RARE DISEASE
Marfan syndrome
Marfan syndrome
Marfan syndrome
Synonyms: MFS
Synonyms: MFS
Synonyms: MFS
Drug discovery
3
drugs
With orphan designations
Overview
Marfan syndrome is an autosomal dominant connective tissue disorder caused by fibrillin-1 gene mutations, leading to cardiovascular, skeletal, ocular, and vascular manifestations. Key features include aortic root dilation, lens dislocation, and disproportionate skeletal growth. Complications such as aortic dissection, mitral valve prolapse, and retinal detachment drive morbidity and mortality. Management involves beta-blockers, angiotensin receptor blockers, prophylactic aortic surgery (at 4.5–5 cm), and multidisciplinary monitoring [1][6][11].
Therapies
Pharmacologic: Beta-blockers (atenolol) or ARBs (losartan) to reduce aortic stress [3][10][16].
Surgical: Prophylactic aortic root replacement at 4.5–5 cm; valve-sparing techniques preferred [6][11][17].
Multidisciplinary care: Annual cardiac imaging, ophthalmologic exams, and orthopedic/physiotherapy interventions [8][16].
Categories: rare bone diseases, rare circulatory system diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare ophthalmic disorders, rare surgical thoracic diseases, rare systemic and rheumatological diseases
Research Papers
1,632 drug discovery papers about Marfan syndrome, with 3 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,632 drug discovery papers about Marfan syndrome, with 3 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-06-17 | Fibrillin-1 Inhibits Early Adipogenic Commitment Via αvβ3 Integrin Signaling.
Extracellular fibrillin-1 is present in many tissues, including adipose tissue. Mutations in fibrillin-1 cause Marfan syndrome, paradoxically presenting with either low body fat at younger ages or frequently increased adiposity in older individuals. The latter correlated well with data obtained with the Fbn1mgR/mgR mice, which show that global fibrillin-1 deficiency leads to sex-dependent obesity by negatively regulating early adipogenic stem cell differentiation. However, the underlying cell receptors and mechanisms remained unknown. Here, we used recombinant fibrillin-1 fragments harboring either an active RGD integrin-binding motif (rFBN1-N-RGD) or an inactive RGA motif (rFBN1-N-RGA) and tested their roles in adipogenic differentiation with primary mesenchymal progenitors isolated from bone marrow or fat tissue, as well as with adipogenic 3T3-L1 cells. rFBN1-N-RGD inhibited adipogenic differentiation in all cell models when present during the early commitment phase but not during the maturation phase, whereas the rFBN1-N-RGA control was inactive. siRNA-mediated gene silencing or pharmacologic inhibition of integrin αvβ3, but not α5β1, rescued rFBN1-N-RGD-dependent inhibition of adipogenic differentiation. Fibrillin-1 engagement of integrin αvβ3 triggered activation of the downstream focal adhesion kinase (Fak)-Src kinase (Src) signaling cascade, driving extracellular signal-regulated kinase (Erk) activation. This cascade suppressed early adipogenic transcriptional programs by restraining Cebpα and Pparγ activation, thereby maintaining progenitor cells in a committed but undifferentiated state. Pharmacological inhibition of Fak, Src and Erk restored the anti-adipogenic effect of rFBN1-N-RGD. These data establish the integrin αvβ3-Fak-Src-Erk axis as an important signaling pathway by which fibrillin-1 imposes an adipogenic checkpoint during the early adipogenic commitment phase, thereby limiting excessive differentiation.
2026-06-11 | Lymphatic dysfunction and ZFP36 deficiency contribute to myxomatous valve degeneration in Marfan Syndrome mice.
Enhanced TGFβ signaling caused by mutations in Fibrillin-1 (FBN1) in patients with Marfan syndrome (MFS) leads to myxomatous degeneration of the mitral valve (MDMV). MDMV can result in mitral valve prolapse, severe regurgitation, and sudden cardiac death. However, it remains unknown whether lymphatic vessel (LV) dysfunction contributes to MDMV development in MFS. Here, we show that lymphangiogenesis in murine mitral valves (MVs) begins postnatally. However, this process is inhibited in a mouse MFS model, Fbn1 mutant (Fbn1C1039G/+) mice, accompanied by disrupted lymphatic cell-cell junctions, impaired lymphatic drainage, and an abnormally widespread distribution of MHCII+ infiltrating macrophages. Treatment of Fbn1 mutant mice with VEGF-C156S, a selective VEGFR3 agonist, stimulates the ERK and Akt pathways, increases LV density in MVs, and ameliorates MDMV. Fbn1 mutant MVs display disorganized valvular endothelial cells (VECs) and decreased expression of the anti-inflammatory modulator Zfp36 (zinc finger protein 36) in VECs and immune cells. Treatment with FTY720 (Fingolimod), a ZFP36 activator and S1P antagonist, rescues MDMV phenotypes in Fbn1 mutant mice by reducing immune cell infiltration and restoring lymphatic cell junctions and drainage. These findings suggest that the Fbn1 mutation causes LV hypoplasia and defective lymphatic drainage in MVs, driven in part by pro-inflammatory VECs, leading to MFS-related MDMV.
2026-05-28 | HSPB7 Deficiency Drives Aortic Aneurysm Progression in Marfan Syndrome Through Vascular Smooth Muscle Cell Phenotypic Switching.
Marfan syndrome (Mfs) arises from mutations in FBN1, predisposing individuals to thoracic aortic aneurysm (TAA) through abnormal smooth muscle cell behaviour. The role of HSPB7 in Mfs-related TAA remains poorly understood. By integrating multi-omics analysis with hiPSC-derived VSMCs from patients with Mfs, we elucidated the molecular landscape of Mfs-associated TAA. Analysis revealed immune cell infiltration, a reduced proportion of VSMCs, and altered intercellular communication. Pathway analyses indicated changes in cell adhesion, extracellular matrix (ECM) remodelling, and immune signalling, with downregulated metabolic pathways. Findings suggest structural, immune, and metabolic imbalances in Mfs-TAA pathogenesis. Downregulation of HSPB7 was associated with altered proliferation, migration, and metabolic activity. Overexpression of HSPB7 in patient-specific hiPSC-derived VSMCs attenuated these pathological features and promoted a more contractile phenotype. These findings suggest that HSPB7 may be involved in the regulation of VSMCs' phenotypic modulation in Mfs-TAA and provide mechanistic insight into disease-associated cellular alterations.
2026-03-08 | PINCH proteins orchestrate vascular mural cell homeostasis through integrated signaling and transcriptional networks.
Vascular mural cells (VMCs) are crucial for vascular stability, and their dysfunction underlies cardiovascular pathologies including atherosclerosis and aortic aneurysms. PINCH proteins are core focal adhesion components mediating integrin signaling, yet their roles in VMC development remain elusive. Here, we generated mice with conditional deletion of both PINCH1 and PINCH2 in Pdgfrb-lineage VMCs, which resulted in perinatal lethality accompanied by severe arterial enlargement, hemorrhage and defective angiogenesis. Mutant VMCs exhibited profound defects in cytoskeletal organization, proliferation, differentiation, adhesion and extracellular matrix assembly. Multi-omics analyses revealed that PINCH deficiency dysregulated phospho-signaling networks, hyperactivating PDGFR/EGFR/AKT/ERK and STAT/NF-κB pathways while impairing integrin-FAK-SRC and cell cycle-associated pathways (p53, p27). RNA-seq demonstrated altered expression of genes enriched in immune response (CD74, Tlr2), cytoskeleton (TUBB3, ACTA2) and VMC differentiation (Rgs5, Kcnj8, ABCC9). Importantly, we identified PINCH1 as a nuclear transcriptional coregulator that directly represses proliferative-inflammatory programs while promoting contractile-adhesive and cytoskeletal organization signatures. The clinical relevance of these findings is underscored by downregulation of PINCH genes in human atherosclerosis and Marfan syndrome aneurysms, with conserved dysregulation of key PINCH targets including CD74 and RGS5. Our work reveals a dual cytoplasmic-nuclear mechanism for PINCH in maintaining vascular homeostasis, providing both mechanistic insights and therapeutic targets for vascular diseases.
2026-01-01 | Aortic biomechanics in paediatric and adolescent patients with Marfan syndrome
Abstract not currently available.
small molecules
2026-08-03 | Lymphatic therapies open the valve in Marfan syndrome.
Myxomatous degeneration of the mitral valve (MDMV) is a common cardiovascular manifestation of Marfan syndrome (MFS), yet the role of lymphatic vessels in the disease progression remains unknown. In this Commentary, we discuss the study by Tan, Kume, and colleagues, which identifies defective lymphangiogenesis as a previously unrecognized driver of MDMV. Their work demonstrates that impaired lymphatic development and drainage promote valve inflammation through reduced ZFP36-mediated antiinflammatory signaling, whereas restoration of lymphatic function or pharmacological activation of ZFP36 with the FDA-approved drug FTY720 ameliorates disease progression. These findings establish lymphatic vessels as critical regulators of mitral valve homeostasis and support exploration of lymphatic-targeted therapeutic opportunities for MFS-associated valvular disease.
2026-07-17 | Genetic Bone Diseases: A Scoping Review of Pathology, Symptoms, Diagnosis, Treatment, and New Horizons.
Genetic bone diseases are a rare group of afflictions suffered by the general population. However, their rarity should not diminish research efforts to help patients understand and treat their diseases. This review summarizes the pathology, symptoms, diagnosis, and treatment insight into six well-known genetic bone diseases. Only six bone diseases are included due to the relatively low prevalence of them as whole limiting our scope to ensure accurate information and attention is provided for each disease individually. A literature search of PubMed is conducted, including studies published within the past five years (January 2020-December 2025). Thirty-six studies met inclusion criteria, and no significant risk of bias is identified among the selected articles. Study findings are synthesized into disease overview, clinical and radiographic features, and diagnostic and treatment approaches. Actively developing or novel therapies relevant to each disease are also included. These treatments include: fresolimumab for osteogenesis imperfecta, small interfering ribonucleic acid (RNA) therapy for Osteopetrosis, denosumab for Paget's disease of bone, vosoritide/recifercept/infigratinib for achondroplasia, mesenchymal stem cell therapy for craniosynostosis, and combination losartan and atenolol therapy for Marfan syndrome. These treatments are generally more recently acknowledged in literature and are either actively undergoing research or require further research to determine their efficacy.
2026-07-13 | Sex-Dependent Vascular Responses to Atorvastatin Across Multiple Arterial Beds in a Mouse Model of Marfan Syndrome.
Marfan syndrome (MFS) is characterized by progressive aortic aneurysm formation resulting from mutations in the fibrillin-1 (Fbn1) gene. Although the thoracic aorta is the primary site of pathology, accumulating evidence indicates that vascular dysfunction in MFS extends beyond the aorta to involve multiple arterial beds. Statins have been shown to attenuate aneurysm progression in experimental models of MFS; however, their effects on systemic vascular remodeling and arterial stiffness outside the aorta remain poorly characterized. In this study, we investigated the impact of chronic atorvastatin therapy on vascular structure and hemodynamic function across multiple vascular beds in the Fbn1^C1041G/+^ mouse model of MFS. Male and female control and MFS mice received drinking water with or without atorvastatin (1 g/kg/day) from 4 weeks to 6 months of age, enabling the effects of atorvastatin to be assessed in both healthy and MFS arteries. High-frequency ultrasound imaging was used to assess vascular parameters in the aorta, left common carotid artery (LCCA), and posterior cerebral artery (PCA). Atorvastatin treatment significantly attenuated aortic root dilation in both male and female MFS mice and reduced aortic pulse wave velocity (PWV), indicating improved arterial compliance. In the carotid circulation, atorvastatin significantly reduced LCCA wall thickness and carotid PWV, although carotid wall strain did not improve. Atorvastatin raised both systolic and diastolic blood pressure in male and female MFS mice relative to untreated MFS animals, reaching levels not significantly different from untreated controls in both sexes, while having little effect in healthy controls apart from a rise in female diastolic pressure. In the posterior cerebral artery, peak systolic velocity, a hemodynamic index rather than a direct measure of perfusion, showed similarly sex-dependent changes, increasing in female MFS mice but decreasing further in males after atorvastatin. Collectively, these findings demonstrate that atorvastatin exerts systemic but heterogeneous vascular effects in MFS, improving arterial stiffness and structural remodeling across multiple arterial beds while producing sex-specific hemodynamic responses that warrant further investigation.
2026-07-07 | Fibronectin-induced overactivation of αVβ3-PI3K-PIP3-PDK1-ILK signaling drives aortic disease in Marfan syndrome.
Thoracic aortic aneurysms and dissections (TAAD), a life-threatening complication of Marfan syndrome (MFS), lack curative therapies. Our previous studies revealed that versican accumulation drives MFS aortopathy through AKT-NO pathway overactivation, but the upstream mechanisms remained unclear. Here, we show that versican-driven fibronectin (FN) accumulation activates an αVβ3-PI3K-PIP3-PDK1-ILK signaling cascade leading to AKT-NOS2 upregulation and aortic disease. FN accumulates in aortas of MFS patients and mice of both sexes and correlates with increased αVβ3 integrin and ILK expression. Disrupting FN assembly or inhibiting αVβ3, PI3K, PIP3, PDK1 or ILK prevents FN-induced AKT activation and NOS2 upregulation, restores vascular contractility, and limits aortic dilation in MFS mice. Inhibition of ILK or PDK1, aortic silencing of Ilk, or smooth muscle-specific deletion of Ilk reverses or prevents aortic growth. Together, these findings define a mechanistically integrated FN-αVβ3-PI3K-PIP3-PDK1-ILK-AKT-NOS2 signaling cascade in MFS and support its causative role in human TAAD, highlighting its components as potential targets for therapeutic intervention.
2026-06-30 | Mechanotransduction in Marfan Syndrome and Related Aortic Disorders: Insights from Transcriptomic Analyses
Heritable thoracic aortic diseases (HTADs) comprise a genetically heterogeneous group of disorders predisposing patients to thoracic aortic aneurysm and dissection, yet current medical therapies remain limited to slowing disease progression rather than preventing aortic wall failure. Although pathogenic variants affect diverse genes encoding extracellular matrix (ECM) components, smooth muscle contractile proteins, and signaling molecules, these defects converge on disruption of the mechanobiological systems that maintain aortic wall integrity. The thoracic aorta functions as a mechanically integrated tissue in which endothelial cells, vascular smooth muscle cells, fibroblasts, immune cells and ECM continuously sense and respond to pulsatile biomechanical forces. Genetic perturbations affecting ECM architecture, contractile force generation, or growth factor signaling alter force transmission across this multicellular network, leading to maladaptive mechanotransduction, cellular phenotypic modulation, and progressive aneurysm formation. Using Marfan syndrome as a paradigmatic ECM-driven aortic disease, this review synthesizes current understanding of how altered biomechanics, biochemical signaling and immune responses reshape intercellular communication and activate disease-associated signaling pathways, including dysregulated TGF-β, nitric oxide, angiotensin receptor, calcium-dependent, and metabolic signaling. We highlight how single-cell transcriptomic analyses have elaborated changes in different cell-level functions including, ECM degradation, iron homeostasis, circadian/stress responses. Changes in iron metabolism in different cell types in the aorta suggest possible coordinated metabolic changes in aneurysm progression. These mechanistic insights enable the identification of cell-type–specific pathogenic programs and therapeutic discovery through systems-level approaches. We highlight the translational opportunities and challenges emerging from mouse models and human studies, emphasizing that therapeutic efficacy depends not only on pathway selection but also on disease stage, cellular context, and timing of intervention. Together, these findings support a model in which HTAD progression reflects dynamic, multicellular failure of mechanobiological homeostasis and provide a framework for the development of more precise, mechanism-based therapies.
gene therapies
2026-07-04 | Marfan Syndrome: Molecular Basis, Clinical Spectrum, Diagnosis, and Management- A Comprehensive Review
Marfan syndrome (MFS) is a hereditary connective tissue disorder primarily caused by mutations in the FBN1 gene, leading to abnormalities in extracellular microfibril formation and dysregulation of transforming growth factor-beta (TGF-β) signaling. The disorder exhibits autosomal dominant inheritance and presents with significant clinical variability, affecting the cardiovascular, skeletal, and ocular systems. Among these, cardiovascular complications such as aortic root dilation, aneurysm, and dissection represent the most life-threatening manifestations. Advances in diagnostic approaches, particularly the revised Ghent criteria, have improved diagnostic accuracy by integrating clinical features, imaging findings, and genetic testing. Imaging modalities such as echocardiography, magnetic resonance imaging, and computed tomography play a critical role in early detection and monitoring of disease progression. Genetic testing further enhances diagnostic precision, especially in atypical cases. Management strategies focus on preventing complications and improving survival. Pharmacological treatments, including beta-blockers and angiotensin receptor blockers, reduce hemodynamic stress and modulate TGF-β signaling. Surgical interventions, particularly prophylactic aortic root replacement, are essential in high-risk patients. A multidisciplinary approach involving cardiology, genetics, ophthalmology, and orthopedics is crucial for optimal patient care. Emerging diagnostic tools such as next-generation sequencing and biomarker-based assessments, along with novel therapeutic strategies including gene therapy and targeted molecular treatments, hold promise for future disease management. Continued research into the molecular mechanisms of MFS is essential to transition from symptomatic treatment to disease-modifying therapies and to further improve patient outcomes.
2026-06-19 | The impact of FBN1 variant types on pregnancy-related aortic dissection in women with Marfan syndrome.
Pregnancy in women with Marfan syndrome (MFS) increases the risk of aortic dissection, yet management based solely on aortic root diameter often fails to predict this complication, particularly Stanford type B dissection. Haploinsufficient (HI) FBN1 variants are associated with more severe aortic phenotypes. We investigated the relationship between FBN1 genotype and pregnancy-related aortic dissection in women with MFS. We retrospectively analyzed women with genetically confirmed MFS whose pregnancies progressed beyond the second trimester and who were managed at a single tertiary referral center between 1993 and 2024. FBN1 variants were categorized as HI or non-HI. Pregnancy-related aortic dissection-defined as occurring during pregnancy or within six months postpartum-was evaluated in relation to variant type. Thirty-five women (15 HI, 20 non-HI) were included. Pregnancy-related aortic dissection occurred in 11 women: seven were referred after the dissection occurred and nine were Stanford type B. The incidence was higher in the HI group than in the non-HI group (9/15 [60%] vs 2/20 [10%], P = 0.002). Pre-pregnancy native aortic root diameters did not differ between those with and without dissection. Additional risk factors included undiagnosed with MFS at the time of dissection and absence of β-blocker therapy. HI FBN1 variants were associated with pregnancy-related aortic dissection in this cohort. Stanford type B dissection may occur even with mild aortic dilation, highlighting the limitations of diameter-based risk stratification. Incorporating FBN1 genotype into preconception counseling and pregnancy management may improve maternal outcomes. However, given the retrospective single-center design, prospective validation is warranted.
2026-03-11 | Genotype-Guided Risk Stratification of Mitral Valve Surgery in Marfan Syndrome.
Although genotype-based risk stratification for aortic disease has been extensively studied in Marfan syndrome (MFS), mitral valve disease has received less attention despite being a major cardiovascular complication requiring surgery in up to 16% of cases. The authors aimed to evaluate genotype-specific differences in mitral valve disease progression and surgical intervention to inform precision medicine approaches in MFS. This retrospective cohort study included 437 MFS patients with pathogenic FBN1 variants (2006-2024). Variants were classified by molecular mechanism (premature termination codon [PTC] variants vs in-frame variants [IFVs]) and genomic location. Time-to-event cause-specific analysis assessed genotype-specific risks for mitral valve surgery. Among 437 patients, 206 (47.1%) had PTC variants and 231 (52.9%) IFVs. Mitral valve surgery was performed in 38 patients (8.7%) at median age of 25.0 years. Among IFVs, those within the DNCD region (Dominant Negative variants affecting Cysteine residues and in-frame Deletions; exons 26-37 and 44-50) showed markedly higher 30-year cumulative incidence of mitral valve surgery (23.8% [95% CI: 11.7%-35.9%] vs 1.24% [95% CI: 0.0%-2.96%] in other IFVs and 3.20% [95% CI: 0.66%-5.77%] in PTC variants). IFVs within the DNCD region showed the earliest onset of mitral valve surgery in childhood/adolescence, whereas PTC variants demonstrated delayed risk beginning around age 30 years. Cox analysis confirmed IFVs within the DNCD region had highest risk of mitral valve surgery for patients aged ≤30 years (HR: 7.83 vs PTC variants; 95% CI: 3.14-19.57; P < 0.001) with robust discrimination (C-index = 0.725). IFVs within the DNCD region confer the highest risk for mitral valve surgery with distinct age-dependent patterns. These findings enable genotype-guided risk stratification with age-specific surveillance protocols, potentially transforming clinical management in MFS.
2025-11-15 | Gene editing for inherited cardiac conditions: A new frontier in cardiology.
Inherited cardiac conditions (ICCs) such as hypertrophic cardiomyopathy and Marfan syndrome pose significant global health challenges, often rooted in complex genetic mutations. Recent advances in gene editing, particularly the CRISPR/Cas9 system, have opened new avenues for precise, personalized interventions. This review examines the current landscape of gene editing in cardiology, with emphasis on its scientific promise, integration with epigenetics, gene therapy, and artificial intelligence, and its potential to transform clinical outcomes. Key gene editing strategies are analyzed for their efficacy and translational potential. The review also explores ongoing clinical trials and emerging research, offering practical insights for future studies. Ethical implications are critically evaluated, with proposed frameworks to address concerns around safety, equity, and long-term consequences. By synthesizing these developments, this review underscores the urgent need for continued interdisciplinary research in the quest to mitigate inherited cardiac diseases.
2025-09-03 | Therapeutic Opportunities of Marfan Syndrome: Current Perspectives.
Marfan syndrome (MFS) is a hereditary connective tissue disorder that is primarily caused by mutations in the fibrillin-1 (FBN1) gene. This disease predominantly affects the eyes, bones, and cardiovascular system, with cardiovascular complications posing the most significant threat to life. Currently, conventional treatments, which are based on pharmacological management and surgical interventions, aim to slow disease progression and manage life-threatening cardiovascular complications. Emerging technologies such as CRISPR-Cas9 gene editing and induced pluripotent stem cell (iPSC) have advanced the understanding of FBN1 mutation heterogeneity and disease mechanisms beyond TGF-β signaling, providing novel platforms for drug discovery and personalized therapeutic exploration. This review explores recent progress in MFS therapies, focusing on surgical innovations, emerging medicine and therapeutic targets, while discussing the potential future applications of gene therapy.
cell therapies
2026-05-01 | A46-07 Spontaneous Pneumothorax as a Complication of Marfan Syndrome
Abstract Marfan syndrome is an autosomal dominant connective tissue disease that typically affects the musculoskeletal, cardiovascular, and ocular systems. This is due to a mutation encoding fibrillin, resulting in complications from defective connective tissue (Elastin primarily). Pulmonary manifestations, although not classical, can also be seen, which can present as the following: emphysema, pneumothorax, sleep apnea, asthma, bronchiectasis, and interstitial lung disease. We present a case of a patient with Marfan syndrome complicated by spontaneous secondary pneumothorax (SSP). We present a case of a 49-year-old male with a prior medical history of Marfan syndrome with multiple complications, such as aortic dissection requiring aortic graft and valve replacement, retinal detachment, and an extensive smoking history (40 pack years), who presented with a sudden onset of chest pain and shortness of breath. Chest imaging showed a large right-sided pneumothorax with mediastinal shift. A pigtail chest tube catheter was placed successfully with reexpansion of the right lung. CT imaging revealed paraseptal emphysematous changes with prominent right-sided blebs. Due to the patient having a high risk of recurrent pneumothorax in the setting of prior diagnosed Marfan syndrome and emphysema with blebs on imaging, pleurodesis with surgical resection was pursued. Our patient subsequently went under right-sided VATS with upper lobe resection/bleb resection, mechanical pleurodesis, and complete pleurectomy. Pathology showed lung tissue with emphysematous changes, subpleural blebs, and fibroelastotic subpleural scarring with focal calcification. In addition to these changes was eosinophil-rich inflammation in the pleura. His post-operative course was uncomplicated, and subsequently discharged. Our case demonstrates potential pulmonary complications from underlying Marfan syndrome. Marfan syndrome is typically diagnosed in younger adults rather than in the 4th decade of life, as seen in our patient. The lifetime incidence of pneumothorax is reported to be 4-14% in those with Marfan’s. Although pneumothorax is not commonly a presenting feature, it is prevalent enough to be included as a criterion for diagnosis. SSP results from bullae with predilection in the apices. Management of SSP in these cases is to prevent recurrence, in addition to tube thoracostomy placement. Although there is a lack of data in adults, the incidence of recurrent pneumothorax if conservative measures are pursued initially in adolescents can be as high as 78%; therefore, definitive surgical management is recommended initially in those with Marfan’s. The surgical approach should include VATS with wedge resection, and bullectomy should be performed as bullae are the likely cause of SSP if identified. This abstract is funded by: None
2026-03-17 | SPP1high fibrogenic macrophages mediate protective fibrotic remodeling and promote vascular stability in hypertension-associated aortic dissection.
Hypertension-associated aortic dissection (HTN-AD) features intense immune activation and extracellular matrix disruption, yet the cellular programs that promote aortic-wall stabilization remain unclear. We aimed to identify macrophage states associated with vascular integrity and to determine whether these states could be mechanistically or therapeutically leveraged. Single-cell RNA sequencing was performed on thoracic aortas from HTN-AD, Marfan syndrome-associated AD, and donor controls (n = 3 per group). Peripheral and tear-adjacent blood samples were analyzed in patients with HTN-AD, MS-AD, and healthy donors (n = 30 per group), with paired intraoperative tear-adjacent sampling performed when available (n = 10). Circulating monocytes and serum cytokines were profiled by flow cytometry and ELISA. Functional validation included TGF-β1 conditioning of human monocytes and murine macrophages and adoptive transfer experiments in a murine AD model. A distinct SPP1high fibrogenic macrophage population was enriched in diseased aortas and transcriptionally bridged low-inflammatory macrophages and matrix-active states. Patients with HTN-AD displayed increased tear-adjacent non-classical monocytes and higher monocytic SPP1, correlating with serum TGF-β1 and a shorter ICU stay. TGF-β1 induced an SPP1-dependent fibrogenic program in macrophages while suppressing inflammatory markers. Myeloid Spp1 deficiency aggravated aortic dilatation and wall disruption, whereas adoptive transfer of TGF-β1-conditioned SPP1high macrophages reduced false lumen formation, improved collagen organization, decreased IL-1β and IL-6 expression, and enhanced survival. A TGF-β1-SPP1 axis drives the emergence of SPP1high fibrogenic macrophages that support structural stabilization of the dissected aorta. Targeting this reparative myeloid program may offer a mechanistically informed therapeutic strategy for acute aortic syndromes.
2026-03-08 | Two Cases of Successful Kidney Transplantation From a 39-Year-Old Male Deceased Donor With Marfan Syndrome: A Case Series.
BACKGROUND Marfan syndrome is a multisystemic, autosomal dominant connective tissue disorder caused by mutations in the fibrillin-1 gene. It is associated with life-threatening complications, especially aortic aneurysms and dissections, and has a global prevalence of 1 in 3000-5000 individuals. Although kidney transplantation is the standard treatment for end-stage renal disease (ESRD), deceased kidney donors with Marfan syndrome remain uncommon due to concerns about connective tissue fragility. Emerging reports, however, indicate that kidneys from such donors may be safely used. This report describes 2 successful kidney transplantations from a 39-year-old male donor with confirmed Marfan syndrome. CASE REPORT Case 1. The donor died from subarachnoid hemorrhage and had a history of aortic arch replacement for aortic dissection. Both kidneys were retrieved from the retroperitoneal space, prepared according to standard protocols, and stored in University of Wisconsin Store Protect Plus organ preservation solution under static cold storage at 4°C. Case 2. A 59-year-old man with ESRD secondary to diabetic nephropathy underwent his first kidney transplantation. He was hemodialyzed with residual diuresis. The right kidney was transplanted without complications, and the recipient achieved immediate and stable graft function. Case 3. The second recipient was a 34-year-old man with ESRD due to vesicoureteral reflux and obstructive nephropathy, also on hemodialysis with preserved diuresis. Left kidney transplantation proceeded uneventfully. He experienced delayed graft function, which resolved with appropriate management, resulting in satisfactory renal recovery. CONCLUSIONS These cases support the growing evidence that kidneys from donors with Marfan syndrome can function effectively after transplantation. Such donors may represent a valuable and underutilized resource, with the potential to expand the kidney donor pool safely.
2025-11-17 | Pediatric Marfan Syndrome and Heart Transplantation: Insights From the PHIS Database.
Marfan syndrome (MFS) is a connective tissue disorder associated with significant cardiovascular complications, including heart failure. Orthotopic heart transplantation (OHT) is considered controversial in this population due to concerns about post-transplant aortic complications, particularly in children. We conducted a retrospective review of the Pediatric Health Information System (PHIS) database to identify patients under 18 years of age with a diagnosis of MFS who underwent OHT between 2004 and 2024. Patients were propensity matched (3:1) to non-MFS OHT recipients. Outcomes included graft failure, aortic events, and re-transplant-free survival. Ten pediatric MFS patients were identified among 5493 OHT recipients. The median age at OHT was 12.5 years. Over a median follow-up of 3.73 years, no in-hospital mortalities or repeat transplants were observed; two patients experienced rejection, and one developed aortic root dilation without requiring intervention. Propensity-matched analysis showed no significant differences in rejection, aortic events, or transplant-free survival between MFS and non-MFS cohorts. Though rare, pediatric MFS patients undergoing OHT demonstrated excellent short-term outcomes with no MFS-related surgical complications. These findings challenge current exclusionary practices and support further research into long-term outcomes.
2025-09-17 | Personalized External Aortic Root Support (PEARS) in the Treatment of Marfan Syndrome and Bicuspid Aortic Valve Aneurysms: First Case Series in the American Continent.
Conventional surgical approaches for aortic root aneurysms, including valved grafts and valve-sparing techniques, present inherent limitations such as the requirement for anticoagulation and the potential for late reoperation. Personalized External Aortic Root Support (PEARS), utilizing the ExoVasc® implant, represents a novel approach that aims to overcome these limitations. This report presents the initial clinical experience with the ExoVasc® PEARS implant in the Americas, encompassing 10 patients (six males, age range 30 - 52 years, mean age 37.8 years) diagnosed with aortic root aneurysms. Indications for PEARS included Marfan syndrome (eight patients, including one reoperation), bicuspid aortic valve (two patients, including one with anomalous coronary artery), and associated valvular dysfunction. Cardiopulmonary bypass was utilized in four cases. No major adverse postoperative events were observed. Postoperative recovery was generally uneventful, with minor complications, including pericarditis and atrial fibrillation, successfully managed with medical therapy. Aortic dimensions remained stable at 30-day and one-year follow-ups. This initial experience demonstrates the feasibility, safety, and efficacy of the PEARS technique for the treatment of aortic root aneurysms. Potential advantages over traditional approaches include the possibility for off-pump procedures, reduced risk of aortic valve dysfunction, shorter hospital stays, and elimination of the need for long-term anticoagulation therapy. Further investigation is warranted to evaluate the long-term durability and clinical outcomes of this innovative approach.
other
2026-06-26 | The Efficacy of Antihypertensive Drugs and miR-632 Inhibition on Parietal Remodeling in a Model of Marfan Thoracic Aortic Aneurysm.
Marfan syndrome (MFS) is a connective tissue disorder caused by FBN1 mutations, leading to elastic fiber disarray and early thoracic aortic aneurysm (TAA) formation. Currently, pharmacological treatments lack specificity and only delay progression. We previously reported a specific TGFβ-driven miR-632 upregulation in MFS TAA tissues and blood causing smooth muscle cell dedifferentiation and aortic wall degeneration. This study evaluated the effects of three conventional antihypertensive drugs (β-blocker, ACE inhibitor, and sartan) on parietal remodeling, comparing them with a miR-632 inhibitor in an ex vivo TGFβ1-induced model of MFS TAA. Using an ex vivo paired experimental framework based on independent biological pools of human TAA tissue, gene expression and Western blot analyses demonstrated that only losartan significantly reduced miR-632 and vascular degeneration markers. Notably, combined treatment with ramipril and carvedilol compromised losartan's efficacy, highlighting the need for careful therapeutic selection. In this ex vivo setting, miR-632 inhibition demonstrated a promising capacity to counteract aortic remodeling, serving as a mechanistic proof-of-concept that warrants further preclinical in vivo validation. Our data emphasize that choosing the right treatment in MFS aortopathy requires understanding its specific impact on cellular pathways. Our findings identify losartan as the most effective standard drug in this model, while suggesting miR-632 as a potential future target to stabilize the aortic wall and, prospectively, delay surgery.
2025-11-01 | Exploration of cyclophilin A antibody anti-eCypA as a new approach in the treatment of marfan syndrome
Abstract Background Marfan syndrome (MFS) is a rare genetic disease characterized by the development of aortic aneurysms with a high risk of complications such as aortic dissection. Current treatment options are limited to advanced surgical procedures with the risk of complications. Thus, alternative, less invasive therapeutic approaches are required. Previous studies suggested that the selective inhibition of extracellular cyclophilin A (CypA), a danger-associated molecular pattern (DAMP) secreted in response to vascular stress, reduces the formation of abdominal aortic aneurysms. Therefore, we aimed to explore the effects of selectively inhibiting CypA on aortic aneurysm formation and wall architecture in MFS using fibrillin-1-deficient mice (mgR/mgR), a well-characterized murine model for MFS. Methods Over the course of four weeks, male mgR/mgR mice were subcutaneously injected with the CypA antibody anti-eCypA or an idiotypic IgG control. Ultrasound examination was performed on the baseline and after two and four weeks of treatment. Moreover, we assessed the diameter of the thoracic aorta using innovative MRI scans four weeks after the beginning of the treatment. Furthermore, the aortic wall constitution was evaluated by performing immunhistochemistry, zymography and elastin staining of aortic tissue. Results The analysis of elastin breaks by Elastin van Gieson staining in the aortic wall of the mice showed a significant decrease of elastin breaks in treatment compared to control group. While analysis of the ultrasound images showed an enlarged aortic diameter in both groups after four weeks, the increase in the treated group was less pronounced than in the control group. Interestingly, two weeks of treatment did not lead to a strong increase in diameter in either group, suggesting the main formation of aneurysms develops rather between weeks two and four. Importantly, the results of the MRI scan analysis were consistent with the ultrasound findings. Notably, we found marked decrease in gelatinase activity following treatment and a reduction in EMMPRIN and VCAM1 expression in the aortic wall in mice subjected to anti-eCypA treatment. Conclusion Our results suggest a beneficial effect of anti-eCypA in the remodelling of the aortic wall in MFS, demanding further exploration with a larger animal cohort. Ultimately, CypA inhibition employing anti-eCypA may present a valuable alternative to more invasive surgical strategies for the treatment of MFS.
2025-10-01 | MON-809 "Strengthening Bones, Supporting Lives: Romosozumab in Osteoporosis Management for Marfan Syndrome"
Abstract Disclosure: S. Shanthosh Kumar: None. Z. Shafique: None. K. Selk: None. Introduction: We present a case reporting clinically significant outcome in management of osteoporosis with Romosozumab in a 61 year old female with a history of Marfan Syndrome (MFS). CASE PRESENTATION Our patient has medical history remarkable for Marfan syndrome, osteoporosis, remote history of grave’s disease(1996) treated with radioactive iodine ablation, primary hyperparathyroidism with surgical cure(2012), and post-menopausal status at age 50. For osteoporosis, patient was previously on alendronate followed by raloxifene with a combined treatment course of approximately 15 years. A baseline DEXA scan was not available, however, a repeat study in 2023 demonstrated a bone mineral density (BMD) of 0.761 g/cm2 (T score -3.5) at the lumbar spine and 0.647 g/cm2 (T score -2.8) at the left femoral neck. Her parathyroid hormone, phosphorus, calcium, thyroid, and serum electrophoresis testing were unrevealing. Given the severity of osteoporosis, she was deemed a candidate for an anabolic agent, Romosozumab. Following completion of monthly infusions of Romosozumab for 12 months, a repeat DEXA scan in 2024 showed an interval increase in BMD at the lumbar spine (0.830 g/cm2, T score -2.9) and hip (femoral neck 0.736, T score -2.2) with the least significant change indicating this was a significant change. CASE DISCUSSION MFS is an autosomal dominant condition resulting from a mutation in the fibrillin-1 gene. Affected adults have lower axial bone mineral density, specifically in their lumbar spine and hip. Risk of osteoporosis and fracture risk has been reported to be higher in patients with MFS as compared to matched reference populations. Affected individuals are now living longer and therefore, addressing fracture risk reduction is imperative. Although she had received treatment with both alendronate and raloxifene, these two agents were unsuccessful in effectively halting bone loss and facilitating bone formation. Although our patient also had multiple other risk factors as mentioned earlier, these were promptly identified and received definitive therapy, thereby making them less likely to lead to ongoing progression. Romosozumab is a humanized monoclonal antibody with anabolic and antiresorptive benefits. It binds and inhibits sclerostin thereby promoting bone formation and inhibiting bone resorption. Given the severity of her osteoporosis, our patient completed a 12-month course of therapy without any significant side effects and was found to have clinically significant improvement in her axial bone mineral density. Conclusion To our knowledge, there are no case reports on use of Romosozumab in the MFS population with osteoporosis. This case report highlights this therapy as a possible effective therapeutic intervention but also recognizes the need for ongoing research to establish standard and effective treatment guidelines for management of osteoporosis in MFS. Presentation: Monday, July 14, 2025
2025-06-05 | Diagnosis of skeletal fragility due to Loeys-Dietz syndrome and treatment with romosozumab followed by denosumab.
Loeys-Dietz syndrome (LDS) is an autosomal dominant, inherited connective tissue disorder caused by a pathogenic variant in TGF-β signaling-related genes. LDS is associated with a high risk of low bone mineral density (BMD) and fractures. We present a case report of a 43-year-old premenopausal woman with skeletal fragility who was diagnosed with LDS type 4 due to a large heterozygous deletion in the TGFB2 gene. Upon initial referral, she was evaluated for secondary osteoporosis. Although mild abnormalities in calcium metabolism, menstrual irregularities, and lack of exercise were observed, they were not associated with this condition. However, a thorough family history and physical examination raised the suspicion of Marfan syndrome and related disorders, which were subsequently confirmed using genetic testing. Treatment with romosozumab for 1 year increased the lumbar spine BMD from 0.750 g/cm2 (Z-score -2.1) to 0.881 g/cm2 (Z-score -1.0) and the femoral neck BMD from 0.407 g/cm2 (Z-score - 3.0) to 0.428 g/cm2 (Z-score - 2.6), with a slight increase in total hip BMD from 0.525 g/cm2 (Z-score -2.6) to 0.527 g/cm2 (Z-score -2.4). Subsequent therapy with denosumab for 1 year further improved the lumbar spine BMD to 0.939 g/cm2 (Z-score, -0.5), femoral neck BMD to 0.496 g/cm2 (Z-score, -2.0), and total hip BMD to 0.552 g/cm2 (Z-score, -2.2). To our knowledge, this is the first case report of an improvement in BMD with romosozumab, followed by denosumab, for skeletal fragility due to LDS. Our findings suggest that this treatment regimen may be an effective therapeutic option for the management of skeletal fragility in patients with LDS.
2025-01-16 | Inhibition of aortic CX3CR1+ macrophages mitigates thoracic aortic aneurysm progression in Marfan syndrome in mice.
The pathogenesis of thoracic aortic aneurysm (TAA) in Marfan syndrome (MFS) is generally attributed to vascular smooth muscle cell (VSMC) pathologies. However, the role of immune cell-mediated inflammation remains elusive. Single-cell RNA sequencing identified a subset of CX3CR1+ macrophages mainly located in the intima in the aortic roots and ascending aortas of Fbn1C1041G/+ mice, further validated in MFS patients. Specific elimination of CX3CR1+ cells by diphtheria toxin in Cx3cr1-CreERT2iDTRF/+Fbn1C1041G/+ mice efficiently ameliorated TAA progression. Administering the monoclonal antibodies to respectively neutralize TNF-α and IGF1 produced by CX3CR1+ cells from MFS patients greatly suppressed the cocultured MFS patient-specific induced pluripotent stem cell-derived VSMC inflammation. BM transplantation and parabiosis revealed that CX3CR1+ macrophages are mainly originated from BM-derived monocytes. Targeting TNF-α and IGF1 in CX3CR1+ macrophages via shRNA lentivirus transduction in BM cells efficiently suppressed TAA development in BM-transplanted Fbn1C1041G/+ mice. Application of the CCR2 antagonist RS504393 to inhibit monocyte infiltration markedly reduced the accumulation of CX3CR1+ macrophages and subsequently alleviated TAA progression in Fbn1C1041G/+ mice. In summary, CX3CR1+ macrophages mainly located in aortic intima mediate TAA formation by paracrinally causing VSMC inflammation, and targeting them offers a potential antiinflammatory therapeutic strategy for MFS-related TAA.
proteins
2026-06-17 | Fibrillin-1 Inhibits Early Adipogenic Commitment Via αvβ3 Integrin Signaling.
Extracellular fibrillin-1 is present in many tissues, including adipose tissue. Mutations in fibrillin-1 cause Marfan syndrome, paradoxically presenting with either low body fat at younger ages or frequently increased adiposity in older individuals. The latter correlated well with data obtained with the Fbn1mgR/mgR mice, which show that global fibrillin-1 deficiency leads to sex-dependent obesity by negatively regulating early adipogenic stem cell differentiation. However, the underlying cell receptors and mechanisms remained unknown. Here, we used recombinant fibrillin-1 fragments harboring either an active RGD integrin-binding motif (rFBN1-N-RGD) or an inactive RGA motif (rFBN1-N-RGA) and tested their roles in adipogenic differentiation with primary mesenchymal progenitors isolated from bone marrow or fat tissue, as well as with adipogenic 3T3-L1 cells. rFBN1-N-RGD inhibited adipogenic differentiation in all cell models when present during the early commitment phase but not during the maturation phase, whereas the rFBN1-N-RGA control was inactive. siRNA-mediated gene silencing or pharmacologic inhibition of integrin αvβ3, but not α5β1, rescued rFBN1-N-RGD-dependent inhibition of adipogenic differentiation. Fibrillin-1 engagement of integrin αvβ3 triggered activation of the downstream focal adhesion kinase (Fak)-Src kinase (Src) signaling cascade, driving extracellular signal-regulated kinase (Erk) activation. This cascade suppressed early adipogenic transcriptional programs by restraining Cebpα and Pparγ activation, thereby maintaining progenitor cells in a committed but undifferentiated state. Pharmacological inhibition of Fak, Src and Erk restored the anti-adipogenic effect of rFBN1-N-RGD. These data establish the integrin αvβ3-Fak-Src-Erk axis as an important signaling pathway by which fibrillin-1 imposes an adipogenic checkpoint during the early adipogenic commitment phase, thereby limiting excessive differentiation.
2026-06-11 | Lymphatic dysfunction and ZFP36 deficiency contribute to myxomatous valve degeneration in Marfan Syndrome mice.
Enhanced TGFβ signaling caused by mutations in Fibrillin-1 (FBN1) in patients with Marfan syndrome (MFS) leads to myxomatous degeneration of the mitral valve (MDMV). MDMV can result in mitral valve prolapse, severe regurgitation, and sudden cardiac death. However, it remains unknown whether lymphatic vessel (LV) dysfunction contributes to MDMV development in MFS. Here, we show that lymphangiogenesis in murine mitral valves (MVs) begins postnatally. However, this process is inhibited in a mouse MFS model, Fbn1 mutant (Fbn1C1039G/+) mice, accompanied by disrupted lymphatic cell-cell junctions, impaired lymphatic drainage, and an abnormally widespread distribution of MHCII+ infiltrating macrophages. Treatment of Fbn1 mutant mice with VEGF-C156S, a selective VEGFR3 agonist, stimulates the ERK and Akt pathways, increases LV density in MVs, and ameliorates MDMV. Fbn1 mutant MVs display disorganized valvular endothelial cells (VECs) and decreased expression of the anti-inflammatory modulator Zfp36 (zinc finger protein 36) in VECs and immune cells. Treatment with FTY720 (Fingolimod), a ZFP36 activator and S1P antagonist, rescues MDMV phenotypes in Fbn1 mutant mice by reducing immune cell infiltration and restoring lymphatic cell junctions and drainage. These findings suggest that the Fbn1 mutation causes LV hypoplasia and defective lymphatic drainage in MVs, driven in part by pro-inflammatory VECs, leading to MFS-related MDMV.
2026-05-28 | HSPB7 Deficiency Drives Aortic Aneurysm Progression in Marfan Syndrome Through Vascular Smooth Muscle Cell Phenotypic Switching.
Marfan syndrome (Mfs) arises from mutations in FBN1, predisposing individuals to thoracic aortic aneurysm (TAA) through abnormal smooth muscle cell behaviour. The role of HSPB7 in Mfs-related TAA remains poorly understood. By integrating multi-omics analysis with hiPSC-derived VSMCs from patients with Mfs, we elucidated the molecular landscape of Mfs-associated TAA. Analysis revealed immune cell infiltration, a reduced proportion of VSMCs, and altered intercellular communication. Pathway analyses indicated changes in cell adhesion, extracellular matrix (ECM) remodelling, and immune signalling, with downregulated metabolic pathways. Findings suggest structural, immune, and metabolic imbalances in Mfs-TAA pathogenesis. Downregulation of HSPB7 was associated with altered proliferation, migration, and metabolic activity. Overexpression of HSPB7 in patient-specific hiPSC-derived VSMCs attenuated these pathological features and promoted a more contractile phenotype. These findings suggest that HSPB7 may be involved in the regulation of VSMCs' phenotypic modulation in Mfs-TAA and provide mechanistic insight into disease-associated cellular alterations.
2026-03-08 | PINCH proteins orchestrate vascular mural cell homeostasis through integrated signaling and transcriptional networks.
Vascular mural cells (VMCs) are crucial for vascular stability, and their dysfunction underlies cardiovascular pathologies including atherosclerosis and aortic aneurysms. PINCH proteins are core focal adhesion components mediating integrin signaling, yet their roles in VMC development remain elusive. Here, we generated mice with conditional deletion of both PINCH1 and PINCH2 in Pdgfrb-lineage VMCs, which resulted in perinatal lethality accompanied by severe arterial enlargement, hemorrhage and defective angiogenesis. Mutant VMCs exhibited profound defects in cytoskeletal organization, proliferation, differentiation, adhesion and extracellular matrix assembly. Multi-omics analyses revealed that PINCH deficiency dysregulated phospho-signaling networks, hyperactivating PDGFR/EGFR/AKT/ERK and STAT/NF-κB pathways while impairing integrin-FAK-SRC and cell cycle-associated pathways (p53, p27). RNA-seq demonstrated altered expression of genes enriched in immune response (CD74, Tlr2), cytoskeleton (TUBB3, ACTA2) and VMC differentiation (Rgs5, Kcnj8, ABCC9). Importantly, we identified PINCH1 as a nuclear transcriptional coregulator that directly represses proliferative-inflammatory programs while promoting contractile-adhesive and cytoskeletal organization signatures. The clinical relevance of these findings is underscored by downregulation of PINCH genes in human atherosclerosis and Marfan syndrome aneurysms, with conserved dysregulation of key PINCH targets including CD74 and RGS5. Our work reveals a dual cytoplasmic-nuclear mechanism for PINCH in maintaining vascular homeostasis, providing both mechanistic insights and therapeutic targets for vascular diseases.
2026-01-01 | Aortic biomechanics in paediatric and adolescent patients with Marfan syndrome
Abstract not currently available.
small molecules
2026-08-03 | Lymphatic therapies open the valve in Marfan syndrome.
Myxomatous degeneration of the mitral valve (MDMV) is a common cardiovascular manifestation of Marfan syndrome (MFS), yet the role of lymphatic vessels in the disease progression remains unknown. In this Commentary, we discuss the study by Tan, Kume, and colleagues, which identifies defective lymphangiogenesis as a previously unrecognized driver of MDMV. Their work demonstrates that impaired lymphatic development and drainage promote valve inflammation through reduced ZFP36-mediated antiinflammatory signaling, whereas restoration of lymphatic function or pharmacological activation of ZFP36 with the FDA-approved drug FTY720 ameliorates disease progression. These findings establish lymphatic vessels as critical regulators of mitral valve homeostasis and support exploration of lymphatic-targeted therapeutic opportunities for MFS-associated valvular disease.
2026-07-17 | Genetic Bone Diseases: A Scoping Review of Pathology, Symptoms, Diagnosis, Treatment, and New Horizons.
Genetic bone diseases are a rare group of afflictions suffered by the general population. However, their rarity should not diminish research efforts to help patients understand and treat their diseases. This review summarizes the pathology, symptoms, diagnosis, and treatment insight into six well-known genetic bone diseases. Only six bone diseases are included due to the relatively low prevalence of them as whole limiting our scope to ensure accurate information and attention is provided for each disease individually. A literature search of PubMed is conducted, including studies published within the past five years (January 2020-December 2025). Thirty-six studies met inclusion criteria, and no significant risk of bias is identified among the selected articles. Study findings are synthesized into disease overview, clinical and radiographic features, and diagnostic and treatment approaches. Actively developing or novel therapies relevant to each disease are also included. These treatments include: fresolimumab for osteogenesis imperfecta, small interfering ribonucleic acid (RNA) therapy for Osteopetrosis, denosumab for Paget's disease of bone, vosoritide/recifercept/infigratinib for achondroplasia, mesenchymal stem cell therapy for craniosynostosis, and combination losartan and atenolol therapy for Marfan syndrome. These treatments are generally more recently acknowledged in literature and are either actively undergoing research or require further research to determine their efficacy.
2026-07-13 | Sex-Dependent Vascular Responses to Atorvastatin Across Multiple Arterial Beds in a Mouse Model of Marfan Syndrome.
Marfan syndrome (MFS) is characterized by progressive aortic aneurysm formation resulting from mutations in the fibrillin-1 (Fbn1) gene. Although the thoracic aorta is the primary site of pathology, accumulating evidence indicates that vascular dysfunction in MFS extends beyond the aorta to involve multiple arterial beds. Statins have been shown to attenuate aneurysm progression in experimental models of MFS; however, their effects on systemic vascular remodeling and arterial stiffness outside the aorta remain poorly characterized. In this study, we investigated the impact of chronic atorvastatin therapy on vascular structure and hemodynamic function across multiple vascular beds in the Fbn1^C1041G/+^ mouse model of MFS. Male and female control and MFS mice received drinking water with or without atorvastatin (1 g/kg/day) from 4 weeks to 6 months of age, enabling the effects of atorvastatin to be assessed in both healthy and MFS arteries. High-frequency ultrasound imaging was used to assess vascular parameters in the aorta, left common carotid artery (LCCA), and posterior cerebral artery (PCA). Atorvastatin treatment significantly attenuated aortic root dilation in both male and female MFS mice and reduced aortic pulse wave velocity (PWV), indicating improved arterial compliance. In the carotid circulation, atorvastatin significantly reduced LCCA wall thickness and carotid PWV, although carotid wall strain did not improve. Atorvastatin raised both systolic and diastolic blood pressure in male and female MFS mice relative to untreated MFS animals, reaching levels not significantly different from untreated controls in both sexes, while having little effect in healthy controls apart from a rise in female diastolic pressure. In the posterior cerebral artery, peak systolic velocity, a hemodynamic index rather than a direct measure of perfusion, showed similarly sex-dependent changes, increasing in female MFS mice but decreasing further in males after atorvastatin. Collectively, these findings demonstrate that atorvastatin exerts systemic but heterogeneous vascular effects in MFS, improving arterial stiffness and structural remodeling across multiple arterial beds while producing sex-specific hemodynamic responses that warrant further investigation.
2026-07-07 | Fibronectin-induced overactivation of αVβ3-PI3K-PIP3-PDK1-ILK signaling drives aortic disease in Marfan syndrome.
Thoracic aortic aneurysms and dissections (TAAD), a life-threatening complication of Marfan syndrome (MFS), lack curative therapies. Our previous studies revealed that versican accumulation drives MFS aortopathy through AKT-NO pathway overactivation, but the upstream mechanisms remained unclear. Here, we show that versican-driven fibronectin (FN) accumulation activates an αVβ3-PI3K-PIP3-PDK1-ILK signaling cascade leading to AKT-NOS2 upregulation and aortic disease. FN accumulates in aortas of MFS patients and mice of both sexes and correlates with increased αVβ3 integrin and ILK expression. Disrupting FN assembly or inhibiting αVβ3, PI3K, PIP3, PDK1 or ILK prevents FN-induced AKT activation and NOS2 upregulation, restores vascular contractility, and limits aortic dilation in MFS mice. Inhibition of ILK or PDK1, aortic silencing of Ilk, or smooth muscle-specific deletion of Ilk reverses or prevents aortic growth. Together, these findings define a mechanistically integrated FN-αVβ3-PI3K-PIP3-PDK1-ILK-AKT-NOS2 signaling cascade in MFS and support its causative role in human TAAD, highlighting its components as potential targets for therapeutic intervention.
2026-06-30 | Mechanotransduction in Marfan Syndrome and Related Aortic Disorders: Insights from Transcriptomic Analyses
Heritable thoracic aortic diseases (HTADs) comprise a genetically heterogeneous group of disorders predisposing patients to thoracic aortic aneurysm and dissection, yet current medical therapies remain limited to slowing disease progression rather than preventing aortic wall failure. Although pathogenic variants affect diverse genes encoding extracellular matrix (ECM) components, smooth muscle contractile proteins, and signaling molecules, these defects converge on disruption of the mechanobiological systems that maintain aortic wall integrity. The thoracic aorta functions as a mechanically integrated tissue in which endothelial cells, vascular smooth muscle cells, fibroblasts, immune cells and ECM continuously sense and respond to pulsatile biomechanical forces. Genetic perturbations affecting ECM architecture, contractile force generation, or growth factor signaling alter force transmission across this multicellular network, leading to maladaptive mechanotransduction, cellular phenotypic modulation, and progressive aneurysm formation. Using Marfan syndrome as a paradigmatic ECM-driven aortic disease, this review synthesizes current understanding of how altered biomechanics, biochemical signaling and immune responses reshape intercellular communication and activate disease-associated signaling pathways, including dysregulated TGF-β, nitric oxide, angiotensin receptor, calcium-dependent, and metabolic signaling. We highlight how single-cell transcriptomic analyses have elaborated changes in different cell-level functions including, ECM degradation, iron homeostasis, circadian/stress responses. Changes in iron metabolism in different cell types in the aorta suggest possible coordinated metabolic changes in aneurysm progression. These mechanistic insights enable the identification of cell-type–specific pathogenic programs and therapeutic discovery through systems-level approaches. We highlight the translational opportunities and challenges emerging from mouse models and human studies, emphasizing that therapeutic efficacy depends not only on pathway selection but also on disease stage, cellular context, and timing of intervention. Together, these findings support a model in which HTAD progression reflects dynamic, multicellular failure of mechanobiological homeostasis and provide a framework for the development of more precise, mechanism-based therapies.
gene therapies
2026-07-04 | Marfan Syndrome: Molecular Basis, Clinical Spectrum, Diagnosis, and Management- A Comprehensive Review
Marfan syndrome (MFS) is a hereditary connective tissue disorder primarily caused by mutations in the FBN1 gene, leading to abnormalities in extracellular microfibril formation and dysregulation of transforming growth factor-beta (TGF-β) signaling. The disorder exhibits autosomal dominant inheritance and presents with significant clinical variability, affecting the cardiovascular, skeletal, and ocular systems. Among these, cardiovascular complications such as aortic root dilation, aneurysm, and dissection represent the most life-threatening manifestations. Advances in diagnostic approaches, particularly the revised Ghent criteria, have improved diagnostic accuracy by integrating clinical features, imaging findings, and genetic testing. Imaging modalities such as echocardiography, magnetic resonance imaging, and computed tomography play a critical role in early detection and monitoring of disease progression. Genetic testing further enhances diagnostic precision, especially in atypical cases. Management strategies focus on preventing complications and improving survival. Pharmacological treatments, including beta-blockers and angiotensin receptor blockers, reduce hemodynamic stress and modulate TGF-β signaling. Surgical interventions, particularly prophylactic aortic root replacement, are essential in high-risk patients. A multidisciplinary approach involving cardiology, genetics, ophthalmology, and orthopedics is crucial for optimal patient care. Emerging diagnostic tools such as next-generation sequencing and biomarker-based assessments, along with novel therapeutic strategies including gene therapy and targeted molecular treatments, hold promise for future disease management. Continued research into the molecular mechanisms of MFS is essential to transition from symptomatic treatment to disease-modifying therapies and to further improve patient outcomes.
2026-06-19 | The impact of FBN1 variant types on pregnancy-related aortic dissection in women with Marfan syndrome.
Pregnancy in women with Marfan syndrome (MFS) increases the risk of aortic dissection, yet management based solely on aortic root diameter often fails to predict this complication, particularly Stanford type B dissection. Haploinsufficient (HI) FBN1 variants are associated with more severe aortic phenotypes. We investigated the relationship between FBN1 genotype and pregnancy-related aortic dissection in women with MFS. We retrospectively analyzed women with genetically confirmed MFS whose pregnancies progressed beyond the second trimester and who were managed at a single tertiary referral center between 1993 and 2024. FBN1 variants were categorized as HI or non-HI. Pregnancy-related aortic dissection-defined as occurring during pregnancy or within six months postpartum-was evaluated in relation to variant type. Thirty-five women (15 HI, 20 non-HI) were included. Pregnancy-related aortic dissection occurred in 11 women: seven were referred after the dissection occurred and nine were Stanford type B. The incidence was higher in the HI group than in the non-HI group (9/15 [60%] vs 2/20 [10%], P = 0.002). Pre-pregnancy native aortic root diameters did not differ between those with and without dissection. Additional risk factors included undiagnosed with MFS at the time of dissection and absence of β-blocker therapy. HI FBN1 variants were associated with pregnancy-related aortic dissection in this cohort. Stanford type B dissection may occur even with mild aortic dilation, highlighting the limitations of diameter-based risk stratification. Incorporating FBN1 genotype into preconception counseling and pregnancy management may improve maternal outcomes. However, given the retrospective single-center design, prospective validation is warranted.
2026-03-11 | Genotype-Guided Risk Stratification of Mitral Valve Surgery in Marfan Syndrome.
Although genotype-based risk stratification for aortic disease has been extensively studied in Marfan syndrome (MFS), mitral valve disease has received less attention despite being a major cardiovascular complication requiring surgery in up to 16% of cases. The authors aimed to evaluate genotype-specific differences in mitral valve disease progression and surgical intervention to inform precision medicine approaches in MFS. This retrospective cohort study included 437 MFS patients with pathogenic FBN1 variants (2006-2024). Variants were classified by molecular mechanism (premature termination codon [PTC] variants vs in-frame variants [IFVs]) and genomic location. Time-to-event cause-specific analysis assessed genotype-specific risks for mitral valve surgery. Among 437 patients, 206 (47.1%) had PTC variants and 231 (52.9%) IFVs. Mitral valve surgery was performed in 38 patients (8.7%) at median age of 25.0 years. Among IFVs, those within the DNCD region (Dominant Negative variants affecting Cysteine residues and in-frame Deletions; exons 26-37 and 44-50) showed markedly higher 30-year cumulative incidence of mitral valve surgery (23.8% [95% CI: 11.7%-35.9%] vs 1.24% [95% CI: 0.0%-2.96%] in other IFVs and 3.20% [95% CI: 0.66%-5.77%] in PTC variants). IFVs within the DNCD region showed the earliest onset of mitral valve surgery in childhood/adolescence, whereas PTC variants demonstrated delayed risk beginning around age 30 years. Cox analysis confirmed IFVs within the DNCD region had highest risk of mitral valve surgery for patients aged ≤30 years (HR: 7.83 vs PTC variants; 95% CI: 3.14-19.57; P < 0.001) with robust discrimination (C-index = 0.725). IFVs within the DNCD region confer the highest risk for mitral valve surgery with distinct age-dependent patterns. These findings enable genotype-guided risk stratification with age-specific surveillance protocols, potentially transforming clinical management in MFS.
2025-11-15 | Gene editing for inherited cardiac conditions: A new frontier in cardiology.
Inherited cardiac conditions (ICCs) such as hypertrophic cardiomyopathy and Marfan syndrome pose significant global health challenges, often rooted in complex genetic mutations. Recent advances in gene editing, particularly the CRISPR/Cas9 system, have opened new avenues for precise, personalized interventions. This review examines the current landscape of gene editing in cardiology, with emphasis on its scientific promise, integration with epigenetics, gene therapy, and artificial intelligence, and its potential to transform clinical outcomes. Key gene editing strategies are analyzed for their efficacy and translational potential. The review also explores ongoing clinical trials and emerging research, offering practical insights for future studies. Ethical implications are critically evaluated, with proposed frameworks to address concerns around safety, equity, and long-term consequences. By synthesizing these developments, this review underscores the urgent need for continued interdisciplinary research in the quest to mitigate inherited cardiac diseases.
2025-09-03 | Therapeutic Opportunities of Marfan Syndrome: Current Perspectives.
Marfan syndrome (MFS) is a hereditary connective tissue disorder that is primarily caused by mutations in the fibrillin-1 (FBN1) gene. This disease predominantly affects the eyes, bones, and cardiovascular system, with cardiovascular complications posing the most significant threat to life. Currently, conventional treatments, which are based on pharmacological management and surgical interventions, aim to slow disease progression and manage life-threatening cardiovascular complications. Emerging technologies such as CRISPR-Cas9 gene editing and induced pluripotent stem cell (iPSC) have advanced the understanding of FBN1 mutation heterogeneity and disease mechanisms beyond TGF-β signaling, providing novel platforms for drug discovery and personalized therapeutic exploration. This review explores recent progress in MFS therapies, focusing on surgical innovations, emerging medicine and therapeutic targets, while discussing the potential future applications of gene therapy.
cell therapies
2026-05-01 | A46-07 Spontaneous Pneumothorax as a Complication of Marfan Syndrome
Abstract Marfan syndrome is an autosomal dominant connective tissue disease that typically affects the musculoskeletal, cardiovascular, and ocular systems. This is due to a mutation encoding fibrillin, resulting in complications from defective connective tissue (Elastin primarily). Pulmonary manifestations, although not classical, can also be seen, which can present as the following: emphysema, pneumothorax, sleep apnea, asthma, bronchiectasis, and interstitial lung disease. We present a case of a patient with Marfan syndrome complicated by spontaneous secondary pneumothorax (SSP). We present a case of a 49-year-old male with a prior medical history of Marfan syndrome with multiple complications, such as aortic dissection requiring aortic graft and valve replacement, retinal detachment, and an extensive smoking history (40 pack years), who presented with a sudden onset of chest pain and shortness of breath. Chest imaging showed a large right-sided pneumothorax with mediastinal shift. A pigtail chest tube catheter was placed successfully with reexpansion of the right lung. CT imaging revealed paraseptal emphysematous changes with prominent right-sided blebs. Due to the patient having a high risk of recurrent pneumothorax in the setting of prior diagnosed Marfan syndrome and emphysema with blebs on imaging, pleurodesis with surgical resection was pursued. Our patient subsequently went under right-sided VATS with upper lobe resection/bleb resection, mechanical pleurodesis, and complete pleurectomy. Pathology showed lung tissue with emphysematous changes, subpleural blebs, and fibroelastotic subpleural scarring with focal calcification. In addition to these changes was eosinophil-rich inflammation in the pleura. His post-operative course was uncomplicated, and subsequently discharged. Our case demonstrates potential pulmonary complications from underlying Marfan syndrome. Marfan syndrome is typically diagnosed in younger adults rather than in the 4th decade of life, as seen in our patient. The lifetime incidence of pneumothorax is reported to be 4-14% in those with Marfan’s. Although pneumothorax is not commonly a presenting feature, it is prevalent enough to be included as a criterion for diagnosis. SSP results from bullae with predilection in the apices. Management of SSP in these cases is to prevent recurrence, in addition to tube thoracostomy placement. Although there is a lack of data in adults, the incidence of recurrent pneumothorax if conservative measures are pursued initially in adolescents can be as high as 78%; therefore, definitive surgical management is recommended initially in those with Marfan’s. The surgical approach should include VATS with wedge resection, and bullectomy should be performed as bullae are the likely cause of SSP if identified. This abstract is funded by: None
2026-03-17 | SPP1high fibrogenic macrophages mediate protective fibrotic remodeling and promote vascular stability in hypertension-associated aortic dissection.
Hypertension-associated aortic dissection (HTN-AD) features intense immune activation and extracellular matrix disruption, yet the cellular programs that promote aortic-wall stabilization remain unclear. We aimed to identify macrophage states associated with vascular integrity and to determine whether these states could be mechanistically or therapeutically leveraged. Single-cell RNA sequencing was performed on thoracic aortas from HTN-AD, Marfan syndrome-associated AD, and donor controls (n = 3 per group). Peripheral and tear-adjacent blood samples were analyzed in patients with HTN-AD, MS-AD, and healthy donors (n = 30 per group), with paired intraoperative tear-adjacent sampling performed when available (n = 10). Circulating monocytes and serum cytokines were profiled by flow cytometry and ELISA. Functional validation included TGF-β1 conditioning of human monocytes and murine macrophages and adoptive transfer experiments in a murine AD model. A distinct SPP1high fibrogenic macrophage population was enriched in diseased aortas and transcriptionally bridged low-inflammatory macrophages and matrix-active states. Patients with HTN-AD displayed increased tear-adjacent non-classical monocytes and higher monocytic SPP1, correlating with serum TGF-β1 and a shorter ICU stay. TGF-β1 induced an SPP1-dependent fibrogenic program in macrophages while suppressing inflammatory markers. Myeloid Spp1 deficiency aggravated aortic dilatation and wall disruption, whereas adoptive transfer of TGF-β1-conditioned SPP1high macrophages reduced false lumen formation, improved collagen organization, decreased IL-1β and IL-6 expression, and enhanced survival. A TGF-β1-SPP1 axis drives the emergence of SPP1high fibrogenic macrophages that support structural stabilization of the dissected aorta. Targeting this reparative myeloid program may offer a mechanistically informed therapeutic strategy for acute aortic syndromes.
2026-03-08 | Two Cases of Successful Kidney Transplantation From a 39-Year-Old Male Deceased Donor With Marfan Syndrome: A Case Series.
BACKGROUND Marfan syndrome is a multisystemic, autosomal dominant connective tissue disorder caused by mutations in the fibrillin-1 gene. It is associated with life-threatening complications, especially aortic aneurysms and dissections, and has a global prevalence of 1 in 3000-5000 individuals. Although kidney transplantation is the standard treatment for end-stage renal disease (ESRD), deceased kidney donors with Marfan syndrome remain uncommon due to concerns about connective tissue fragility. Emerging reports, however, indicate that kidneys from such donors may be safely used. This report describes 2 successful kidney transplantations from a 39-year-old male donor with confirmed Marfan syndrome. CASE REPORT Case 1. The donor died from subarachnoid hemorrhage and had a history of aortic arch replacement for aortic dissection. Both kidneys were retrieved from the retroperitoneal space, prepared according to standard protocols, and stored in University of Wisconsin Store Protect Plus organ preservation solution under static cold storage at 4°C. Case 2. A 59-year-old man with ESRD secondary to diabetic nephropathy underwent his first kidney transplantation. He was hemodialyzed with residual diuresis. The right kidney was transplanted without complications, and the recipient achieved immediate and stable graft function. Case 3. The second recipient was a 34-year-old man with ESRD due to vesicoureteral reflux and obstructive nephropathy, also on hemodialysis with preserved diuresis. Left kidney transplantation proceeded uneventfully. He experienced delayed graft function, which resolved with appropriate management, resulting in satisfactory renal recovery. CONCLUSIONS These cases support the growing evidence that kidneys from donors with Marfan syndrome can function effectively after transplantation. Such donors may represent a valuable and underutilized resource, with the potential to expand the kidney donor pool safely.
2025-11-17 | Pediatric Marfan Syndrome and Heart Transplantation: Insights From the PHIS Database.
Marfan syndrome (MFS) is a connective tissue disorder associated with significant cardiovascular complications, including heart failure. Orthotopic heart transplantation (OHT) is considered controversial in this population due to concerns about post-transplant aortic complications, particularly in children. We conducted a retrospective review of the Pediatric Health Information System (PHIS) database to identify patients under 18 years of age with a diagnosis of MFS who underwent OHT between 2004 and 2024. Patients were propensity matched (3:1) to non-MFS OHT recipients. Outcomes included graft failure, aortic events, and re-transplant-free survival. Ten pediatric MFS patients were identified among 5493 OHT recipients. The median age at OHT was 12.5 years. Over a median follow-up of 3.73 years, no in-hospital mortalities or repeat transplants were observed; two patients experienced rejection, and one developed aortic root dilation without requiring intervention. Propensity-matched analysis showed no significant differences in rejection, aortic events, or transplant-free survival between MFS and non-MFS cohorts. Though rare, pediatric MFS patients undergoing OHT demonstrated excellent short-term outcomes with no MFS-related surgical complications. These findings challenge current exclusionary practices and support further research into long-term outcomes.
2025-09-17 | Personalized External Aortic Root Support (PEARS) in the Treatment of Marfan Syndrome and Bicuspid Aortic Valve Aneurysms: First Case Series in the American Continent.
Conventional surgical approaches for aortic root aneurysms, including valved grafts and valve-sparing techniques, present inherent limitations such as the requirement for anticoagulation and the potential for late reoperation. Personalized External Aortic Root Support (PEARS), utilizing the ExoVasc® implant, represents a novel approach that aims to overcome these limitations. This report presents the initial clinical experience with the ExoVasc® PEARS implant in the Americas, encompassing 10 patients (six males, age range 30 - 52 years, mean age 37.8 years) diagnosed with aortic root aneurysms. Indications for PEARS included Marfan syndrome (eight patients, including one reoperation), bicuspid aortic valve (two patients, including one with anomalous coronary artery), and associated valvular dysfunction. Cardiopulmonary bypass was utilized in four cases. No major adverse postoperative events were observed. Postoperative recovery was generally uneventful, with minor complications, including pericarditis and atrial fibrillation, successfully managed with medical therapy. Aortic dimensions remained stable at 30-day and one-year follow-ups. This initial experience demonstrates the feasibility, safety, and efficacy of the PEARS technique for the treatment of aortic root aneurysms. Potential advantages over traditional approaches include the possibility for off-pump procedures, reduced risk of aortic valve dysfunction, shorter hospital stays, and elimination of the need for long-term anticoagulation therapy. Further investigation is warranted to evaluate the long-term durability and clinical outcomes of this innovative approach.
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2026-06-26 | The Efficacy of Antihypertensive Drugs and miR-632 Inhibition on Parietal Remodeling in a Model of Marfan Thoracic Aortic Aneurysm.
Marfan syndrome (MFS) is a connective tissue disorder caused by FBN1 mutations, leading to elastic fiber disarray and early thoracic aortic aneurysm (TAA) formation. Currently, pharmacological treatments lack specificity and only delay progression. We previously reported a specific TGFβ-driven miR-632 upregulation in MFS TAA tissues and blood causing smooth muscle cell dedifferentiation and aortic wall degeneration. This study evaluated the effects of three conventional antihypertensive drugs (β-blocker, ACE inhibitor, and sartan) on parietal remodeling, comparing them with a miR-632 inhibitor in an ex vivo TGFβ1-induced model of MFS TAA. Using an ex vivo paired experimental framework based on independent biological pools of human TAA tissue, gene expression and Western blot analyses demonstrated that only losartan significantly reduced miR-632 and vascular degeneration markers. Notably, combined treatment with ramipril and carvedilol compromised losartan's efficacy, highlighting the need for careful therapeutic selection. In this ex vivo setting, miR-632 inhibition demonstrated a promising capacity to counteract aortic remodeling, serving as a mechanistic proof-of-concept that warrants further preclinical in vivo validation. Our data emphasize that choosing the right treatment in MFS aortopathy requires understanding its specific impact on cellular pathways. Our findings identify losartan as the most effective standard drug in this model, while suggesting miR-632 as a potential future target to stabilize the aortic wall and, prospectively, delay surgery.
2025-11-01 | Exploration of cyclophilin A antibody anti-eCypA as a new approach in the treatment of marfan syndrome
Abstract Background Marfan syndrome (MFS) is a rare genetic disease characterized by the development of aortic aneurysms with a high risk of complications such as aortic dissection. Current treatment options are limited to advanced surgical procedures with the risk of complications. Thus, alternative, less invasive therapeutic approaches are required. Previous studies suggested that the selective inhibition of extracellular cyclophilin A (CypA), a danger-associated molecular pattern (DAMP) secreted in response to vascular stress, reduces the formation of abdominal aortic aneurysms. Therefore, we aimed to explore the effects of selectively inhibiting CypA on aortic aneurysm formation and wall architecture in MFS using fibrillin-1-deficient mice (mgR/mgR), a well-characterized murine model for MFS. Methods Over the course of four weeks, male mgR/mgR mice were subcutaneously injected with the CypA antibody anti-eCypA or an idiotypic IgG control. Ultrasound examination was performed on the baseline and after two and four weeks of treatment. Moreover, we assessed the diameter of the thoracic aorta using innovative MRI scans four weeks after the beginning of the treatment. Furthermore, the aortic wall constitution was evaluated by performing immunhistochemistry, zymography and elastin staining of aortic tissue. Results The analysis of elastin breaks by Elastin van Gieson staining in the aortic wall of the mice showed a significant decrease of elastin breaks in treatment compared to control group. While analysis of the ultrasound images showed an enlarged aortic diameter in both groups after four weeks, the increase in the treated group was less pronounced than in the control group. Interestingly, two weeks of treatment did not lead to a strong increase in diameter in either group, suggesting the main formation of aneurysms develops rather between weeks two and four. Importantly, the results of the MRI scan analysis were consistent with the ultrasound findings. Notably, we found marked decrease in gelatinase activity following treatment and a reduction in EMMPRIN and VCAM1 expression in the aortic wall in mice subjected to anti-eCypA treatment. Conclusion Our results suggest a beneficial effect of anti-eCypA in the remodelling of the aortic wall in MFS, demanding further exploration with a larger animal cohort. Ultimately, CypA inhibition employing anti-eCypA may present a valuable alternative to more invasive surgical strategies for the treatment of MFS.
2025-10-01 | MON-809 "Strengthening Bones, Supporting Lives: Romosozumab in Osteoporosis Management for Marfan Syndrome"
Abstract Disclosure: S. Shanthosh Kumar: None. Z. Shafique: None. K. Selk: None. Introduction: We present a case reporting clinically significant outcome in management of osteoporosis with Romosozumab in a 61 year old female with a history of Marfan Syndrome (MFS). CASE PRESENTATION Our patient has medical history remarkable for Marfan syndrome, osteoporosis, remote history of grave’s disease(1996) treated with radioactive iodine ablation, primary hyperparathyroidism with surgical cure(2012), and post-menopausal status at age 50. For osteoporosis, patient was previously on alendronate followed by raloxifene with a combined treatment course of approximately 15 years. A baseline DEXA scan was not available, however, a repeat study in 2023 demonstrated a bone mineral density (BMD) of 0.761 g/cm2 (T score -3.5) at the lumbar spine and 0.647 g/cm2 (T score -2.8) at the left femoral neck. Her parathyroid hormone, phosphorus, calcium, thyroid, and serum electrophoresis testing were unrevealing. Given the severity of osteoporosis, she was deemed a candidate for an anabolic agent, Romosozumab. Following completion of monthly infusions of Romosozumab for 12 months, a repeat DEXA scan in 2024 showed an interval increase in BMD at the lumbar spine (0.830 g/cm2, T score -2.9) and hip (femoral neck 0.736, T score -2.2) with the least significant change indicating this was a significant change. CASE DISCUSSION MFS is an autosomal dominant condition resulting from a mutation in the fibrillin-1 gene. Affected adults have lower axial bone mineral density, specifically in their lumbar spine and hip. Risk of osteoporosis and fracture risk has been reported to be higher in patients with MFS as compared to matched reference populations. Affected individuals are now living longer and therefore, addressing fracture risk reduction is imperative. Although she had received treatment with both alendronate and raloxifene, these two agents were unsuccessful in effectively halting bone loss and facilitating bone formation. Although our patient also had multiple other risk factors as mentioned earlier, these were promptly identified and received definitive therapy, thereby making them less likely to lead to ongoing progression. Romosozumab is a humanized monoclonal antibody with anabolic and antiresorptive benefits. It binds and inhibits sclerostin thereby promoting bone formation and inhibiting bone resorption. Given the severity of her osteoporosis, our patient completed a 12-month course of therapy without any significant side effects and was found to have clinically significant improvement in her axial bone mineral density. Conclusion To our knowledge, there are no case reports on use of Romosozumab in the MFS population with osteoporosis. This case report highlights this therapy as a possible effective therapeutic intervention but also recognizes the need for ongoing research to establish standard and effective treatment guidelines for management of osteoporosis in MFS. Presentation: Monday, July 14, 2025
2025-06-05 | Diagnosis of skeletal fragility due to Loeys-Dietz syndrome and treatment with romosozumab followed by denosumab.
Loeys-Dietz syndrome (LDS) is an autosomal dominant, inherited connective tissue disorder caused by a pathogenic variant in TGF-β signaling-related genes. LDS is associated with a high risk of low bone mineral density (BMD) and fractures. We present a case report of a 43-year-old premenopausal woman with skeletal fragility who was diagnosed with LDS type 4 due to a large heterozygous deletion in the TGFB2 gene. Upon initial referral, she was evaluated for secondary osteoporosis. Although mild abnormalities in calcium metabolism, menstrual irregularities, and lack of exercise were observed, they were not associated with this condition. However, a thorough family history and physical examination raised the suspicion of Marfan syndrome and related disorders, which were subsequently confirmed using genetic testing. Treatment with romosozumab for 1 year increased the lumbar spine BMD from 0.750 g/cm2 (Z-score -2.1) to 0.881 g/cm2 (Z-score -1.0) and the femoral neck BMD from 0.407 g/cm2 (Z-score - 3.0) to 0.428 g/cm2 (Z-score - 2.6), with a slight increase in total hip BMD from 0.525 g/cm2 (Z-score -2.6) to 0.527 g/cm2 (Z-score -2.4). Subsequent therapy with denosumab for 1 year further improved the lumbar spine BMD to 0.939 g/cm2 (Z-score, -0.5), femoral neck BMD to 0.496 g/cm2 (Z-score, -2.0), and total hip BMD to 0.552 g/cm2 (Z-score, -2.2). To our knowledge, this is the first case report of an improvement in BMD with romosozumab, followed by denosumab, for skeletal fragility due to LDS. Our findings suggest that this treatment regimen may be an effective therapeutic option for the management of skeletal fragility in patients with LDS.
2025-01-16 | Inhibition of aortic CX3CR1+ macrophages mitigates thoracic aortic aneurysm progression in Marfan syndrome in mice.
The pathogenesis of thoracic aortic aneurysm (TAA) in Marfan syndrome (MFS) is generally attributed to vascular smooth muscle cell (VSMC) pathologies. However, the role of immune cell-mediated inflammation remains elusive. Single-cell RNA sequencing identified a subset of CX3CR1+ macrophages mainly located in the intima in the aortic roots and ascending aortas of Fbn1C1041G/+ mice, further validated in MFS patients. Specific elimination of CX3CR1+ cells by diphtheria toxin in Cx3cr1-CreERT2iDTRF/+Fbn1C1041G/+ mice efficiently ameliorated TAA progression. Administering the monoclonal antibodies to respectively neutralize TNF-α and IGF1 produced by CX3CR1+ cells from MFS patients greatly suppressed the cocultured MFS patient-specific induced pluripotent stem cell-derived VSMC inflammation. BM transplantation and parabiosis revealed that CX3CR1+ macrophages are mainly originated from BM-derived monocytes. Targeting TNF-α and IGF1 in CX3CR1+ macrophages via shRNA lentivirus transduction in BM cells efficiently suppressed TAA development in BM-transplanted Fbn1C1041G/+ mice. Application of the CCR2 antagonist RS504393 to inhibit monocyte infiltration markedly reduced the accumulation of CX3CR1+ macrophages and subsequently alleviated TAA progression in Fbn1C1041G/+ mice. In summary, CX3CR1+ macrophages mainly located in aortic intima mediate TAA formation by paracrinally causing VSMC inflammation, and targeting them offers a potential antiinflammatory therapeutic strategy for MFS-related TAA.
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Drug Discovery Landscape
3 orphan drug designations for Marfan syndrome.
3 orphan drug designations for Marfan syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
enzastaurin | small molecules | FDA | 2025-04-14 | — | Aytu BioPharma, Inc. |
Allopurinol | small molecules | EMA | 2025-03-25 | — | Consorcio Centro De Investigacion Biomedica En Red |
losartan | small molecules | FDA | 2011-12-12 | — | National Marfan Foundation |
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