Search Results (472)

Peritoneal dialysis (PD) has long been an established modality of renal replacement therapy for patients with end-stage kidney disease (ESKD). Despite the modality’s advantages, significant inter-individual variability exists in peritoneal membrane transport characteristics, ultrafiltration capacity, and long-term technique survival. While PD therapy-related factors, such as dialysis solution composition, peritonitis episodes, and duration of therapy, contribute to these outcomes, genetic factors also play important roles in peritoneal membrane biology. Genetic studies have identified polymorphisms in genes involved in angiogenesis, inflammation, fibrosis, and endothelial function that influence PD outcomes. Variants in genes such as vascular endothelial growth factor, interleukin-6, transforming growth factor-β1, angiotensin-converting enzyme, endothelial nitric oxide synthase, and aquaporin-1 have all been reported to be associated with differences in peritoneal transport and susceptibility to membrane failure. These genetic discoveries provide significant insights into the pathways that lead to alterations in the PD membrane structure and function. This review article aims to explore current evidence on key genetic determinants of peritoneal membrane transport, inflammatory responses, and fibrotic transformation in PD, and to discuss their potential implications for personalised dialysis therapy and future research. Full article

N-glycosylation, particularly terminal mannose exposure, is a critical quality attribute affecting macrophage targeting and the clinical efficacy of enzyme replacement therapy for Gaucher disease. This study developed a universal, sensitive, and quantitative method to compare the N-glycan profiles of three recombinant human glucocerebrosidase products from different expression systems: imiglucerase, velaglucerase alfa, and velaglucerase beta. Using 2-aminobenzamide labeling combined with HILIC-UPLC-FLD and high-resolution mass spectrometry, an N-glycan profiling platform was established. A multidimensional calibration system integrating retention time, glucose unit values, and mass-to-charge ratios was constructed, and collision-induced dissociation tandem MS was used to identify isomers and phosphorylated glycans. The method showed good specificity, linearity, precision, and accuracy. Glycan profiling revealed clear product-dependent differences: imiglucerase was enriched in core-fucosylated Man3 structures, velaglucerase alfa was dominated by Man9 and contained more phosphorylated and sialylated glycans, whereas velaglucerase beta showed a highly homogeneous Man5 profile. These findings demonstrate how distinct manufacturing strategies shape glycosylation patterns and provide a basis for biosimilar development and comparability assessment. Full article

Background/Objectives: Mucopolysaccharidoses (MPS) are lysosomal storage disorders characterized by impaired glycosaminoglycan degradation, leading to multisystem involvement and progressive growth impairment. Longitudinal growth data in MPS IVA and MPS IIIA, including the association of ERT with growth outcomes, remain limited. This study aimed to characterize growth trajectories in MPS IVA and MPS IIIA and to assess the association of ERT with Elosulfase alfa on growth outcomes in MPS IVA patients. Methods: We retrospectively analyzed growth data from 39 patients with MPS subtypes IIIA and IVA followed at a single center between 2004 and 2024. Height and weight standard deviation scores (SDS) were calculated relative to CDC growth references and modeled using linear mixed-effects models (LMM). In the MPS IVA subgroup, the effect of ERT with Elosulfase alfa was assessed using LMM and paired SDS comparisons. Results: Growth impairment was evident across both subtypes with distinct trajectories. MPS IIIA patients showed significant height decline after age six with progressive weight loss in later childhood. MPS IVA patients exhibited persistently severe short stature and a tendency toward overweight with advancing age. Among the 16 MPS IVA patients treated with Elosulfase alfa who were included in the analysis, height SDS declined significantly during treatment (−0.127 SDS/year [95% CI: −0.194, −0.061], p < 0.001), and the rate of decline was not significantly affected by age at ERT initiation (interaction p = 0.53). Conclusions: ERT with Elosulfase alfa did not prevent progressive height loss relative to population norms. The rate of height SDS decline was not significantly influenced by the timing of ERT initiation (interaction p = 0.53), and causal conclusions cannot be drawn from this observational data. Full article

Gaucher disease is a prototypical lysosomal sphingolipid storage disorder caused by pathogenic variants in GBA1, resulting in glucocerebrosidase deficiency and accumulation of bioactive lipids, including glucosylceramide and glucosylsphingosine (lyso-Gb1). While non-neuronopathic Gaucher disease is effectively managed with enzyme replacement and substrate reduction therapies, neuronopathic forms remain largely refractory to treatment due to progressive central nervous system (CNS) involvement and limited penetration of current therapies across the blood–brain barrier. Disease pathobiology extends beyond lysosomal substrate accumulation to encompass dysregulated sphingolipid signaling, particularly sphingosine-1-phosphate (S1P)-mediated “inside-out” signaling, alongside neuroinflammation, oxidative stress, and glial activation, which collectively drive neurodegeneration. In this review, we synthesize current knowledge on sphingolipid metabolism and signaling in neuronopathic Gaucher disease and integrate these mechanisms into a three-tier, CNS-focused biomarker framework. The first tier comprises substrate-proximal markers of lysosomal burden (lyso-Gb1), which reflect GCase deficiency and correlate with systemic disease severity but incompletely capture CNS pathology. The second tier comprises markers of glial activation and neuroinflammation (glial fibrillary acidic protein [GFAP], glycoprotein non-metastatic melanoma protein B [GPNMB]), which reflect the downstream neuroimmune response to sphingolipid accumulation. The third tier comprises markers of neuroaxonal injury (neurofilament light chain [NfL]), which index irreversible neuronal damage as the terminal consequence of uncontrolled CNS disease. Together, these tiers map distinct but mechanistically interconnected stages of disease progression, from lysosomal dysfunction through glial activation to neuroaxonal loss, enabling stage-specific interpretation of biomarker signals that single-analyte approaches cannot provide. We further examine how S1P-mediated inside-out signaling links intracellular lipid dysregulation to extracellular neuroimmune and neurovascular responses and how the blood–brain barrier shapes compartment-dependent biomarker behavior across cerebrospinal fluid and blood. By grounding biomarker selection in this mechanistic cascade, the framework provides explicit criteria for pairing analytes across tiers, interpreting discordance between peripheral and CNS compartments, and designing multi-modal endpoints for clinical trials of CNS-penetrant therapies. Despite these advances, significant challenges remain, including limited longitudinal datasets, variability in assay methodologies, and incomplete validation of biomarkers as surrogates of CNS disease progression. Addressing these gaps will require harmonized, multi-modal approaches integrating biochemical, functional, and imaging measures. By positioning neuronopathic Gaucher disease as a model of sphingolipid-driven neurodegeneration, this review highlights opportunities for biomarker-guided therapeutic development relevant to Gaucher disease and the broader spectrum of sphingolipid-associated neurological disorders. Full article

Geroprotective molecules are currently being actively investigated for the prevention of skin aging. An overview of geroprotectors in dermatology encompasses agents such as antioxidants, ultraviolet (UV) photoprotective agents, chemical peels, and carbon dioxide (CO₂) lasers, each with inherent limitations, including poor tolerability in individuals with sensitive skin. Regarding biostimulators, high-molecular-weight peptides (exceeding 500 kDa) exhibit limited cutaneous bioavailability, underscoring the need for low-molecular-weight geroprotective compounds. One such candidate is dehydroepiandrosterone DHEA, a neurosteroid with anti-aging and anti-stress properties, which also serves as a precursor to sex steroids. Although topical hormone replacement therapy with estrogens and androgens is being utilized, it remains confined to formal hormone replacement regimens and is associated with a significant adverse effect profile. The aim of this review was to analyze the key molecular mechanisms underlying the effects of DHEA on the skin, with particular emphasis on its metabolism and sex- and age-dependent mechanisms of action. Additionally, this review seeks to elucidate the factors contributing to the absence of approved topical DHEA formulations and to outline the potential of DHEA as an anti-aging agent in dermatological applications. DHEA has demonstrated significant skin-improving effects in several studies; its investigation has been predominantly confined to postmenopausal women. Furthermore, the outcome measures employed in these studies lacked specificity. DHEA is not permitted for use in cosmetic products within the European Union due to its hormonal activity. Its use is only allowed as an extemporaneous formulation under the established regulatory frameworks of individual countries. The indications for its use and the appropriate dosage for men and women must be clearly defined based on the results of future clinical studies. Promising research directions include the pharmacogenetic characterization of steroidogenic enzymes and sex hormone receptors, as well as the evaluation of DHEA in both sexes, specifically in premenopausal women and in men presenting with late-onset hypogonadism. Additionally, the biological effects of the primary metabolites of DHEA, androstenedione, and 5-androstenediol, on the cutaneous function remain unexplored, including their potential anti-aging activity mediated through retinoid receptor activation. Full article

Fabry disease is an X-linked lysosomal storage disease that leads to the intracellular accumulation of glycosphingolipids in many tissues and fluids, including the kidneys. We report a single family with Fabry disease that includes seven patients carrying the pathogenic variant c.797A>C in the GLA gene, with remarkable variability in kidney involvement, assessed based on clinical, biological, and histological data. The patients were monitored for 2–9 years, and all received enzyme replacement therapy. Kidney involvement was variable and included severely decreased GFR with significant proteinuria, mildly to moderately decreased GFR with proteinuria, mildly decreased GFR with microalbuminuria or normoalbuminuria, hyperfiltration with normoalbuminuria, and preserved kidney function. All patients who underwent kidney biopsy presented with Fabry-specific lesions and, in some cases, chronic histological damage. This study provides valuable insights into kidney involvement evaluated through kidney biopsy, personalized management strategies for family members according to their phenotype, and long-term follow-up of kidney function. We underscore the importance of molecular screening of the GLA gene in all family members for early identification of the disease and early initiation of specific treatments that can prevent or delay the progression of this disease. Full article

Background: Congenital sucrase–isomaltase deficiency (CSID) may mimic functional gastrointestinal disorders (FGIDs) and is likely underrecognized in pediatric practice. This study aimed to determine the frequency of sucrase–isomaltase (SI) gene variants among children with FGIDs and to evaluate genotype–phenotype associations and treatment-related quality-of-life outcomes. Methods: In this prospective cross-sectional study, children aged 0–18 years diagnosed with FGIDs according to Rome IV criteria were enrolled between May 2022 and January 2023. All patients underwent next-generation sequencing for SI gene variants. Clinical characteristics, FGID subtypes, and anthropometric data were recorded. Variant-positive patients received dietary sucrose restriction, and selected patients were treated with sacrosidase enzyme replacement. Symptom severity was assessed using the Numeric Rating Scale, and quality of life was evaluated with the Pediatric Quality of Life Inventory (PedsQL 4.0). Results: Among 290 children with FGIDs, SI gene variants were identified in 17 patients (5.9%). Variants were more frequently detected in children with irritable bowel syndrome–like symptoms. Clinical presentation was heterogeneous, and no consistent genotype–phenotype correlation was observed. Dietary intervention was associated with symptom improvement in compliant patients, while sacrosidase therapy led to significant improvements in both child- and parent-reported PedsQL scores. Conclusions: Sucrase–isomaltase deficiency is not uncommon among children with FGIDs and should be considered, particularly in those with IBS-like symptoms or diet-related complaints. Integrating genetic evaluation with targeted dietary and enzyme-based therapy may improve symptom control and quality of life in selected pediatric patients. Full article

Neurodegenerative diseases (NDDs) in children represent a heterogeneous group of rare but collectively significant disorders characterized by progressive neurological decline, developmental regression, and substantial morbidity and mortality. Unlike adult-onset neurodegeneration, pediatric conditions are predominantly genetic and frequently arise from defects in fundamental cellular pathways, including lysosomal degradation, mitochondrial oxidative phosphorylation, peroxisomal lipid metabolism, and myelin maintenance. This comprehensive review synthesizes current knowledge regarding the epidemiology, molecular classification, pathophysiology, and emerging therapeutic strategies of major pediatric neurodegenerative disorders. Epidemiological data indicate a “rare-but-many” landscape, where individually uncommon diseases collectively impose a measurable population burden. Mechanistically, disease progression reflects converging processes such as toxic substrate accumulation, impaired autophagy–lysosome flux, mitochondrial bioenergetic failure, oxidative stress, neuroinflammation, and glial dysfunction. Representative groups discussed include lysosomal storage disorders, leukodystrophies, mitochondrial encephalopathies, peroxisomal disorders, and other monogenic neurodegenerative syndromes. Advances in next-generation sequencing, metabolic profiling, and neuroimaging have substantially improved diagnostic accuracy and enabled earlier detection, including through newborn screening programs. Therapeutic paradigms are shifting from primarily supportive care toward mechanism-based interventions, including enzyme replacement therapy, hematopoietic stem cell transplantation, substrate reduction strategies, and gene therapy approaches. Early molecular diagnosis is increasingly recognized as critical for optimizing outcomes, particularly in disorders amenable to presymptomatic intervention. Continued integration of genomic medicine, standardized epidemiologic surveillance, and translational research will be essential to refine disease classification, improve prognostication, and expand access to targeted therapies. Collectively, pediatric neurodegenerative diseases exemplify the intersection of developmental neurobiology and inherited metabolic dysfunction, underscoring the need for multidisciplinary, precision-based clinical strategies. Full article

Background: Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is a rare X-linked lysosomal storage disorder caused by pathogenic variants in the iduronate-2-sulfatase gene, leading to progressive multisystem involvement. Although international management guidelines exist, challenges in their implementation across different healthcare systems remain insufficiently addressed. This study aimed to establish a national expert consensus in Türkiye on the treatment and management of MPS II, aligning local practice with international standards. Methods: A modified Delphi methodology was conducted using two rounds of online surveys supported by three steering committee meetings. The process involved 10 experienced clinicians and a scientific committee of six professors. Based on international guidelines and country-specific clinical challenges, 72 consensus statements and 84 exploratory questions were developed. Statements achieving ≥ 80% agreement were accepted as consensus. Results: Consensus supported initiating enzyme replacement therapy (ERT) in both severe and attenuated MPS II, guided by functional and cognitive status. Severe cognitive impairment was not considered an exclusion criterion for ERT, given its somatic benefits. Experts agreed on continuing ERT into adulthood with individualized discontinuation decisions. Routine evaluations every 6–12 months, including respiratory, cardiac, and neurocognitive assessments, were recommended. Additional consensus areas included individualized premedication strategies, structured transition to adult care, selective home infusion, annual patient-reported outcome assessments, and the establishment of a national MPS II registry. Hematopoietic stem cell transplantation was not endorsed. Conclusions: This Delphi study demonstrates strong expert consensus on MPS II management in Türkiye, providing a practical framework to guide clinical practice, support alignment with international recommendations, and inform future policy and research priorities. Full article

Generalized Arterial Calcification of Infancy (GACI) is a rare autosomal recessive disorder characterized by pathological calcium deposition in large and medium-sized arteries, leading to severe cardiovascular complications such as hypertension, heart failure, and stroke. The mortality rate is approximately 50% within the first six months of life if untreated. The disease is primarily caused by mutations in the ENPP1 or ABCC6 genes, resulting in a deficiency of inorganic pyrophosphate (PPi), a key inhibitor of arterial calcification. This review provides a comprehensive overview of the pathophysiology, genetic basis, and clinical features of GACI. In addition, we summarize current and emerging therapeutic strategies, including enzyme replacement therapy with recombinant ENPP1 (INZ-701), critically discussing available preclinical and early clinical evidence, as well as current limitations. Full article

Marine bacteria are increasingly explored as alternative microbial platforms for the production of high-value biopharmaceuticals. In this study, we investigate the Antarctic marine bacterium Pseudoalteromonas haloplanktis TAC125 (PhTAC125), an unconventional host capable of yielding soluble and biologically active human cyclin-dependent kinase-like 5 (hCDKL5). This serine/threonine kinase plays a crucial role in neuronal development, and its deficiency causes CDKL5 Deficiency Disorder, a severe and currently untreatable neurodevelopmental disease. Recombinant production of hCDKL5 is a prerequisite for the development of enzyme replacement therapy; however, current manufacturing processes remain insufficient for industrial translation, particularly in terms of product quality and functional consistency. To address these limitations, we developed dedicated analytical strategies: protein accumulation was quantified using a customised sandwich Enzyme-Linked Immunosorbent Assay (ELISA) designed to selectively detect full-length hCDKL5, while protein functionality was assessed by mass spectrometry-based quantification of autophosphorylation, a critical determinant of kinase activation. These complementary tools were applied to characterise hCDKL5 production under different growth conditions. Overall, this work establishes an integrated analytical framework aligned with a Quality by Design approach, enabling the simultaneous assessment of yield, structural integrity, and functional activation, and providing a robust basis for rational process optimisation towards scalable hCDKL5 manufacturing. Full article

Bietti crystalline dystrophy (BCD) is a hereditary retinal disease caused by loss-of-function mutations in the CYP4V2 gene. Gene replacement therapy using rAAV-hCYP4V2 represents a promising therapeutic strategy, requiring robust bioassays for product quality control. This study developed and validated a sensitive LC-MS/MS method for quantifying CYP4V2 enzyme activity. Lysates from HeLa-AAVR cells transduced with rAAV-hCYP4V2 (MOI = 3 × 10⁵) were used, with lauric acid as substrate supplemented with cytochrome P450 reductase, cytochrome b5, and NADPH. The ω-hydroxylated product (12-hydroxy lauric acid) was quantified using tolbutamide as an internal standard. Method validation followed ICH guidelines. Results demonstrated excellent specificity with negligible background in negative controls. Linearity was achieved over 0.5–100 ng/mL (R² > 0.99), with an average recovery of 100.6%. Intra-batch and inter-batch precision RSDs were <47.8% and <28.4%, respectively. Product stability was maintained for ≥4 weeks at −80°C. The method was successfully applied to three AAV serotypes (AAV2, AAV8, and AAV2/8), with all RSDs < 23.9%. This validated LC-MS/MS bioassay provides a crucial quality control tool for potency assessment, process development, batch release, and stability studies of rAAV-hCYP4V2 gene therapy products. Full article

Arginase 1 (ARG1) deficiency (ARG1-D) is a rare genetic disorder due to loss of ARG1, the final enzyme in the urea cycle. ARG1-D hepatocytes are impaired in converting arginine into urea, resulting in elevated peripheral arginine and ammonia, which leads to progressive neurological symptoms. Current therapeutic strategies mainly focus on managing plasma arginine and ammonia level, but long-term outcomes remain poor. While no approved treatment specific for ARG1-D is available in the United States, a recombinant protein-based enzyme replacement therapy is available in Europe. Recently, extracellular vesicles (EVs) are emerging as a powerful therapeutic vehicle. By using Capricor’s StealthX^TM platform, EVs were engineered to express human ARG1 on their surface or encapsulated within. Regardless of their localization on the EV membrane, nanograms of ARG1 carried by EVs were biologically active and able to convert arginine into urea as potent as micrograms of human recombinant ARG1 (rHuArg1). Furthermore, ARG1-encapsulating EVs (STX-Arg1-in) were able to deliver ARG1 intracellularly but not EVs carrying ARG1 on their surface or rHuArg1. STX-Arg1-in EVs were further evaluated in a series of in vivo studies, and the results showed that STX-Arg1-in EVs were non-toxic and able to restore arginase activities in the liver of Arg1^−/− mice, which led to a lowered plasma arginine concentration similar to that in wild-type mice. Most importantly, Arg1-in EVs expanded the lifespan of the lethal neonatal Arg1 deficiency mouse model. Taken together, our data suggested StealthX^TM-engineered STX-Arg1-in EVs have a better safety profile due to the extremely low dosage and have great potential as a novel enzyme replacement strategy for patients suffering from ARG1-D. Significance statement: Intracellular delivery of recombinant protein and improved llifespanare endpoints of successful enzyme replacement therapy for the treatment of ARG1-D. Using the StealthX platform, a fully functional ARG1 enzyme was engineered to be carried inside of the extracellular vesicles, which allowed for the intracellular delivery of ARG1 protein in vitro and in vivo, with an improvement of lifespan in a lethal neonatal mouse model of Arg1 deficiency. More importantly, no toxicity was observed, and efficacy was achieved with a low dose, setting the base for an improved therapeutic approach. Full article

Glucosylsphingosine (lyso-Gb1) serves as a biomarker for evaluating disease activity in Gaucher disease (GD). While treatment-related changes are documented, the dynamics of lyso-Gb1 during untreated states remain poorly understood. This retrospective, longitudinal cohort study utilized a large GD database comprising 701 patients and over 6200 visits with lyso-Gb1 measurements. Patients with at least two untreated visits were included in the analysis (n = 272). A significant change was defined as ≥50 ng/mL for lyso-Gb1, ≥1 g/dL for hemoglobin, and ≥50 × 10⁹/L for platelet count. Multivariable logistic regression analyses identified clinical factors associated with lyso-Gb1 decline or an increase. During untreated states, 35 patients (12.9%; 95% CI 9.4–17.5%) exhibited a decline in lyso-Gb1, with a median decrease of 96.3 ng/mL. This decline was more common in females (OR 3.50, p = 0.032) and associated with higher initial lyso-Gb1 levels (p < 0.001) and baseline hemoglobin (p = 0.032). An increase in lyso-Gb1 was observed in 98 patients (36.0%; 95% CI 30.5–41.9%), with a median rise of 135.1 ng/mL. This increase correlated with lower baseline platelet counts (p = 0.003), lower baseline hemoglobin (p = 0.002), and longer follow-up duration (p = 0.001). In many cases, lyso-Gb1 increases were observed without a preceding change in hemoglobin or platelet count. In summary, declines in lyso-Gb1 in untreated states are rare but possible. The association with female sex may reflect inflammatory effects. Although increases in lyso-Gb1 were expected without treatment, they occurred mainly in patients with higher disease severity markers. Nevertheless, most patients in the untreated states remained stable within ±50 ng/mL. These findings demonstrate a heterogeneous trajectory of lyso-Gb1 across untreated states and highlight the importance of interpreting lyso-Gb1 changes within the clinical context when making treatment decisions. Full article

Pompe disease (PD) is a neuromuscular autosomal recessive disorder caused by mutation in the GAA gene, which encodes acid α-glucosidase (GAA), an enzyme responsible for hydrolyzing glycogen to glucose. Deficiency of this enzyme leads to pathological accumulation of glycogen in almost all tissues of the body, with the most pronounced effects in cardiac and skeletal muscle, as well as in the central nervous system. Two major clinical forms of PD are recognized: infantile-onset PD, characterized by almost complete absence of GAA activity and severe cardiomyopathy and neurological abnormalities, and late-onset PD, which primarily presents with impairment of respiratory and motor function. Since 2006, enzyme replacement therapy with recombinant GAA has been used to treat PD, improving survival and quality of life. However, this approach has several limitations: the need for lifelong infusions, the risk of immune responses, and the inability of the enzyme to cross the blood–brain barrier, which is particularly critical for infantile-onset PD. Consequently, alternative strategies are being developed, including gene therapy using adeno-associated virus vectors for GAA delivery to target tissues; these approaches are currently in phase I/II clinical trials. Transplantation of genetically modified hematopoietic stem cells also represents a promising therapeutic strategy, offering a single-intervention treatment with long-lasting effects. This review discusses the molecular mechanisms of PD, current and emerging disease models, and therapeutic approaches, which together open prospects for the development of potentially one-time curative treatments, despite persistent challenges such as immunogenicity and the need for long-term efficacy monitoring. Full article