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
643 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:
643 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:
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.
2026-08-10 | 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.
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.
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.
2026-08-17 | 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.
2026-08-10 | 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.
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.
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.
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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 | Regulator | Orphan designation | Approval | 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 | 2026-03-18 | — | The Progeria Research Foundation |
salicylsalicylic acid | small molecules | FDA | 2024-07-03 | — | 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 | 2022-08-10 | — | Global Medical Services Sp. z o.o. |
peptide conjugated phosphorodiamidate morpholino oligomer | oligonucleotides | FDA | 2020-09-08 | — | — |
Lonafarnib [Zokinvy] | small molecules | EMA | 2018-12-14 | 2022-07-19 | TMC Pharma (EU) Limited |
progerinin | small molecules | FDA | 2018-10-02 | — | PRG S&T Co., Ltd. |
lonafarnib [ZOKINVY] | small molecules | FDA | 2011-04-18 | 2020-11-20 | Sentynl Therapeutics, Inc. |
Pravastatin / zoledronic acid | small molecules | EMA | 2010-06-09 | — | Prenyl BIO SAS |
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