Search Results (463)

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

Fetal therapy has evolved into a rapidly advancing field with the potential to alter the natural history of many severe congenital and genetic disorders before irreversible injury occurs. Progress in prenatal imaging, molecular diagnostics, and fetal intervention techniques now enables the earlier identification of disease and, in select settings, targeted prenatal treatment. This review synthesizes the current landscape of fetal therapies, spanning established surgical interventions for structural anomalies and emerging biologic and molecular approaches, including enzyme replacement therapy, stem cell-based strategies, gene therapy, and gene editing. The intrauterine environment provides a distinct therapeutic context, with developmental plasticity, immune immaturity, enhanced tissue accessibility, and relatively permissive central nervous system exposure that together define a time-sensitive window for intervention. Preclinical studies and early clinical experience across both structural anomalies and genetic disorders, including lysosomal storage disorders, osteogenesis imperfecta, and spinal muscular atrophy, support the premise that prenatal treatment can preserve organ development and improve pediatric outcomes. However, translation remains constrained by procedural risks, uncertainty regarding long-term safety and durability, ethical and regulatory complexities, and challenges with equitable access, alongside the need for robust comparative evidence versus early postnatal therapy. As the field advances, multidisciplinary collaboration, rigorous trial design with meaningful developmental endpoints, and ethically grounded implementation frameworks will be essential to guide responsible clinical adoption and maximize benefit for children and families. Full article

Background: Angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) were historically considered contraindicated in severe aortic stenosis (AS) due to theoretical haemodynamic risks. Contemporary evidence increasingly challenges this paradigm, yet data on preoperative use and postoperative outcomes remain limited. We examined the association between preoperative ACEi/ARB use and mortality following aortic valve replacement. Methods: We conducted a retrospective cohort study of 198 consecutive patients undergoing transcatheter (TAVI) or surgical aortic valve replacement (SAVR) at a single tertiary centre between May 2020 and March 2025. Complete one-year follow up was available for 185 patients (93%). The primary outcome was one-year all-cause mortality. Multivariable logistic regression adjusted for age, sex, hypertension, diabetes, LVEF, and procedure type. Results: Of 198 patients, 80 (40%) were receiving ACEi/ARB therapy preoperatively. ACEi/ARB users had a higher prevalence of hypertension (82% vs. 53%, p < 0.001) and diabetes (48% vs. 27%, p = 0.005) but similar age, valve area, and ejection fraction. Unadjusted one-year mortality was lower in the ACEi/ARB group (7% vs. 19%; odds ratio [OR] 0.33, 95% CI 0.12–0.91, p = 0.030). After multivariable adjustment for confounders including age, diabetes, and hypertension, the association did not reach statistical significance (adjusted OR 0.33, 95% CI 0.10–1.12, p = 0.075). Among diabetic patients, unadjusted one-year mortality was numerically lower in the ACEi/ARB group (12% vs. 35%, p = 0.038); however, six subgroup comparisons were performed and this result would not survive Bonferroni correction (threshold p < 0.008). This exploratory finding should be interpreted with caution given the small sample size and absence of adjustment for confounders. Conclusions: Preoperative ACEi/ARB use was associated with lower unadjusted one-year mortality, but this association did not reach statistical significance after multivariable adjustment and residual confounding cannot be excluded. ACEi/ARB use was not associated with increased mortality in this cohort. These hypothesis-generating findings from a single-centre observational study require confirmation in adequately powered prospective trials. Full article

We conducted a cost-effectiveness analysis of a universal newborn screening (NBS) program for infantile-onset Pompe disease (IOPD) compared with clinical identification in newborns. The analytical model combined a decision tree and a Markov model. The incremental cost-effectiveness ratio (ICER) was estimated over a lifetime horizon, applying a 2% annual discount rate from the public healthcare payer’s perspective. In a cohort of 727,288 individuals, 2.4 patients were expected to have IOPD. The cumulative quality-adjusted life years (QALYs) gained per patient were estimated to be 7.9 when clinically diagnosed and treated with enzyme replacement therapy, and 28.9 when identified through universal NBS. The ICER was 174 million JPY per QALY. Sensitivity and scenario analyses indicated that the parameters most affecting the ICER were the NBS test cost, the quality-of-life value for ambulatory patients, the prevalence of IOPD, and the cost of enzyme replacement therapy. Although considerable uncertainty exists in the analysis, the findings suggest that implementing NBS solely for detecting infantile-onset cases poses challenges in terms of cost-effectiveness, primarily due to the rarity of the disease and the high costs associated with testing and treatment. Full article

Background: Despite the availability of effective therapies for Gaucher disease (GD), management of skeletal disease manifestations remains challenging. Methods: This phase 4 SHP-GCB-402 study evaluated the effect of velaglucerase alfa on lumbar spine (LS) bone outcomes in patients with type 1 GD. Results: Twenty-one patients with documented bone pathology received ≥1 dose of velaglucerase alfa 60 U/kg; 16 completed this study. The primary endpoint—change from baseline to 24 months in an LS bone mineral density (BMD) Z-score measured by dual-energy X-ray absorptiometry—showed a numerical improvement from baseline (mean [SD] −1.93 [0.88]) to 24 months (−1.76 [1.00]), although statistical significance was not reached (p = 0.1077). These changes are not consistent with previous velaglucerase alfa studies. To contextualize these findings, a pooled analysis of 24-month data from previous velaglucerase alfa trials was conducted. In this cohort (n = 40), a statistically significant mean (SD) increase in the LS BMD Z-score of 0.55 (0.58; p < 0.0001) was observed, supporting the therapeutic potential of velaglucerase alfa in improving skeletal outcomes. Additionally, SHP-GCB-402 demonstrated a significant reduction in the bone marrow burden (BMB) score (mean change from baseline: −3.0 [2.27]; p = 0.0005), indicating a positive effect on bone marrow infiltration. All patients experienced ≥1 treatment-emergent adverse event, mostly of mild/moderate severity. Conclusions: The observed numerical improvements in BMD and significant improvements in BMB in SHP-GCB-402 along with pooled BMD data suggest that velaglucerase alfa may confer skeletal benefits while maintaining a consistent safety profile. Full article

Background/Objectives: Fabry disease (FD) is a lysosomal storage disorder characterized by progressive renal and cardiac involvement and an increased burden of cardiovascular and cerebrovascular events. While cardiac magnetic resonance imaging (CMR) has significantly advanced structural assessment, circulating biomarkers reflecting disease-related cardiac manifestations remain incompletely understood. We therefore investigated adiponectin and leptin, two adipokines involved in inflammatory, metabolic, and fibrotic pathways, in relation to cardiac involvement and analyzed long-term lipid trajectories in FD. Methods: This longitudinal observational study included 49 patients with FD with 149 study visits. Circulating adiponectin, leptin, NT-proBNP, and conventional lipid parameters were assessed longitudinally and stratified by FD-specific therapy status and sex. Multivariable linear regression was performed to evaluate independent associations with log-transformed NT-proBNP values. Results: Adiponectin was positively associated with NT-proBNP, reflecting cardiac involvement, independent of age, sex, BMI, and eGFR (p < 0.001). Higher adiponectin levels were observed in patients with left ventricular hypertrophy or low T1 and those with fibrosis, detected by CMR (p = 0.009 and p < 0.001, respectively). This association was mainly seen in patients receiving FD-specific therapy, raising the question of whether this reflects underlying organ involvement or treatment effects. Leptin demonstrated weaker, inverse associations. Adiponectin, leptin, Triglycerides, total cholesterol, and HDL- and LDL-cholesterol levels remained stable over long-term follow-up, irrespective of FD-specific therapy or sex. Conclusions: In FD, adiponectin appears to be associated with cardiac involvement, and conventional lipid parameters remained unchanged over time. These findings suggest that alterations in adipokines, rather than progressive dyslipidemia, may reflect disease-related cardiac manifestations. Full article

Calcific aortic valve disease (CAVD) is an active pathological process driven by complex cellular and molecular mechanisms rather than passive aging. The disease is characterized by endothelial dysfunction, lipid infiltration, inflammation, extracellular matrix remodeling, and osteogenic differentiation of valvular interstitial cells, ultimately leading to hydroxyapatite deposition and progressive valve calcification. Key signaling pathways, including Notch, Wnt/β-catenin, BMP2, and TGF-β, play critical roles in osteogenic reprogramming, while inflammatory cytokines such as IL-6, IL-1β, and TNF-α contribute to a pro-calcific microenvironment. To summarize current knowledge on CAVD pathophysiology and emerging therapeutic strategies, relevant preclinical studies were identified through searches of PubMed, and clinical trials were identified through ClinicalTrials.gov. Evidence indicates that extracellular matrix remodeling, fibrosis, and dysregulated phosphate metabolism, particularly involving TNAP and DPP-4, further accelerate disease progression. Despite advances in understanding disease mechanisms, effective pharmacological therapies remain limited, with the current treatment largely restricted to valve replacement. Emerging therapeutic approaches targeting molecular pathways, including enzyme inhibition, RNA-based therapeutics, and advanced drug delivery systems, may offer promising strategies for disease modification. A deeper understanding of CAVD pathophysiology may facilitate the development of targeted therapies to delay or prevent disease progression. Full article

Background/Objectives: Eliglustat is an oral therapy for Gaucher disease type 1 (GD1) that may reduce infusion-related logistical burden, particularly in resource-constrained settings. Post-approval evidence from routine clinical practice in China remains limited. This study evaluated its real-world effectiveness and safety in Chinese adults with GD1. Methods: This retrospective, multicenter study included adults with GD1 receiving eliglustat monotherapy for ≥6 months. Outcomes included plasma glucosylsphingosine (lyso-Gb1), hemoglobin (HGB), platelet count (PLT), liver and spleen volumes, and adverse events (AEs). Depending on distribution, paired changes were analyzed using paired t tests or Wilcoxon signed-rank tests. p < 0.05 was considered statistically significant. Results: Nineteen patients were included in the effectiveness analysis, with a median follow-up of 7 months (range, 6–9). Lyso-Gb1 decreased from 468 to 210 ng/mL (p < 0.0001). HGB increased from 123 to 131 g/L (p = 0.147); among six patients with baseline anemia, 83.3% improved and 33.3% normalized. PLT increased from 109 to 132 × 10⁹/L (p = 0.019); among 12 patients with baseline thrombocytopenia, 58.3% improved. Liver volume decreased from 1808 to 1747 mL (p = 0.016) (1.22 to 1.01 multiples of normal; p < 0.001). Spleen volume decreased from 473 to 452 mL (p = 0.016) (4.69 to 5.17 multiples of normal; p = 0.015). Lyso-Gb1 reduction was greater in patients without prior enzyme replacement therapy (ERT) exposure than in those with prior ERT exposure (−55.1% vs. −43.1%; p = 0.049). In the safety analysis group (n = 90), suspected drug-related AEs occurred in 27.8% of patients, mainly gastrointestinal or skin-related, and were limited to grade I/II. No serious AE or treatment discontinuation occurred. Conclusions: In routine clinical practice in China, eliglustat was associated with rapid substantial reductions in plasma lyso-Gb1, early improvements in hematologic and visceral parameters, and favorable short-term tolerability in adults with GD1. Full article

Background and Objectives: Functional dyspepsia (FD) often overlaps with Pancreatic Exocrine Insufficiency (PEI), leading to diagnostic delays. We aimed to evaluate the prevalence of PEI in patients presenting dyspeptic symptoms using the survey-based PEI test and to assess the clinical response to Pancreatic Enzyme Replacement Therapy (PERT). Methods: This study included 91 patients with PEI and 58 control subjects. PEI was evaluated using the PEI Patient-Reported Outcome (PRO) instrument and classified as mild, moderate, or severe according to the 18-item PEI test. Objective fat malabsorption was assessed by the acid steatocrit method using a gravimetric assay. Patients diagnosed with PEI received PERT, and treatment response was evaluated at follow-up with a repeat PEI test. Results: When the case and control groups were compared in terms of PEI scores, a statistically significant difference was found (p < 0.001). Fecal steatocrit value was found to be statistically significant with the PEI score (p = 0.017). No statistically significant difference was found between amylase, lipase, vitamin D, vitamin B12, and folic acid and the PEI score (p = 0.789, p = 0.299, p = 0.865, p = 0.153, and p = 0.855, respectively). A statistically significant difference was found between the pre-treatment PEI score and the post-treatment PEI score (p < 0.001). The mean pre-treatment PEI score was 1.52 ± 0.50, while the post-treatment PEI score was 0.42 ± 0.48. Approximately 72% reduction in PEI score was observed with treatment. Conclusions: The PEI test may represent a useful, non-invasive tool for identifying suspected pancreatic dysfunction in patients initially diagnosed with functional dyspepsia. Early integration of this tool into clinical practice can improve symptom control and prevent the misclassification of PEI as a purely functional disorder. Full article