Hierarchical homeostatic failure in Hutchinson-Gilford progeria syndrome: From nuclear lesion to systemic decline.
Hutchinson-Gilford progeria syndrome (HGPS) is a fatal laminopathy caused by an LMNA mutation that generates progerin, a permanently farnesylated, truncated form of prelamin A. Although progerin's structural effects are well established, prior reviews have largely cataloged its downstream consequences, genome instability, proteostasis failure, inflammation, stem-cell dysfunction and matrix remodeling, as parallel, largely independent processes. Here, two decades of mechanistic evidence are reorganized into a single evidence-ranked hierarchy spanning four interconnected levels of homeostasis, nuclear, cellular, tissue and organismal, that explicitly separates established mechanisms from inferred cross-scale links. Progerin perturbs post-mitotic nuclear reassembly, but several defining abnormalities emerge or intensify during interphase and across successive cell generations, indicating progressive maintenance failure rather than a purely static structural model. Nuclear dysfunction is associated with impaired proteostasis, stress adaptation and lineage competence; these cellular defects can be amplified by extracellular-matrix remodeling, chronic inflammation, and reduced regenerative capacity. Evidence is strongest for nuclear and cellular mechanisms, whereas a continuous nucleus-to-organism sequence remains an integrative, testable model. When fragmented mechanisms are ordered across biological scales, this framework helps explain disease latency, tissue selectivity, partial reversibility, and the rationale for combination therapy. Lonafarnib, proteostasis-directed interventions, JAK-STAT inhibition and genome-, RNA-, and progerin-directed strategies are therefore considered complementary approaches acting at distinct levels of the hierarchy. HGPS is not a replica of physiological aging, but a genetically defined system that reveals how persistent nuclear stress can progressively erode conserved adaptive networks.
2026-08-17 | Excessive disulfide bonds in Lamin A/C contribute to premature human aging.
Nuclear lamins provide structural integrity to the nuclear envelope through coiled-coil dimer meshworks. Lamin A contains a C-terminal immunoglobulin (Ig)-like domain and a cysteine-rich unstructured tail, whereas lamin C lacks the latter, retaining only one cysteine within the Ig-like domain. Mutations R435C and R471C in the Ig-like domain are linked to progeroid syndromes, fatal disorders characterized by premature aging. Here, we elucidate a pathogenic mechanism driven by aberrant disulfide cross-linking. We found that the R435C mutation, but not R471C, facilitates successive disulfide bond formation between Ig-like domains in vitro using purified recombinant proteins, causing nuclear deformation in lamin C-overexpressing cells. In lamin A-overexpressing cells, both R435C and R471C mutations induce additional intermolecular disulfide bonds involving the lamin A-specific cysteine residues in the C-terminal tail. Importantly, we demonstrate that glutathione and its precursor, N-acetyl cysteine, can disrupt these aberrant bonds. Using Caenorhabditis elegans as an in vivo model, we show that the orthologous cysteine mutation causes progeria phenotypes, which are suppressed by antioxidant treatment. These findings identify aberrant disulfide cross-linking as a key driver of progeria and suggest antioxidant therapies as a potential treatment strategy. Our study offers broader implications for vertebrate aging, suggesting that oxidative stress-mediated changes in lamin architecture are a conserved mechanism contributing to the loss of nuclear structural integrity and age-dependent nuclear aberration.
2026-08-07 | Attenuating LRRK2 activity ameliorates progerin-induced aging phenotypes in HGPS models and during physiological aging
Abstract Hutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare premature aging disorder caused by progerin, a truncated lamin A variant generated by a silent de novo mutation activating a cryptic splice site in LMNA . The resulting morphological, epigenetic, genomic, and proteostasic defects closely recapitulate some hallmarks of cellular aging. Here, we identify the Parkinson’s disease-associated kinase LRRK2 as a critical regulator of HGPS pathology and physiological aging. Rab29-mediated LRRK2 hyperactivation exacerbates progerin-induced cellular aging, whereas LRRK2 knockdown or overexpression of its opposing phosphatase, PPM1H, ameliorates progerin-induced defects. Progerin-expressing cells exhibit altered intracellular trafficking, which is regulated by LRRK2 and links diverse aging hallmarks. Consistent with these findings, reducing LRRK2 levels mitigates cellular aging phenotypes in physiologically aged cells, and loss of the C. elegans ortholog lrk-1 preserves aging-associated loss of motility and extends organismal lifespan. Together, our findings establish LRRK2 as a central node in cellular aging and position it as a potential therapeutic target for aging-related defects in both HGPS and physiological aging.
2026-08-04 | Hutchinson Gilford Syndrome - Literature Review
Hutchinson–Gilford Progeria Syndrome (HGPS) is a rare, progressive genetic disorder characterized by accelerated aging in children due to mutations in the LMNA gene, resulting in the accumulation of the abnormal protein progerin. Although affected children appear healthy at birth, clinical manifestations such as growth retardation, alopecia, lipodystrophy, skeletal abnormalities, and premature cardiovascular disease typically develop within the first two years of life. Cardiovascular complications remain the leading cause of mortality, with an average life expectancy of approximately 14–15 years. This literature review summarizes the epidemiology, genetic basis, molecular pathophysiology, clinical manifestations, diagnostic approaches, and current management strategies for HGPS. It also highlights recent therapeutic advances, including lonafarnib, mTOR inhibitors, antisense oligonucleotide therapy, and gene-editing technologies such as CRISPR-Cas9 protein, which offer promising future treatment options. Early diagnosis through molecular genetic testing and multidisciplinary management are essential for improving survival and quality of life. Continued research into disease mechanisms and targeted therapies is crucial for developing effective long-term treatments for this devastating disorder.
oligonucleotides
2026-07-02 | AI-driven therapeutic antisense oligonucleotide for processing-deficient progeroid laminopathies.
Progeroid laminopathies (PLs), including Hutchinson-Gilford progeria syndrome (HGPS), are rare premature aging disorders in which cardiovascular complications drive early mortality. Antisense oligonucleotides (ASOs) represent a promising therapeutic strategy, yet optimal design principles and their impact on cardiovascular pathology remain insufficiently defined. We developed an AI-driven pipeline to design ASOs targeting the 3'UTR of LMNA transcripts to suppress processing-deficient pathogenic lamin A isoforms. Lead candidates were evaluated in patient-derived induced pluripotent stem cell-derived cardiomyocytes (PL-iCMs), 3D cardiac organoids, and LMNA transgenic mouse models. Efficacy, toxicity, and systemic transcriptional responses were assessed using molecular, histological, and serum biochemical analyses. The optimized ASO, LM2556, selectively reduced progerin and farnesylated pre-lamin A expression while preserving lamin C. LM2556 mitigated cellular senescence and improved structural and functional phenotypes in PL-iCMs and cardiac organoids. In vivo, LM2556 decreased pathogenic lamin A isoforms across multiple tissues without evidence of hepatotoxicity or nephrotoxicity. Long-term administration ameliorated progeroid features, improved cardiovascular pathology, extended median lifespan by 82.86%, and enhanced overall healthspan in LMNA transgenic mice. These findings establish an AI-based framework for therapeutic ASO design and provide proof-of-concept evidence that targeting the 3'UTR of LMNA transcripts can effectively suppress pathogenic lamin A isoforms and ameliorate systemic progeroid phenotypes. This work was funded by the National Natural Science Foundation of China (82450116 and 82502251).
2026-06-18 | Biomarkers and therapies associated with Hutchinson-Gilford Progeria Syndrome.
Hutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare premature aging disorder caused predominantly by a de novo LMNA c.1824C>T mutation that produces progerin, a truncated and permanently farnesylated lamin A isoform. Progerin accumulation disrupts nuclear lamina integrity and chromatin organization, inducing persistent DNA damage responses, telomere attrition, mitochondrial dysfunction, and cellular senescence. These processes drive a multisystem clinical phenotype characterized by growth impairment, lipodystrophy, musculoskeletal abnormalities, and rapidly progressive vascular disease, with cardiovascular events as the leading cause of mortality. Biomarkers could be used in clinical trials and preclinical models for research purposes. Current candidates span four major categories: (i) molecular markers, including LMNA genotype, progerin levels, γH2AX/pATM signaling, telomere shortening, and epigenetic alterations; (ii) cellular markers reflecting oxidative stress, mitochondrial impairment, and senescence-associated secretory phenotype (SASP); (iii) systemic inflammatory and immune mediators; and (iv) vascular structural and functional indices such as arterial stiffness and endothelial dysfunction, which correlate strongly with survival. Preclinical progeroid mouse models and LMNA-edited minipigs have facilitated translational validation of these biomarker axes. Therapeutic approaches now extend beyond farnesyltransferase inhibition. Lonafarnib improves vascular outcomes and survival; however, persistent cardiovascular decline indicates residual unmet need. Emerging interventions-including mTOR modulation, senolytics, anti-inflammatory agents, metabolic support, antisense oligonucleotides, and gene-editing strategies targeting progerin production-may benefit from biomarker-guided implementation. The integration of multi-parameter biomarker panels with mechanism-based combination therapies represents a promising direction toward precision management in HGPS.
2026-04-03 | STING causes replication stress and nascent DNA degradation via SAMHD1.
STING is a key innate immune adaptor, classically activated by cytosolic DNA via cGAS-cGAMP to induce type I interferon signaling. While its cytoplasmic role is well defined, recent studies reveal that STING participates in non-canonical signaling pathways and localizes at the nuclear envelope and chromatin, where its functions remain poorly understood. In Hutchinson Gilford Progeria Syndrome (HGPS), a premature aging disease caused by expression of lamin A mutant protein named progerin, STING accumulates in the nucleus and drives chronic inflammation. Here, we show that replication stress (RS) is a trigger of STING nuclear accumulation and binding to chromatin. In addition, we uncover a previously unrecognized role for nuclear STING binding to nascent DNA and promoting RS in progeria and tumor cells. Mechanistically, STING contributes to replication fork slowing and stalling by limiting dNTPs availability. In addition, STING hinders replication fork protection/stability upon stalling, by facilitating MRE11-mediated nascent DNA degradation (NDD). We also find that STING contribution to depletion of dNTPs and NDD is mediated by SAMHD1. As such, SAMHD1 knockdown phenocopies STING abrogation in progeria cells and rescues replication fork speed and stability in STING-overexpressing tumor cells. These findings define a pathological STING-SAMHD1 axis that drives RS and genome instability in both progeria cells and tumor cells with elevated STING activity, uncovering a feedforward loop between innate immune signaling and impaired DNA replication.
2025-10-28 | Selection of specific and efficient siRNAs in new cellular model for Hutchinson-Gilford progeria syndrome therapy.
Hutchinson-Gilford progeria syndrome is a fatal genetic disorder caused by a point mutation in the gene encoding the nuclear envelope protein lamin A/C. The most frequent mutation leads to the synthesis of a shorter version of lamin A named progerin, which accumulates under the nuclear membrane, leading to nuclear lamina disorganization and affecting gene expression and signaling. In our study, we designed a set of small interfering RNA (siRNA) sequences for the selective and efficient downregulation of progerin level and tested them in our new progeria HeLa cellular model and patients' fibroblasts. We showed efficient downregulation of progerin level without affecting endogenous lamin A or lamin C levels. Additionally, we observed an additive effect of the combination of our siRNAs with lonafarnib-the sole drug approved by the Food and Drug Administration for progeria syndrome therapy. The selected siRNAs also worked efficiently in all three tested patient fibroblast lines, even after extended post-transfection incubation with low siRNA doses. Therefore, we believe that the development of genetic drugs may be a promising therapeutic tool for Hutchinson-Gilford progeria syndrome.
2025-08-28 | Deregulated miR-145 and miR-27b in Hutchinson-Gilford progeria syndrome: implications for adipogenesis.
Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal disorder that causes premature aging, affecting approximately one in 4-8 million births. Most cases result from a mutation in the lamin A/C (LMNA) gene, leading to the production of progerin, an aberrant lamin A variant that disrupts nuclear architecture and alters gene expression, including microRNA (miRNA) deregulation. This study aimed to investigate the molecular mechanisms underlying HGPS and aging using global miRNA sequencing to identify key deregulated miRNAs. Both miR-145 and miR-27b were significantly altered in HGPS. Functional experiments further revealed their crucial role in adipogenesis. Downregulation of these miRNAs in HGPS cells enhanced adipocyte differentiation, whereas their upregulation in control cells suppressed this process. These findings indicate that elevated levels of miR-145-5p and miR-27b-3p impair adipogenesis, providing mechanistic insights into HGPS pathophysiology and highlight new potential therapeutic avenues for both HGPS and metabolic disorders.
gene therapies
2026-09-18 | Genomic splice-donor disruption rescues systemic disease in progeria
Abstract RNA splicing determines which protein isoforms a gene produces, and aberrant splice-site activation can cause severe disease 1,2 . In Hutchinson–Gilford progeria syndrome, a synonymous LMNA mutation strengthens a cryptic 5′ splice donor site to produce progerin, a toxic lamin A isoform driving premature cardiovascular death 3,4 . Within this cryptic donor, the activating mutation lies near the canonical GT dinucleotide required for splice-site recognition. A single guide can therefore preferentially pair with the mutant sequence while positioning Cas9 cleavage at this dinucleotide. Here we show that CRISPR/Cas9-mediated disruption of this splice site suppresses progerin without requiring precise correction of the activating mutation and prolongs lifespan in progeroid mice. In patient-derived fibroblasts and induced pluripotent stem cell-derived mesenchymal stem cells, this intervention reduced progerin by 92.7–96.8% while retaining lamin A and lamin C expression. A single neonatal injection of AAV9 carrying the corresponding mouse guide increased median survival from 115 to 279 days in Cas9-expressing Lmna G609G/G609G mice. Treatment attenuated aortic, skeletal and multiorgan pathology. Treated homozygous pairs produced 52 offspring across seven litters. These findings establish pathogenic splice signals as genomic targets for sustained suppression of toxic isoforms while retaining canonical gene output.
2026-09-03 | In Vivo Base Editing Partially Rescues Bone Dysplasia in a Mouse Model of Hutchinson-Gilford Progeria Syndrome.
Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder affecting tissues of mesenchymal origin. Most patients harbor a c.1824C>T/p.G608= variant, commonly described as G608G, in exon 11 of LMNA that leads to aberrant splicing and production of the toxic progerin protein. In addition to cardiovascular, dermal, and adipose tissue deterioration, HGPS mouse models also develop progressive bone dysplasia that occurs in patients. Here we characterize the efficacy of in vivo mutation correction with an adenine base editor (ABE) to rescue structural and functional defects in HGPS transgenic murine bone tissue. Treatment of double-copy transgenic osteoblast cultures with a lentiviral-delivered CRISPR-Cas9 ABE achieved nearly 40% gene correction in vitro, resulting in significant reduction of progerin transcripts and protein, in the absence of selective agents. Furthermore, gene correction improved progeroid osteoblasts' capacity to deposit and mineralize extracellular matrix compared to untreated cultures. In vivo, a single intravenous dose of AAV9-delivered ABE corrected the mutation, achieving ~14%, ~22%, ~10% and < 1% correction in bone by six months of age when administered at P3, P14, 1 and 4 months of age, respectively. Partially rescued bone structural and physical parameters were observed in P14-treated mice with concomitant normalization of gene transcriptional programs and intracellular signaling pathways involved in bone remodeling. This work demonstrates in vivo delivery of a locus-specific DNA base editor to bone tissue, delineates the timing of treatment required for maximum efficacy, and suggests that this system might be tailored for application to other monogenic bone disorders.
2026-07-31 | Single-cell analysis of the progeria arterial wall reveals progerin-induced progressive, cell type-specific dysfunction and somatic mutation accumulation
Abstract Background The premature aging disorder Hutchinson-Gilford Progeria Syndrome (HGPS) is caused by de novo LMNA mutations producing the aberrant Lamin A isoform progerin. HGPS patients die from cardiovascular disease, with their arteries showing extensive cellular and structural remodeling, but the mechanisms driving vascular dysfunction are not fully understood. Methods To define molecular processes underlying progressive vascular degeneration in HGPS, we performed single-cell RNA-sequencing (scRNA-seq) of aortic arch cells from LmnaG609G/G609G mice without atheroprone stimuli. These mice carry the murine equivalent of the most common HGPS-causing mutation and faithfully recapitulate the vascular phenotype. Sequencing was performed at multiple ages to capture disease-related and time-dependent transcriptional changes. We used Smart-seq2 for sequencing, due to its high sensitivity and full-length transcript coverage. Histology, immunostaining and in situ hybridization were used for arterial characterization. Results The aortic arch of LmnaG609G/G609G mice exhibited a gradual age-dependent vascular smooth muscle cell (VSMC) loss, accompanied by a transient proliferation surge, and ultimately by increased apoptosis. scRNA-seq identified transcriptionally distinct cell populations with unique features that evolved during disease progression. Disease-enriched VSMCs at early stages were characterized by elevated endoplasmic reticulum (ER) stress. With disease development, these VSMCs further underwent phenotypic switching toward a fibroblast-like state, which was predicted to expand through non-cell-autonomous mechanisms. At later stages, disease-enriched VSMCs upregulated apoptotic gene expression, partially coinciding with sustained ER stress. Furthermore, progeria VSMCs showed an increase in both DNA damage and somatic SNVs, with the increased number of SNVs correlating with high expression of ER stress, ROS and p53-related genes. In contrast, progeria-enriched fibroblasts either became activated or increased their cartilage production and showed a delayed accumulation of somatic SNVs compared to VSMCs, highlighting both a cell-type-specific progerin response and differences in somatic mutation susceptibility. Conclusions Our study shows that progerin leads to somatic mutation accumulation particularly in VSMCs, highlighting the need for early, cell-type-specific therapeutic intervention in HGPS to prevent permanent vascular tissue damage. In addition, the cell-type-specific molecular dynamics of the aortic arch VSMCs and fibroblasts during HGPS disease progression are provided in a user-friendly searchable scRNA-seq database available for preclinical research targeting vascular aging.
2026-07-15 | Analysis code for "Mutation-Agnostic Base Editing of the Progerin Farnesylation Site Rescues Hutchinson-Gilford Progeria Syndrome Phenotypes in Neuromuscular Organoids"
Analysis code accompanying Kim et al., "Mutation-agnostic base editing of the progerin farnesylation site rescues Hutchinson-Gilford progeria syndrome phenotypes in neuromuscular organoids" (Nature Communications, 2026). Four independent R scripts. single_cell_processing.R implements the single-cell RNA-seq pipeline: per-sample QC and SCTransform (v2) normalization of the HGPS, EDIT and FATE samples, anchor-based integration of the HGPS+EDIT reference, marker-based cell-type annotation, and label transfer onto the FATE query. WES_gRNA_dependent.R annotates predicted gRNA off-target sites at gene and region (exon/intron/intergenic) level. WES_gRNA_independent.R identifies condition-specific A>G/T>C adenine base-editing events from whole-exome variant calls and tests high-VAF edits for gRNA-spacer match by local alignment. WES_logo.R generates per-position base-composition sequence logos of the edit windows. Genome build: GRCh38/hg38. Two derived input tables are included. Primary sequencing data are deposited externally: single-cell RNA-seq under GEO accession GSE305237, and whole-exome sequencing under BioProject PRJNA1306877.
2026-05-22 | Discovery of NARF-interacting proteins.
Patients with Hutchinson-Gilford Progeria Syndrome manifest molecular defects in the nuclear lamina with unique phenotypic presentation in accelerated aging. The data in sum together with other biochemical and cellular studies suggested a central and critical role for the nuclear lamina in cellular aging, a process related to but separate from organismal aging. We used proteomics for unbiased discovery of NARF-interacting proteins.
other
2026-09-29 | MT-Exo-derived miR-4651 and miR-6126 coordinately regulate the SRSF1-progerin and SP1-PrPᶜ axes to attenuate vascular aging in HGPS.
Hutchinson-Gilford progeria syndrome (HGPS) is characterized by progressive vascular injury that remains incompletely controlled by therapies targeting progerin-associated pathology. Here, we investigated the therapeutic activity and molecular mechanisms of melatonin-preconditioned mesenchymal stromal cell-derived small extracellular vesicles (MT-Exo) using a patient-anchored translational framework integrating longitudinal vascular phenotyping and serial serum samples from an index patient with HGPS with independently sourced HGPS fibroblasts and endothelial-cell models. Serial HGPS serum samples exhibited increased progerin and cellular prion protein (PrPᶜ) signals, together with elevated troponin I, in the setting of progressive multisite vasculopathy. HGPS serum impaired endothelial morphology and angiogenic network formation, whereas recombinant PrPᶜ induced cellular-stress, inflammatory, chromatin, and nuclear-lamina abnormalities. MT-Exo attenuated HGPS serum-induced endothelial dysfunction and reduced progerin, PrPᶜ, p16, and γH2AX abnormalities and lamin A/C disorganization in HGPS fibroblasts. Mechanistically, MT-Exo-enriched miR-4651 directly targeted SRSF1 and attenuated progerin-associated nuclear-lamina abnormalities, whereas MT-Exo-enriched miR-6126 directly targeted SP1 and reduced PRNP/PrPᶜ expression. These two microRNAs therefore acted through distinct but complementary regulatory pathways involving SRSF1-progerin and SP1-PRNP/PrPᶜ signaling. A prespecified patient-informed virtual-cohort analysis of 15 treatment strategies further prioritized a cluster of lonafarnib-based combinations containing MT-Exo, dual miRNA, or miR-6126 for subsequent experimental evaluation, although no single regimen was consistently top-ranked across models. Collectively, these findings identify complementary miR-4651-SRSF1-progerin and miR-6126-SP1-PRNP/PrPᶜ regulatory axes in HGPS vascular aging and provide a mechanistic rationale for preclinical evaluation of MT-Exo- and miRNA-based combination strategies.
2026-08-10 | Targeting RANKL Prevents Bone Loss, Improves Muscle Function and Extends Lifespan in Progeroid Mice.
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by the early development of pathological features associated with aging, ultimately leading to premature death. HGPS primarily affects tissues of mesenchymal origin, as evidenced by the clinical manifestations characteristic of this premature aging disorder, including, but not limited to, osteoporosis, muscle wasting, lipodystrophy, and cardiovascular disease. In this study, we used preclinical mouse models and both genetic and translational approaches to investigate whether an antiresorptive strategy, based on RANKL targeting, ameliorated the bone loss phenotype of progeroid mice. Here we show that osteocyte-derived RANKL deletion in the Zmpste24-/- mouse model of HGPS reverted bone loss in both long bones and vertebrae. These mice also exhibited increased grip strength and improved endurance capacity. Furthermore, Zmpste24-/- mice showed increased survival upon osteocyte-specific RANKL deletion. Notably, the use of a translational approach based on the administration of a neutralizing antibody against RANKL also restored bone mass, reduced muscle fibrosis, and extended the lifespan of Zmpste24-/- mice. Altogether, these findings support that targeting RANKL exerts a beneficial effect on both osseous and extra-osseous phenotypes of HGPS, suggesting the potential of this therapeutic approach to explore in the treatment of this disease.
2025-08-07 | The senescence-inhibitory p53 isoform Δ133p53α: enhancing cancer immunotherapy and exploring novel therapeutic approaches for senescence-associated diseases.
Δ133p53α is a naturally occurring isoform of the tumor suppressor protein p53. Δ133p53α functions as a physiological dominant-negative inhibitor of the full-length p53 protein (commonly referred to as p53). Δ133p53α preferentially inhibits p53-mediated cellular senescence, while it does not inhibit, or may even promote, p53-mediated DNA repair. Owing to this selective inhibitory activity that preserves genome stability, Δ133p53α represents a promising target for enhancement in the prevention and treatment of diseases associated with increased senescence of normal cells. These diseases include Alzheimer's and other neurodegenerative diseases, premature aging diseases such as Hutchinson-Gilford progeria syndrome (HGPS), and idiopathic pulmonary fibrosis (IPF). Current cell-based therapies, which are limited by increased cellular senescence, may also benefit from Δ133p53α-mediated improvements. As an initial application of Δ133p53α in improving therapeutic cells, we here introduce Δ133p53α-armored chimeric antigen receptor (CAR)-T cells. Based on our previous and ongoing studies using various types of senescent human cells in vitro, we also discuss the importance of further exploring the therapeutic potentials of Δ133p53α, with particular focus on HGPS and IPF. The development of mouse models facilitates in vivo evaluation of the therapeutic effects of Δ133p53α, potentially leading to future clinical applications.
2025-05-01 | Mesenchymal Stem Cell Therapy for Hutchinson-Gilford Progeria: Improvements in Arterial Stiffness and Bone Mineral Density in a Single Case.
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder that cause premature aging due to LMNA mutations and progerin accumulation. Although lonafarnib, an FDA-approved farnesyltransferase inhibitor, offers modest extension of life, the disease remains progressive. As progeria is associated with stem cell depletion and mesenchymal stem cell (MSC) therapy has shown efficacy in treating atherosclerosis, we aimed to evaluate its efficacy and safety in HGPS. A 7-year-old male with classic HGPS and preexisting severe cerebrovascular disease received four intravenous infusion of bone marrow-derived MSCs (2.5 × 10⁵ cells/kg) over 8 months. Growth, metabolic, cardiovascular, musculoskeletal, auditory, and inflammatory cytokines were monitored throughout the study. Prophylactic enoxaparin was administered to prevent vascular complications. MSC therapy was associated with improved lean body mass (11.5%), bone mineral density (L-spine z-score: 0.55 → 2.03), reduced arterial stiffness (9.98% reductionin pulse wave velocity), joint range of motion, dentition, and decreased sICAM-1 levels. However, Cardiovascular deterioration continued, and the patient passed away 10 months after the fourth dose, likely due to progression of the underlying vascular disease. No severe adverse effects were attributed to MSC therapy. MSC therapy may offer short-term benefits in arterial stiffness, bone health and inflammation in HGPS without notable safety concerns. Further studies are warranted to validate these findings, explore earlier intervention, and determine long-term efficacy and optimal dosing strategies.
2025-02-18 | Improved Arterial Stiffness and Bone Mineral Density in Hutchinson–Gilford Progeria Treated with Bone Marrow-Derived Mesenchymal Stem Cells: A Case Study and Literature Review
Background/Objectives: Hutchinson‒Gilford progeria syndrome (HGPS) is a rare ge-netic disorder caused by LMNA gene mutations, leading to the accumulation of farne-sylated progerin. It is characterized by severe growth failure, premature aging, rapid progression of atherosclerosis and cardiovascular- related early disease. Lonafarnib, a farnesyltransferase inhibitor, extends life expectancy in HGPS, but it does not stop progression. As Progeria is associated with stem cell depletion and mesenchymal stem cell (MSC) therapy has shown efficacy in treating atherosclerosis, we aimed to evaluate its efficacy and safety in HGPS. Methods: A 7-year-old male with classic HGPS re-ceived intravenous bone marrow-derived MSCs (2.5x10⁵ cells/kg) over four sessions. The first three sessions were administered at one-month intervals, followed by a final session six months later (Months 0, 1, 2, and 8). The study protocol included compre-hensive baseline assessment (growth, metabolic, cardiovascular, musculoskeletal, au-ditory and proinflammatory markers including cytokines). Preventive enoxaparin was administered to mitigate vascular complications. Results: MSC therapy increased lean body mass (total: pre -0.8% vs. post 11.5%), improved BMD (TBLH: pre -20.5% vs. post +2.8%, lumbar: pre +0.6% vs. post +26.5%), decreased PWV by a mean of 9.98%, and promoted weight gain (z score change: pre -1.13 to post + 0.75). Additionally, it en-hanced ROM, improved the low frequency of hearing loss, and consistently reduced sICAM-1. Conclusions: MSC therapy demonstrated potential efficacy in improving clinical outcomes, including arterial stiffness and bone mineral density, with no severe safety concerns related to therapy. Further research is needed for long-term efficacy and to maximize benefits.
proteins
2026-09-17 | HMGA1-HP1β axis regulates premature aging in Hutchinson-Gilford progeria syndrome through chromatin remodeling.
Hutchinson‑Gilford progeria syndrome (HGPS) is a rare premature aging disorder caused by mutations in the LMNA gene. High mobility group A1 (HMGA1) exhibits differential expression patterns across aging models. However, its roles and mechanisms in aging remain unclear. Here, we show a positive correlation between HMGA1 and the heterochromatin protein HP1β in multiple tissues of LmnaG609G/G609G, a classic genetic mouse model of HGPS to recapitulate typical premature aging features, and naturally aging mice, and HP1β was decreased in Hmga1-/- mice. We further demonstrate that HMGA1 mitigates HGPS cellular senescence in a HP1β-dependent manner. Multi-omics reveals that HP1β downregulates angiopoietin-like protein 2 (ANGPTL2) by reducing chromatin accessibility, thereby suppressing SASP factors, and thus, alleviating senescence. Furthermore, HMGA1 stabilizes HP1β by recruiting de-ubiquitinating enzyme USP7. Based on the binding region of HMGA1 with HP1β and USP7, we develop a unique HMGA1 peptide (UHP) that prevents HP1β degradation, thereby ameliorating HGPS cellular senescence and significantly extending the lifespan of LmnaG609G/G609G mice. Our findings elucidate a critical HMGA1-HP1β axis in premature aging and suggest that therapeutic strategies based on UHP may hold promise for HGPS.
2026-04-10 | The senescence-inhibitory p53 isoform Δ133p53α represses the proinflammatory chemokine CXCL10 in progeria model mice and naturally aged mice.
Δ133p53α is a naturally occurring isoform of the human p53 protein that inhibits p53-mediated cellular senescence. We previously reported that transgenic expression of this senescence-inhibitory p53 isoform counteracts aging-associated pathological changes in progeria model mice (heterozygous Lmna G609G/+ ). The anti-aging effect of Δ133p53α was attributed in part to reduced levels of the proinflammatory cytokine IL-6. This study aims to comprehensively profile Δ133p53α-induced changes in cytokines and chemokines. A Luminex-based multiplex quantitative assay was performed using mouse serum samples from transgenic Δ133p53α-expressing Lmna G609G/+ mice and non-expressing controls. Quantitative RT-PCR and RNA in situ hybridization assays were used to assess Cxcl10 expression in mouse tissues. In addition, gene expression datasets from human tissues were analyzed. We confirmed Δ133p53α-mediated repression of serum IL-6 levels. We also found that Δ133p53α reduced serum levels of CXCL1, IL-1α, and CXCL10. We further characterized CXCL10, which has not previously been associated with progeria in mice or humans. Consistent with reduced serum CXCL10 levels, both young (15-week-old) and old (10-month-old) Δ133p53α-expressing Lmna G609G/+ mice showed reduced Cxcl10 expression in the liver, spleen, and brain, major organs that produce CXCL10, compared with age-matched non-expressing controls. In naturally aged wild-type mice (2 years old), transgenic Δ133p53α expression also significantly repressed Cxcl10 expression in the spleen and brain. An inverse association between CXCL10 and Δ133p53α levels was observed in human spleen tissues, suggesting physiological relevance to human aging. CXCL10, a proinflammatory chemokine elevated in both accelerated and natural aging, is a potential target of the anti-inflammatory activity of Δ133p53α.
2026-04-03 | Abstract 6001: Senescence-inhibitory Δ133p53α mitigates accelerated ageing in mice
Abstract Hutchinson-Gilford progeria syndrome (HGPS), a premature aging disorder caused by a de novo LMNA G608G mutation, is characterized by the accumulation of DNA damage and persistent inflammation, which drive accelerated aging and lead to severe clinical manifestations, including skin atrophy, alopecia, and progressive deterioration of the aortic wall due to loss of vascular smooth muscle cells, resulting in severely shortened lifespan. Mouse models of HGPS recapitulate these pathological aging phenotypes, including cardiovascular defects, increased cellular senescence, DNA damage accumulation, systemic inflammation, and shortened lifespan.The human p53 isoform Δ133p53α, which lacks the N-terminal 133 amino acids, is a naturally occurring truncated variant with distinct biological functions. In HGPS patient-derived fibroblasts, Δ133p53α suppresses cellular senescence, reduces pro-inflammatory IL-6 production, limits DNA-damage accumulation, and extends replicative lifespan. These findings suggest that Δ133p53α selectively attenuates p53-mediated cell-cycle arrest and senescence while preserving DNA-repair functions.Here, in a heterozygous HGPS mouse model, we show that transgenic expression of Δ133p53α reproduces these in vitro-observed effects across multiple organs in vivo and extends median lifespan by approximately 10% (387 vs. 358 days, P = 0.0235). In the aorta and skin, Δ133p53α mitigates progeria-associated pathological changes and preserves tissue integrity. Δ133p53α also mitigates spinal kyphosis characteristic of the HGPS mouse phenotype. RNA-sequencing analysis suggests that Δ133p53α promotes mitochondrial function and metabolic fitness. The effects of Δ133p53α in naturally aging mice are under investigation. Our human expression database analysis shows an age-associated downregulation of Δ133p53α in multiple human tissues, including aorta and skin.This study suggests not only a Δ133p53α-based therapeutic approach for HGPS but also broader interventions for preventing or delaying aging. Citation Format: Leo Yamada, Huaitian Liu, Natalia Von Muhlinen, Curtis C. Harris, Izumi Horikawa, . Senescence-inhibitory Δ133p53α mitigates accelerated ageing in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6001.
2026-01-09 | Senescence-inhibitory Δ133p53α counteracts accelerated ageing and mortality.
Research on progeria not only contributes to treatments for the disease but also enhances our understanding of physiological ageing1. Mouse models of progeria recapitulate pathological ageing phenotypes seen in patients, including cardiovascular defects, increased cellular senescence, systemic inflammation, DNA damage accumulation, and shortened lifespan2. In cultured cells from Hutchinson-Gilford progeria syndrome (HGPS) patients, the human p53 isoform Δ133p53α was previously shown to inhibit p53-mediated cellular senescence, proinflammatory IL-6 production, and DNA damage accumulation, and to extend cellular replicative lifespan3. Here we show that, in a heterozygous HGPS mouse model4, transgenic expression of Δ133p53α reproduces these in vitro-observed effects across multiple organs in vivo and extends median lifespan by 11% (387 versus 349 days, P = 0.0379). In the aorta and skin, Δ133p53α abrogates progeria-characteristic pathological changes and preserves tissue integrity. Our data further suggest that Δ133p53α may promote a broad spectrum of ageing-counteracting mechanisms, including bone homeostasis, metabolic fitness, antioxidant defense, youthful epigenome, and tissue stemness. Together with the anti-inflammatory and tissue-preserving effects of Δ133p53α in naturally aged mice and its age-associated downregulation in human tissues, this study suggests that Δ133p53α-based therapeutic strategies may be applicable not only to HGPS but also as broader interventions for preventing or delaying ageing.
2025-12-24 | Why and How Are Infants with Hutchinson-Gilford Progeria Syndrome Born Without Severe Manifestations?
Children with Hutchinson-Gilford progeria syndrome (HGPS) are born without height and weight abnormalities, and postnatal development is delayed from two months of age. The pathophysiological manifestations of HGPS can be categorized into the three tissue systems that are primarily affected: bone and cartilage, the smooth muscular layer of the vasculature, and the dermis layer. To understand the biology of the syndrome's complications resulting from the inherited dominant mutation of the LMNA gene, HGPS has to be considered in embryogenesis. Since the development of the primarily affected HGPS tissues involves a simultaneous contribution of mesodermal and neural crest cells, we hypothesized that the stochastic and heterogeneous coexistence of mesoderm and neural crest cells might be crucial for the onset and manifestation of HGPS. In addition, the expression of Lamin A and/or progerin during embryonic development tends to accumulate in the cell nucleus, causing the syndrome manifestation. Then, how and why are infants with the LMNA gene mutation born without severe deviations? Migration is a distinguishing property of mesoderm and neural crest cells, so that they are continuously subjected to mechanical stimuli throughout development and require normal lamina function. However, the viscoelastic property and the mechanosensor capability to respond to mechanical stress of the HGPS cell nucleus are disturbed. Despite the presence of progerin in development, we assume that high levels of Lamin B1 in cells determine the delayed onset of HGPS after birth. We also hypothesized that progerin toxicity could be managed and prevented, potentially allowing for rescue by the presence of Lamin B1.
small molecules
2026-09-17 | CK2α restriction of STING accumulation underlies systemic aging.
Chronic activation of the cGAS-STING pathway drives inflammaging and cellular senescence. Although nuclear envelope (NE) barrier failure leading to cytoplasmic chromatin leakage is a key trigger, the molecular mechanisms governing STING activity at the NE during aging remain poorly understood. Here, we identify lamin A/C (LMNA) as a critical NE scaffold that orchestrates STING regulation by recruiting both STING and Casein Kinase 2 (CK2α). We demonstrate that LMNA facilitates the phosphorylation of STING at Ser366 by CK2α, which promotes STING turnover and restricts its accumulation, thereby attenuating pathway activation and mitigating senescence in myeloid cells as well as systemic aging. Strikingly, pharmacologic STING inhibition in vivo robustly rescues progeroid phenotypes-including loss of bone density and multi-tissue senescence-and extends lifespan in progeroid mouse models. Moreover, H-151 treatment also ameliorates the premature aging phenotypes induced by myeloid-specific CK2α ablation. In contrast, constitutive STING ablation yields limited survival benefits, revealing that controlled attenuation of STING signaling, rather than complete elimination, drives therapeutic efficacy. Our findings establish the LMNA-CK2-STING axis as a key biochemical mechanism that suppresses innate immune activation at the NE, offering a promising strategy for ameliorating aging and progeroid pathologies.
2026-09-17 | Hierarchical homeostatic failure in Hutchinson-Gilford progeria syndrome: From nuclear lesion to systemic decline.
Hutchinson-Gilford progeria syndrome (HGPS) is a fatal laminopathy caused by an LMNA mutation that generates progerin, a permanently farnesylated, truncated form of prelamin A. Although progerin's structural effects are well established, prior reviews have largely cataloged its downstream consequences, genome instability, proteostasis failure, inflammation, stem-cell dysfunction and matrix remodeling, as parallel, largely independent processes. Here, two decades of mechanistic evidence are reorganized into a single evidence-ranked hierarchy spanning four interconnected levels of homeostasis, nuclear, cellular, tissue and organismal, that explicitly separates established mechanisms from inferred cross-scale links. Progerin perturbs post-mitotic nuclear reassembly, but several defining abnormalities emerge or intensify during interphase and across successive cell generations, indicating progressive maintenance failure rather than a purely static structural model. Nuclear dysfunction is associated with impaired proteostasis, stress adaptation and lineage competence; these cellular defects can be amplified by extracellular-matrix remodeling, chronic inflammation, and reduced regenerative capacity. Evidence is strongest for nuclear and cellular mechanisms, whereas a continuous nucleus-to-organism sequence remains an integrative, testable model. When fragmented mechanisms are ordered across biological scales, this framework helps explain disease latency, tissue selectivity, partial reversibility, and the rationale for combination therapy. Lonafarnib, proteostasis-directed interventions, JAK-STAT inhibition and genome-, RNA-, and progerin-directed strategies are therefore considered complementary approaches acting at distinct levels of the hierarchy. HGPS is not a replica of physiological aging, but a genetically defined system that reveals how persistent nuclear stress can progressively erode conserved adaptive networks.
2026-08-17 | Excessive disulfide bonds in Lamin A/C contribute to premature human aging.
Nuclear lamins provide structural integrity to the nuclear envelope through coiled-coil dimer meshworks. Lamin A contains a C-terminal immunoglobulin (Ig)-like domain and a cysteine-rich unstructured tail, whereas lamin C lacks the latter, retaining only one cysteine within the Ig-like domain. Mutations R435C and R471C in the Ig-like domain are linked to progeroid syndromes, fatal disorders characterized by premature aging. Here, we elucidate a pathogenic mechanism driven by aberrant disulfide cross-linking. We found that the R435C mutation, but not R471C, facilitates successive disulfide bond formation between Ig-like domains in vitro using purified recombinant proteins, causing nuclear deformation in lamin C-overexpressing cells. In lamin A-overexpressing cells, both R435C and R471C mutations induce additional intermolecular disulfide bonds involving the lamin A-specific cysteine residues in the C-terminal tail. Importantly, we demonstrate that glutathione and its precursor, N-acetyl cysteine, can disrupt these aberrant bonds. Using Caenorhabditis elegans as an in vivo model, we show that the orthologous cysteine mutation causes progeria phenotypes, which are suppressed by antioxidant treatment. These findings identify aberrant disulfide cross-linking as a key driver of progeria and suggest antioxidant therapies as a potential treatment strategy. Our study offers broader implications for vertebrate aging, suggesting that oxidative stress-mediated changes in lamin architecture are a conserved mechanism contributing to the loss of nuclear structural integrity and age-dependent nuclear aberration.
2026-08-07 | Attenuating LRRK2 activity ameliorates progerin-induced aging phenotypes in HGPS models and during physiological aging
Abstract Hutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare premature aging disorder caused by progerin, a truncated lamin A variant generated by a silent de novo mutation activating a cryptic splice site in LMNA . The resulting morphological, epigenetic, genomic, and proteostasic defects closely recapitulate some hallmarks of cellular aging. Here, we identify the Parkinson’s disease-associated kinase LRRK2 as a critical regulator of HGPS pathology and physiological aging. Rab29-mediated LRRK2 hyperactivation exacerbates progerin-induced cellular aging, whereas LRRK2 knockdown or overexpression of its opposing phosphatase, PPM1H, ameliorates progerin-induced defects. Progerin-expressing cells exhibit altered intracellular trafficking, which is regulated by LRRK2 and links diverse aging hallmarks. Consistent with these findings, reducing LRRK2 levels mitigates cellular aging phenotypes in physiologically aged cells, and loss of the C. elegans ortholog lrk-1 preserves aging-associated loss of motility and extends organismal lifespan. Together, our findings establish LRRK2 as a central node in cellular aging and position it as a potential therapeutic target for aging-related defects in both HGPS and physiological aging.
2026-08-04 | Hutchinson Gilford Syndrome - Literature Review
Hutchinson–Gilford Progeria Syndrome (HGPS) is a rare, progressive genetic disorder characterized by accelerated aging in children due to mutations in the LMNA gene, resulting in the accumulation of the abnormal protein progerin. Although affected children appear healthy at birth, clinical manifestations such as growth retardation, alopecia, lipodystrophy, skeletal abnormalities, and premature cardiovascular disease typically develop within the first two years of life. Cardiovascular complications remain the leading cause of mortality, with an average life expectancy of approximately 14–15 years. This literature review summarizes the epidemiology, genetic basis, molecular pathophysiology, clinical manifestations, diagnostic approaches, and current management strategies for HGPS. It also highlights recent therapeutic advances, including lonafarnib, mTOR inhibitors, antisense oligonucleotide therapy, and gene-editing technologies such as CRISPR-Cas9 protein, which offer promising future treatment options. Early diagnosis through molecular genetic testing and multidisciplinary management are essential for improving survival and quality of life. Continued research into disease mechanisms and targeted therapies is crucial for developing effective long-term treatments for this devastating disorder.
oligonucleotides
2026-07-02 | AI-driven therapeutic antisense oligonucleotide for processing-deficient progeroid laminopathies.
Progeroid laminopathies (PLs), including Hutchinson-Gilford progeria syndrome (HGPS), are rare premature aging disorders in which cardiovascular complications drive early mortality. Antisense oligonucleotides (ASOs) represent a promising therapeutic strategy, yet optimal design principles and their impact on cardiovascular pathology remain insufficiently defined. We developed an AI-driven pipeline to design ASOs targeting the 3'UTR of LMNA transcripts to suppress processing-deficient pathogenic lamin A isoforms. Lead candidates were evaluated in patient-derived induced pluripotent stem cell-derived cardiomyocytes (PL-iCMs), 3D cardiac organoids, and LMNA transgenic mouse models. Efficacy, toxicity, and systemic transcriptional responses were assessed using molecular, histological, and serum biochemical analyses. The optimized ASO, LM2556, selectively reduced progerin and farnesylated pre-lamin A expression while preserving lamin C. LM2556 mitigated cellular senescence and improved structural and functional phenotypes in PL-iCMs and cardiac organoids. In vivo, LM2556 decreased pathogenic lamin A isoforms across multiple tissues without evidence of hepatotoxicity or nephrotoxicity. Long-term administration ameliorated progeroid features, improved cardiovascular pathology, extended median lifespan by 82.86%, and enhanced overall healthspan in LMNA transgenic mice. These findings establish an AI-based framework for therapeutic ASO design and provide proof-of-concept evidence that targeting the 3'UTR of LMNA transcripts can effectively suppress pathogenic lamin A isoforms and ameliorate systemic progeroid phenotypes. This work was funded by the National Natural Science Foundation of China (82450116 and 82502251).
2026-06-18 | Biomarkers and therapies associated with Hutchinson-Gilford Progeria Syndrome.
Hutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare premature aging disorder caused predominantly by a de novo LMNA c.1824C>T mutation that produces progerin, a truncated and permanently farnesylated lamin A isoform. Progerin accumulation disrupts nuclear lamina integrity and chromatin organization, inducing persistent DNA damage responses, telomere attrition, mitochondrial dysfunction, and cellular senescence. These processes drive a multisystem clinical phenotype characterized by growth impairment, lipodystrophy, musculoskeletal abnormalities, and rapidly progressive vascular disease, with cardiovascular events as the leading cause of mortality. Biomarkers could be used in clinical trials and preclinical models for research purposes. Current candidates span four major categories: (i) molecular markers, including LMNA genotype, progerin levels, γH2AX/pATM signaling, telomere shortening, and epigenetic alterations; (ii) cellular markers reflecting oxidative stress, mitochondrial impairment, and senescence-associated secretory phenotype (SASP); (iii) systemic inflammatory and immune mediators; and (iv) vascular structural and functional indices such as arterial stiffness and endothelial dysfunction, which correlate strongly with survival. Preclinical progeroid mouse models and LMNA-edited minipigs have facilitated translational validation of these biomarker axes. Therapeutic approaches now extend beyond farnesyltransferase inhibition. Lonafarnib improves vascular outcomes and survival; however, persistent cardiovascular decline indicates residual unmet need. Emerging interventions-including mTOR modulation, senolytics, anti-inflammatory agents, metabolic support, antisense oligonucleotides, and gene-editing strategies targeting progerin production-may benefit from biomarker-guided implementation. The integration of multi-parameter biomarker panels with mechanism-based combination therapies represents a promising direction toward precision management in HGPS.
2026-04-03 | STING causes replication stress and nascent DNA degradation via SAMHD1.
STING is a key innate immune adaptor, classically activated by cytosolic DNA via cGAS-cGAMP to induce type I interferon signaling. While its cytoplasmic role is well defined, recent studies reveal that STING participates in non-canonical signaling pathways and localizes at the nuclear envelope and chromatin, where its functions remain poorly understood. In Hutchinson Gilford Progeria Syndrome (HGPS), a premature aging disease caused by expression of lamin A mutant protein named progerin, STING accumulates in the nucleus and drives chronic inflammation. Here, we show that replication stress (RS) is a trigger of STING nuclear accumulation and binding to chromatin. In addition, we uncover a previously unrecognized role for nuclear STING binding to nascent DNA and promoting RS in progeria and tumor cells. Mechanistically, STING contributes to replication fork slowing and stalling by limiting dNTPs availability. In addition, STING hinders replication fork protection/stability upon stalling, by facilitating MRE11-mediated nascent DNA degradation (NDD). We also find that STING contribution to depletion of dNTPs and NDD is mediated by SAMHD1. As such, SAMHD1 knockdown phenocopies STING abrogation in progeria cells and rescues replication fork speed and stability in STING-overexpressing tumor cells. These findings define a pathological STING-SAMHD1 axis that drives RS and genome instability in both progeria cells and tumor cells with elevated STING activity, uncovering a feedforward loop between innate immune signaling and impaired DNA replication.
2025-10-28 | Selection of specific and efficient siRNAs in new cellular model for Hutchinson-Gilford progeria syndrome therapy.
Hutchinson-Gilford progeria syndrome is a fatal genetic disorder caused by a point mutation in the gene encoding the nuclear envelope protein lamin A/C. The most frequent mutation leads to the synthesis of a shorter version of lamin A named progerin, which accumulates under the nuclear membrane, leading to nuclear lamina disorganization and affecting gene expression and signaling. In our study, we designed a set of small interfering RNA (siRNA) sequences for the selective and efficient downregulation of progerin level and tested them in our new progeria HeLa cellular model and patients' fibroblasts. We showed efficient downregulation of progerin level without affecting endogenous lamin A or lamin C levels. Additionally, we observed an additive effect of the combination of our siRNAs with lonafarnib-the sole drug approved by the Food and Drug Administration for progeria syndrome therapy. The selected siRNAs also worked efficiently in all three tested patient fibroblast lines, even after extended post-transfection incubation with low siRNA doses. Therefore, we believe that the development of genetic drugs may be a promising therapeutic tool for Hutchinson-Gilford progeria syndrome.
2025-08-28 | Deregulated miR-145 and miR-27b in Hutchinson-Gilford progeria syndrome: implications for adipogenesis.
Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal disorder that causes premature aging, affecting approximately one in 4-8 million births. Most cases result from a mutation in the lamin A/C (LMNA) gene, leading to the production of progerin, an aberrant lamin A variant that disrupts nuclear architecture and alters gene expression, including microRNA (miRNA) deregulation. This study aimed to investigate the molecular mechanisms underlying HGPS and aging using global miRNA sequencing to identify key deregulated miRNAs. Both miR-145 and miR-27b were significantly altered in HGPS. Functional experiments further revealed their crucial role in adipogenesis. Downregulation of these miRNAs in HGPS cells enhanced adipocyte differentiation, whereas their upregulation in control cells suppressed this process. These findings indicate that elevated levels of miR-145-5p and miR-27b-3p impair adipogenesis, providing mechanistic insights into HGPS pathophysiology and highlight new potential therapeutic avenues for both HGPS and metabolic disorders.
gene therapies
2026-09-18 | Genomic splice-donor disruption rescues systemic disease in progeria
Abstract RNA splicing determines which protein isoforms a gene produces, and aberrant splice-site activation can cause severe disease 1,2 . In Hutchinson–Gilford progeria syndrome, a synonymous LMNA mutation strengthens a cryptic 5′ splice donor site to produce progerin, a toxic lamin A isoform driving premature cardiovascular death 3,4 . Within this cryptic donor, the activating mutation lies near the canonical GT dinucleotide required for splice-site recognition. A single guide can therefore preferentially pair with the mutant sequence while positioning Cas9 cleavage at this dinucleotide. Here we show that CRISPR/Cas9-mediated disruption of this splice site suppresses progerin without requiring precise correction of the activating mutation and prolongs lifespan in progeroid mice. In patient-derived fibroblasts and induced pluripotent stem cell-derived mesenchymal stem cells, this intervention reduced progerin by 92.7–96.8% while retaining lamin A and lamin C expression. A single neonatal injection of AAV9 carrying the corresponding mouse guide increased median survival from 115 to 279 days in Cas9-expressing Lmna G609G/G609G mice. Treatment attenuated aortic, skeletal and multiorgan pathology. Treated homozygous pairs produced 52 offspring across seven litters. These findings establish pathogenic splice signals as genomic targets for sustained suppression of toxic isoforms while retaining canonical gene output.
2026-09-03 | In Vivo Base Editing Partially Rescues Bone Dysplasia in a Mouse Model of Hutchinson-Gilford Progeria Syndrome.
Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder affecting tissues of mesenchymal origin. Most patients harbor a c.1824C>T/p.G608= variant, commonly described as G608G, in exon 11 of LMNA that leads to aberrant splicing and production of the toxic progerin protein. In addition to cardiovascular, dermal, and adipose tissue deterioration, HGPS mouse models also develop progressive bone dysplasia that occurs in patients. Here we characterize the efficacy of in vivo mutation correction with an adenine base editor (ABE) to rescue structural and functional defects in HGPS transgenic murine bone tissue. Treatment of double-copy transgenic osteoblast cultures with a lentiviral-delivered CRISPR-Cas9 ABE achieved nearly 40% gene correction in vitro, resulting in significant reduction of progerin transcripts and protein, in the absence of selective agents. Furthermore, gene correction improved progeroid osteoblasts' capacity to deposit and mineralize extracellular matrix compared to untreated cultures. In vivo, a single intravenous dose of AAV9-delivered ABE corrected the mutation, achieving ~14%, ~22%, ~10% and < 1% correction in bone by six months of age when administered at P3, P14, 1 and 4 months of age, respectively. Partially rescued bone structural and physical parameters were observed in P14-treated mice with concomitant normalization of gene transcriptional programs and intracellular signaling pathways involved in bone remodeling. This work demonstrates in vivo delivery of a locus-specific DNA base editor to bone tissue, delineates the timing of treatment required for maximum efficacy, and suggests that this system might be tailored for application to other monogenic bone disorders.
2026-07-31 | Single-cell analysis of the progeria arterial wall reveals progerin-induced progressive, cell type-specific dysfunction and somatic mutation accumulation
Abstract Background The premature aging disorder Hutchinson-Gilford Progeria Syndrome (HGPS) is caused by de novo LMNA mutations producing the aberrant Lamin A isoform progerin. HGPS patients die from cardiovascular disease, with their arteries showing extensive cellular and structural remodeling, but the mechanisms driving vascular dysfunction are not fully understood. Methods To define molecular processes underlying progressive vascular degeneration in HGPS, we performed single-cell RNA-sequencing (scRNA-seq) of aortic arch cells from LmnaG609G/G609G mice without atheroprone stimuli. These mice carry the murine equivalent of the most common HGPS-causing mutation and faithfully recapitulate the vascular phenotype. Sequencing was performed at multiple ages to capture disease-related and time-dependent transcriptional changes. We used Smart-seq2 for sequencing, due to its high sensitivity and full-length transcript coverage. Histology, immunostaining and in situ hybridization were used for arterial characterization. Results The aortic arch of LmnaG609G/G609G mice exhibited a gradual age-dependent vascular smooth muscle cell (VSMC) loss, accompanied by a transient proliferation surge, and ultimately by increased apoptosis. scRNA-seq identified transcriptionally distinct cell populations with unique features that evolved during disease progression. Disease-enriched VSMCs at early stages were characterized by elevated endoplasmic reticulum (ER) stress. With disease development, these VSMCs further underwent phenotypic switching toward a fibroblast-like state, which was predicted to expand through non-cell-autonomous mechanisms. At later stages, disease-enriched VSMCs upregulated apoptotic gene expression, partially coinciding with sustained ER stress. Furthermore, progeria VSMCs showed an increase in both DNA damage and somatic SNVs, with the increased number of SNVs correlating with high expression of ER stress, ROS and p53-related genes. In contrast, progeria-enriched fibroblasts either became activated or increased their cartilage production and showed a delayed accumulation of somatic SNVs compared to VSMCs, highlighting both a cell-type-specific progerin response and differences in somatic mutation susceptibility. Conclusions Our study shows that progerin leads to somatic mutation accumulation particularly in VSMCs, highlighting the need for early, cell-type-specific therapeutic intervention in HGPS to prevent permanent vascular tissue damage. In addition, the cell-type-specific molecular dynamics of the aortic arch VSMCs and fibroblasts during HGPS disease progression are provided in a user-friendly searchable scRNA-seq database available for preclinical research targeting vascular aging.
2026-07-15 | Analysis code for "Mutation-Agnostic Base Editing of the Progerin Farnesylation Site Rescues Hutchinson-Gilford Progeria Syndrome Phenotypes in Neuromuscular Organoids"
Analysis code accompanying Kim et al., "Mutation-agnostic base editing of the progerin farnesylation site rescues Hutchinson-Gilford progeria syndrome phenotypes in neuromuscular organoids" (Nature Communications, 2026). Four independent R scripts. single_cell_processing.R implements the single-cell RNA-seq pipeline: per-sample QC and SCTransform (v2) normalization of the HGPS, EDIT and FATE samples, anchor-based integration of the HGPS+EDIT reference, marker-based cell-type annotation, and label transfer onto the FATE query. WES_gRNA_dependent.R annotates predicted gRNA off-target sites at gene and region (exon/intron/intergenic) level. WES_gRNA_independent.R identifies condition-specific A>G/T>C adenine base-editing events from whole-exome variant calls and tests high-VAF edits for gRNA-spacer match by local alignment. WES_logo.R generates per-position base-composition sequence logos of the edit windows. Genome build: GRCh38/hg38. Two derived input tables are included. Primary sequencing data are deposited externally: single-cell RNA-seq under GEO accession GSE305237, and whole-exome sequencing under BioProject PRJNA1306877.
2026-05-22 | Discovery of NARF-interacting proteins.
Patients with Hutchinson-Gilford Progeria Syndrome manifest molecular defects in the nuclear lamina with unique phenotypic presentation in accelerated aging. The data in sum together with other biochemical and cellular studies suggested a central and critical role for the nuclear lamina in cellular aging, a process related to but separate from organismal aging. We used proteomics for unbiased discovery of NARF-interacting proteins.
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2026-09-29 | MT-Exo-derived miR-4651 and miR-6126 coordinately regulate the SRSF1-progerin and SP1-PrPᶜ axes to attenuate vascular aging in HGPS.
Hutchinson-Gilford progeria syndrome (HGPS) is characterized by progressive vascular injury that remains incompletely controlled by therapies targeting progerin-associated pathology. Here, we investigated the therapeutic activity and molecular mechanisms of melatonin-preconditioned mesenchymal stromal cell-derived small extracellular vesicles (MT-Exo) using a patient-anchored translational framework integrating longitudinal vascular phenotyping and serial serum samples from an index patient with HGPS with independently sourced HGPS fibroblasts and endothelial-cell models. Serial HGPS serum samples exhibited increased progerin and cellular prion protein (PrPᶜ) signals, together with elevated troponin I, in the setting of progressive multisite vasculopathy. HGPS serum impaired endothelial morphology and angiogenic network formation, whereas recombinant PrPᶜ induced cellular-stress, inflammatory, chromatin, and nuclear-lamina abnormalities. MT-Exo attenuated HGPS serum-induced endothelial dysfunction and reduced progerin, PrPᶜ, p16, and γH2AX abnormalities and lamin A/C disorganization in HGPS fibroblasts. Mechanistically, MT-Exo-enriched miR-4651 directly targeted SRSF1 and attenuated progerin-associated nuclear-lamina abnormalities, whereas MT-Exo-enriched miR-6126 directly targeted SP1 and reduced PRNP/PrPᶜ expression. These two microRNAs therefore acted through distinct but complementary regulatory pathways involving SRSF1-progerin and SP1-PRNP/PrPᶜ signaling. A prespecified patient-informed virtual-cohort analysis of 15 treatment strategies further prioritized a cluster of lonafarnib-based combinations containing MT-Exo, dual miRNA, or miR-6126 for subsequent experimental evaluation, although no single regimen was consistently top-ranked across models. Collectively, these findings identify complementary miR-4651-SRSF1-progerin and miR-6126-SP1-PRNP/PrPᶜ regulatory axes in HGPS vascular aging and provide a mechanistic rationale for preclinical evaluation of MT-Exo- and miRNA-based combination strategies.
2026-08-10 | Targeting RANKL Prevents Bone Loss, Improves Muscle Function and Extends Lifespan in Progeroid Mice.
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by the early development of pathological features associated with aging, ultimately leading to premature death. HGPS primarily affects tissues of mesenchymal origin, as evidenced by the clinical manifestations characteristic of this premature aging disorder, including, but not limited to, osteoporosis, muscle wasting, lipodystrophy, and cardiovascular disease. In this study, we used preclinical mouse models and both genetic and translational approaches to investigate whether an antiresorptive strategy, based on RANKL targeting, ameliorated the bone loss phenotype of progeroid mice. Here we show that osteocyte-derived RANKL deletion in the Zmpste24-/- mouse model of HGPS reverted bone loss in both long bones and vertebrae. These mice also exhibited increased grip strength and improved endurance capacity. Furthermore, Zmpste24-/- mice showed increased survival upon osteocyte-specific RANKL deletion. Notably, the use of a translational approach based on the administration of a neutralizing antibody against RANKL also restored bone mass, reduced muscle fibrosis, and extended the lifespan of Zmpste24-/- mice. Altogether, these findings support that targeting RANKL exerts a beneficial effect on both osseous and extra-osseous phenotypes of HGPS, suggesting the potential of this therapeutic approach to explore in the treatment of this disease.
2025-08-07 | The senescence-inhibitory p53 isoform Δ133p53α: enhancing cancer immunotherapy and exploring novel therapeutic approaches for senescence-associated diseases.
Δ133p53α is a naturally occurring isoform of the tumor suppressor protein p53. Δ133p53α functions as a physiological dominant-negative inhibitor of the full-length p53 protein (commonly referred to as p53). Δ133p53α preferentially inhibits p53-mediated cellular senescence, while it does not inhibit, or may even promote, p53-mediated DNA repair. Owing to this selective inhibitory activity that preserves genome stability, Δ133p53α represents a promising target for enhancement in the prevention and treatment of diseases associated with increased senescence of normal cells. These diseases include Alzheimer's and other neurodegenerative diseases, premature aging diseases such as Hutchinson-Gilford progeria syndrome (HGPS), and idiopathic pulmonary fibrosis (IPF). Current cell-based therapies, which are limited by increased cellular senescence, may also benefit from Δ133p53α-mediated improvements. As an initial application of Δ133p53α in improving therapeutic cells, we here introduce Δ133p53α-armored chimeric antigen receptor (CAR)-T cells. Based on our previous and ongoing studies using various types of senescent human cells in vitro, we also discuss the importance of further exploring the therapeutic potentials of Δ133p53α, with particular focus on HGPS and IPF. The development of mouse models facilitates in vivo evaluation of the therapeutic effects of Δ133p53α, potentially leading to future clinical applications.
2025-05-01 | Mesenchymal Stem Cell Therapy for Hutchinson-Gilford Progeria: Improvements in Arterial Stiffness and Bone Mineral Density in a Single Case.
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder that cause premature aging due to LMNA mutations and progerin accumulation. Although lonafarnib, an FDA-approved farnesyltransferase inhibitor, offers modest extension of life, the disease remains progressive. As progeria is associated with stem cell depletion and mesenchymal stem cell (MSC) therapy has shown efficacy in treating atherosclerosis, we aimed to evaluate its efficacy and safety in HGPS. A 7-year-old male with classic HGPS and preexisting severe cerebrovascular disease received four intravenous infusion of bone marrow-derived MSCs (2.5 × 10⁵ cells/kg) over 8 months. Growth, metabolic, cardiovascular, musculoskeletal, auditory, and inflammatory cytokines were monitored throughout the study. Prophylactic enoxaparin was administered to prevent vascular complications. MSC therapy was associated with improved lean body mass (11.5%), bone mineral density (L-spine z-score: 0.55 → 2.03), reduced arterial stiffness (9.98% reductionin pulse wave velocity), joint range of motion, dentition, and decreased sICAM-1 levels. However, Cardiovascular deterioration continued, and the patient passed away 10 months after the fourth dose, likely due to progression of the underlying vascular disease. No severe adverse effects were attributed to MSC therapy. MSC therapy may offer short-term benefits in arterial stiffness, bone health and inflammation in HGPS without notable safety concerns. Further studies are warranted to validate these findings, explore earlier intervention, and determine long-term efficacy and optimal dosing strategies.
2025-02-18 | Improved Arterial Stiffness and Bone Mineral Density in Hutchinson–Gilford Progeria Treated with Bone Marrow-Derived Mesenchymal Stem Cells: A Case Study and Literature Review
Background/Objectives: Hutchinson‒Gilford progeria syndrome (HGPS) is a rare ge-netic disorder caused by LMNA gene mutations, leading to the accumulation of farne-sylated progerin. It is characterized by severe growth failure, premature aging, rapid progression of atherosclerosis and cardiovascular- related early disease. Lonafarnib, a farnesyltransferase inhibitor, extends life expectancy in HGPS, but it does not stop progression. As Progeria is associated with stem cell depletion and mesenchymal stem cell (MSC) therapy has shown efficacy in treating atherosclerosis, we aimed to evaluate its efficacy and safety in HGPS. Methods: A 7-year-old male with classic HGPS re-ceived intravenous bone marrow-derived MSCs (2.5x10⁵ cells/kg) over four sessions. The first three sessions were administered at one-month intervals, followed by a final session six months later (Months 0, 1, 2, and 8). The study protocol included compre-hensive baseline assessment (growth, metabolic, cardiovascular, musculoskeletal, au-ditory and proinflammatory markers including cytokines). Preventive enoxaparin was administered to mitigate vascular complications. Results: MSC therapy increased lean body mass (total: pre -0.8% vs. post 11.5%), improved BMD (TBLH: pre -20.5% vs. post +2.8%, lumbar: pre +0.6% vs. post +26.5%), decreased PWV by a mean of 9.98%, and promoted weight gain (z score change: pre -1.13 to post + 0.75). Additionally, it en-hanced ROM, improved the low frequency of hearing loss, and consistently reduced sICAM-1. Conclusions: MSC therapy demonstrated potential efficacy in improving clinical outcomes, including arterial stiffness and bone mineral density, with no severe safety concerns related to therapy. Further research is needed for long-term efficacy and to maximize benefits.
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Drug Discovery Landscape
8 orphan drug designations for Hutchinson-Gilford progeria syndrome, including 2 approved therapies.
8 orphan drug designations for Hutchinson-Gilford progeria syndrome, including 2 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
an adenine base editor (ABE) therapy delivered using AAV9, for the correction of 1824 C>T mutation in the LMNA gene | gene editing enzymes | FDA | — | The Progeria Research Foundation |
salicylsalicylic acid | small molecules | FDA | — | J & D Pharmaceuticals LLC |
(7S)-8,8-dimethyl-7-{[(2E)-3-phenyl-2-propen-1-yl]oxy}-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-2-one | small molecules | EMA | — | Global Medical Services Sp. z o.o. |
peptide conjugated phosphorodiamidate morpholino oligomer | oligonucleotides | FDA | — | — |
Lonafarnib [Zokinvy] | small molecules | EMA | Approved | Integral Pharma Solutions EU Limited |
progerinin | small molecules | FDA | PRG S&T Co., Ltd. | |
lonafarnib [ZOKINVY] | small molecules | FDA | Approved | Sentynl Therapeutics, Inc. |
Pravastatin / zoledronic acid | small molecules | EMA | Prenyl BIO SAS |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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