Rising From the Rubble: Air Quality Concerns in Post-Earthquake Afghanistan.

This position paper highlights the dire impacts of environmental and household air pollution, which were responsible for 6.7 million deaths globally in 2019. These deaths occurred predominantly in low- and middle-income countries, with Afghanistan reporting the highest age-adjusted mortality rate. The situation worsens during large-scale disasters like earthquakes, which release more pollutants into the air, exacerbating health risks and leading to severe conditions such as pulmonary diseases. Because political factors may hinder foreign NGOs and similar organizations from providing direct support, the frequent occurrence of earthquakes in Afghanistan underscores the critical need for emergency response training for local residents. Consequently, it is essential to provide ERT training, including the proper use of protective equipment, to local populations as well as disseminating risk communication through online technologies and other appropriate means.

Insights of Fabry disease: Expert consensus approach for screening, diagnosis, and multidisciplinary management in chronic kidney disease.

The prevalence of Fabry disease (FD) among males with chronic kidney disease (CKD) of unknown etiology in Taiwan is 0.6%. Despite this, FD is frequently overlooked in clinical settings. To address this issue, two consensus meetings were conducted in Taiwan-one in August 2022 and another in April 2023. The first meeting established screening criteria based on age, gender, family history, cardiac involvement, and symptoms. The second meeting, with a multidisciplinary team, developed treatment recommendations. The consensus emphasizes the importance of proactive data collection in dialysis units and outpatient follow-ups to enhance FD detection and management. The screening algorithm recommends incorporating FD screening into the diagnostic process for CKD patients, regardless of age. Priority is given to patients with a family history of FD, early stroke history, or classical FD symptoms. Comprehensive screening is also advised for CKD patients without obvious classical symptoms. Screening protocols for males include measuring α-galactosidase A enzyme activity, with reduced activity leading to further tests such as lyso-Gb3 level quantification and genetic analysis. For females, the protocol involves evaluating lyso-Gb3 plasma levels and genetic testing. FD, though often underestimated, is more prevalent than recognized and necessitates a multidisciplinary approach for timely diagnosis. Enhancing awareness and adopting a comprehensive approach are essential for improving patient outcomes.

Electrical resistivity tomography of simulated graves with buried human and pig remains.

Rigorous field assessment in different soil types and climates comparing simulated graves with pig remains and human remains are needed to assess the capabilities and limitations of electrical resistivity tomography (ERT) as a tool to search for unmarked graves. Our study assesses the ERT signals from graves with pig and human remains in a cold, humid continental climate with sandy soils. Two sets of three experimental graves were established: the first set consisted of two graves containing human remains and an empty grave serving as a control, while the second set consisted of two graves with pig remains and a second empty grave. ERT measurements were conducted prior to establishing the graves and were repeated 10 times over seventeen months, except for winter months when measurements were impossible. Each time we acquired eight 18 m long ERT transects using a dipole-dipole electrode array with a unit electrode spacing of 0.5 m and the transects spaced 1 m apart. The measured electrical resistivity decreased for all graves by 14-22 % for measurements conducted up to two months after burial. No further decrease was observed in the control, while resistivity in the graves with human and pig remains continued to decrease by 45-52 % up to the end of our study, seventeen months after burial. The resistivity anomaly in the pig graves shows a contrasting anomaly that is broader than that of the human remains. Our study thus validates the sensitivity of ERT to graves in cold, humid climates with sandy soil.

Longitudinal course of circulating miRNAs in a patient with hypophosphatasia and asfotase alfa treatment: a case report.

Hypophosphatasia (HPP) is characterized by low activity of tissue nonspecific alkaline phosphatase (TNSALP). The enzyme replacement therapy asfotase alfa has been approved for childhood-onset forms of HPP. MicroRNAs (miRNAs) have emerged as a novel disease biomarker, with potential application in therapy monitoring. Circulating miRNAs were analyzed at baseline, months 1, 2, 4, and 16 in a 49-yr-old woman with childhood-onset HPP, chronic musculoskeletal pain, and non-traumatic fractures prior to enzyme replacement therapy. Serum RNA was extracted and sequenced using miRNeasy Mini Kit (Qiagen, Germany), RealSeq Biosciences Kit (Santa Cruz, US) together with miND spike-in control kit (TAmiRNA, Austria) and Illumina NovaSeq 6000 SP1 flow cell (San Diego, US). Brief Pain Inventory Severity and Interference scores (BPI-S/BPI-I), fatigue severity scale (FSS), Patient Global Impression of Improvement (PGI-I), Western Ontario and McMaster university hip disability and osteoarthritis outcome score (WOMAC), fibromyalgia impact questionnaire (FIQ), 6-Minute Walking Test (6-MWT), chair-rise-test (CRT), and handgrip dynamometry (HD) were performed at baseline and different timepoints during the therapy. Out of >800 screened, 84 miRNAs were selected based on differences in expression profiles between 24 HPP patients and 24 healthy controls. Six miRNAs showed a clear graphic trend and were up- or downregulated by ≥50% reads per million (rpm). These included hsa-let-7i-5p (+50%), hsa-miR-1-3p (-66.66%), hsa-miR-1294 (+63.63%), hsa-miR-206 (-85.57%), hsa-miR-375-3p (-71.43%), and hsa-miR-624-5p (+69.44%). hsa-miR-1-3p and hsa-miR-206 were identified as muscle-specific miRNAs. hsa-mir-375-3p, which negatively regulates osteogenesis, was significantly downregulated. In terms of patient-reported outcomes, BPI-S, BPI-I, FSS, PGI-I, WOMAC, and FIQ showed a reduction by -58.62%, -68.29%, -33.33%, -75.00%, -63.29%, and -43.02%, respectively. 6-MWT improved by +33.89% and CRT by -44.46%. Mean hand grip strength of the right/left hand measured by HD improved by +12.50% and + 23.53%, respectively. miRNA profile changes during the therapy with asfotase alfa, accompanying improvements in functionality tests and quality of life scores.

Establishing Treatment Effectiveness in Fabry Disease: Observation-Based Recommendations for Improvement.

Fabry disease (FD, OMIM #301500) is caused by pathogenic GLA gene (OMIM #300644) variants, resulting in a deficiency of the α-galactosidase A enzyme with accumulation of its substrate globotriaosylceramide and its derivatives. The phenotype of FD is highly variable, with distinctive disease features and course in classical male patients but more diverse and often nonspecific features in non-classical and female patients. FD-specific therapies have been available for approximately two decades, yet establishing robust evidence for long-term effectiveness remains challenging. This review aims to identify the factors contributing to this lack of robust evidence for the treatment of FD with enzyme replacement therapy (ERT) (agalsidase-alfa and -beta and pegunigalsidase alfa) and chaperone therapy (migalastat). Major factors that have been identified are study population heterogeneity (concerning sex, age, phenotype, disease stage) and differences in study design (control groups, outcomes assessed), as well as the short duration of studies. To address these challenges, we advocate for patient matching to improve control group compatibility in future FD therapy studies. We recommend international collaboration and harmonization, facilitated by an independent FD registry. We propose a stepwise approach for evaluating the effectiveness of novel treatments, including recommendations for surrogate outcomes and required study duration.

Structural Health Monitoring of Glass Fiber-Reinforced Polymer Laminates with Carbon Nanotube-Coated Glass Fiber Sensing Layer after Low-Velocity Impact Using Electrical Resistance Tomography.

Structural health monitoring (SHM) of composite materials is of great significance in various practical applications. However, it is a challenge to accurately monitor the damage of composites without affecting their mechanical properties. In this paper, an embedded sensing layer based on carbon nanotube-coated glass fiber is designed, combined with electrical resistance tomography (ERT) for in situ damage monitoring. Multi-wall carbon nanotube-coated glass fiber (MWCNT-GF) is prepared and embedded into laminates as an in situ sensing layer. Low-velocity impact experiments demonstrate that the embedded sensing layer has high compatibility with the composite laminates and has no adverse effect on its impact response; although, the energy absorption behavior of glass fiber-reinforced polymer (GFRP) laminates containing MWCNT-GF occurs about 10% earlier than that of GFRP laminates overall. ERT technology is used to analyze the laminates after a low-velocity impact test. The results show that the in situ monitoring method with the embedded MWCNT-GF sensing layer can achieve high precision in imaging localization of impact damage, and the error of the detected damage area is only 4.5%.

Investigation and monitoring of rotational landslides in El Mokkattam plateau Egypt, using integrated geological and geophysical techniques.

Landslides are a rare but hazardous geological phenomenon in Egypt, with the El Mokattam plateau situated in the eastern part of Cairo covering approximately 64 km2 and ranging in elevation from 50 to 205 m. This study aims to identify and monitor landslides in the area using various geophysical methods. Twelve Electrical resistivity tomography (ERT) profiles,twenty-two P-wave Seismic Refraction profiles, twenty-two Refraction microtremors profiles, three ground penetrating radar (GPR) profiles and borehole data were utilized to analyze the occurrence of landslides in the El Mokattam Plateau. Additionally, we employed a relatively new geophysical method, studying high-frequency microtremor sounds emitted from landslide collapses at 22 stations. Our analysis identified steep slopes, jointed or fractured rocks, and irrigation water as primary factors contributing to landslides, with irrigation water acting as a lubricant for clays and promoting ground sliding. Examination of high-frequency microtremor sounds revealed a potential correlation between vertical high-frequency spectra at 100 Hz and landslide collapses, which aids in the identification of landslide-prone zones. Therefore, we conclude that seismological studies, particularly spectral analysis of high-frequency and low-amplitude sounds (microtremors) emitted from soil, offer a promising approach for investigating landslides.

Mapping and monitoring dense non-aqueous phase liquid source zone by fused surface and cross-borehole electrical resistivity tomography.

Effective characterization of dense non-aqueous phase liquid (DNAPL) source zones is crucial for remediating polluted sites. DNAPL often reside as residuals or pools within high-permeability lenses and above impermeable layers due to soil heterogeneity, gravity, and capillary barriers. Given the high cost of drilling, electrical resistivity tomography (ERT) techniques-including surface ERT and cross-borehole ERT, are commonly used for DNAPL source zone mapping and monitoring. However, the low spatial resolution of ERT increases uncertainty in source zone investigations. This study proposes a method for improving DNAPL mapping and monitoring by fusing surface and cross-borehole ERT data. Sandbox experiments were conducted to simulate a heterogeneous DNAPL source zone, employing both ERT methods for static mapping and dynamic monitoring. Reflective light imaging (RLM) was used to visualize DNAPL migration and provide saturation data, allowing for the quantification of ERT's effectiveness in characterizing DNAPL distribution. The results indicate that individual ERT methods face significant challenges in DNAPL source zone mapping due to background interference. Surface ERT alone tends to underestimate the extent of deeper DNAPL source zones. However, fusing surface and cross-borehole ERT results in a complementary enhancement of vertical spatial resolution, thereby improving the characterization of DNAPL source zones. The fusion of static and time-lapse ERT data substantially enhances DNAPL source zone mapping and monitoring capabilities. By calculating the ratio of the ERT-monitored area to the actual area using resistivity change contours (5 %, 10 %, 15 %), it was found that fusing surface and cross-borehole ERT data improved monitoring resolution by 50.48 % compared to surface ERT alone and by 22.95 % compared to cross-borehole ERT. Principal component analysis (PCA) was effective in fusing time-lapse data, while the weighted average method (WAM) outperformed PCA for static resistivity data fusion.

Best Practices for Development and Validation of Enzymatic Activity Assays to Support Drug Development for Inborn Errors of Metabolism and Biomarker Assessment.

Aberrant or dysfunctional cellular enzymes are responsible for a wide range of diseases including cancer, neurodegenerative conditions, and metabolic disorders. Deficiencies in enzyme level or biofunction may lead to intracellular accumulation of substrate to toxic levels and interfere with overall cellular function, ultimately leading to cell damage, disease, and death. Marketed therapeutic interventions for inherited monogenic enzyme deficiency disorders include enzyme replacement therapy and small molecule chaperones. Novel approaches of in vivo gene therapy and ex vivo cell therapy are under clinical evaluation and provide promising opportunities to expand the number of available disease-modifying treatments. To support the development of these different therapeutics, assays to quantify the functional activity of protein enzymes have gained importance in the diagnosis of disease, assessment of pharmacokinetics and pharmacodynamic response, and evaluation of drug efficacy. In this review, we discuss the technical aspects of enzyme activity assays in the bioanalytical context, including assay design and format as well as the unique challenges and considerations associated with assay development, validation, and life cycle management.

Three-dimensional forward modeling and quantitative assessment of electrode offset effects in ERT.

Resistivity data has important applications in geophysical exploration, but the impact of electrode offsets on resistivity response characteristics remains unclear. This study aims to explore the influence of horizontal electrode offset angles and vertical offsets caused by topographical variations on the forward modeling of resistivity data. By analyzing experimental models with different measurement arrays, the paper revealed their influence laws on the buried depth of the target body and resistivity resolution. Utilizing tools like ZondRes3D, we conducted 3D resistivity forward modeling and analyzed the results in detail. It is found that horizontal electrode offsets lead to pseudo-anomalies in the apparent resistivity response, which is related to the offset angles and the number of electrodes. Under different conditions, the horizontal electrode offsets exhibit a "gradient variation" pattern. In addition, topographical variations can also cause distortions and offsets in the apparent resistivity curves and the locations of the anomaly response. Specifically, the measuring lines near the edge of the target bodies are more susceptible to these effects. Based on the comprehensive experimental results, we have drawn several conclusions regarding the impact of electrode offsets and topographical variations, including the effects of offset angles on the pseudo-anomalies, the anomalous response laws under different topographic conditions, as well as anomalous situations under specific angles. These findings provide crucial insights for interpreting resistivity data in geophysical exploration and addressing practical engineering problems, and offer guidance for optimizing measuring line layouts and post-processing terrain correction algorithms.

Clinical insight meets scientific innovation to develop a next generation ERT for Pompe disease.

Years of research into the structure, processing, and function of acid alpha-glucosidase led to the development and 2006 approval of alglucosidase alfa (recombinant human acid alpha-glucosidase, Myozyme®/Lumizyme®), an enzyme replacement therapy and the first approved treatment for Pompe disease. Alglucosidase alfa has been a lifesaving treatment for patients with infantile-onset Pompe disease and radically improved daily life for patients with late-onset Pompe disease; however, long-term experience with alglucosidase alfa unraveled key unmet needs in these populations. Despite treatment, Pompe disease continues to progress, especially from a skeletal muscle perspective, resulting in a multitude of functional limitations. Strong collaboration between the scientific and patient communities led to increased awareness of Pompe disease, a better understanding of disease pathophysiology, knowledge of the clinical course of the disease as patients surpassed the first decade of life, and the strengths and limitations of enzyme replacement therapy. Taken together, these advancements spurred the need for development of a next generation of enzyme replacement therapy and provided a framework for progress toward other novel treatments. This review provides an overview of the development of avalglucosidase alfa as a model to highlight the interaction between clinical experience with existing treatments, the role of the clinician scientist, translational research at both system and cellular levels, and the iterative and collaborative process that optimizes the development of therapeutics.

Histologic and ultrastructural study of intracranial Gaucheroma causing deafness in a patient with Gaucher disease type 3: Effects of substrate reduction therapy.

Hearing loss is frequently associated with Gaucher disease (GD). Gaucher cells are enlarged reticuloendothelial cells containing glucocerebroside in the lysosomes due to deficiency of the glucocerebrosidase. Gaucheromas consist of accumulated Gaucher cells. Gaucher cells accumulate in variable tissues including the liver, spleen, bone marrow, and the middle ear and the mastoid causing conductive hearing loss. Neurons and astrocytes in the central nervous system are affected in neuronopathic GD leading to sensorineural hearing loss. Gaucheromas can develop even in patients treated with enzyme replacement therapy (ERT). We report a 19-year-old female patient with GD type 3 who developed profound bilateral hearing loss associated with intracranial Gaucheroma. Combination therapy of ERT with imiglucerase and substrate reduction therapy (SRT) with eliglustat significantly decreased the size of Gaucher cells and cleared the characteristic microtubular structures in the lysosomes in Gaucher cells. Early implementation of SRT may prevent at least conductive hearing impairment in GD although it may not prevent sensorineural hearing loss due to inner hair cell dysfunction which is also known to be associated with neuronopathic GD.

Clinical outcomes in patients switching from agalsidase beta to migalastat: A Fabry Registry analysis.

Fabry Registry data were analyzed among 83 agalsidase beta-treated patients with Fabry disease who switched to migalastat. Outcomes (estimated glomerular filtration rate [eGFR], urine protein-creatinine ratio [UPCR], plasma globotriaosylceramide [GL-3], plasma globotriaosylsphingosine [lyso-GL-3], interventricular septal wall thickness [IVST], left posterior wall thickness [LPWT], left ventricular mass index [LVMI]) were assessed using linear mixed models to estimate annual change over time in the pre- and postswitch periods. eGFR decreased throughout both periods (preswitch: -0.85 mL/min/1.73 m2/year; postswitch: -1.96 mL/min/1.73 m2/year; both p < 0.0001), with steeper decline postswitch (ppre/post = 0.01) in both classic and late-onset patients. UPCR increased significantly postswitch (ppre/post = 0.003) among classic patients and was stable in both periods among late-onset patients. GL-3 trajectories worsened postswitch across phenotypes (ppre/post = 0.0005 classic, 0.02 late-onset). LPWT was stable preswitch (0.07 mm/year, p = 0.25) and decreased postswitch (-0.51 mm/year, p = 0.0005; ppre/post = 0.0009), primarily among late-onset patients. IVST and LVMI slopes varied significantly by phenotype. Among classic patients, IVST and LVMI were stable and decreasing, respectively preswitch and increasing postswitch (ppre/post = 0.02 IVST, 0.01 LVMI). Among late-onset patients, IVST significantly decreased postswitch (ppre/post = 0.0003); LVMI was stable over time (ppre/post = 0.89). Ultimately, eGFR and GL-3 trajectories worsened postswitch across phenotypes, while UPCR and cardiac measures worsened among classic and stabilized/improved among late-onset patients. These findings indicate variability in long-term outcomes after switching from ERT to migalastat, underscoring the importance of careful monitoring.

Enzyme replacement therapy and immunotherapy lead to significant functional improvement in two children with Pompe disease: a case report.

BACKGROUND: Pompe disease, a rare autosomal recessive disorder caused by acid alpha-glucosidase deficiency, results in progressive glycogen accumulation and multisystem dysfunction. Enzyme replacement therapy with recombinant human acid alpha-glucosidase is the standard of care; however, some patients develop anti-recombinant human acid alpha-glucosidase antibodies, leading to reduced efficacy. This case report presents two infants with early-onset Pompe disease who developed IgG antibodies to enzyme replacement therapy and were subsequently treated with methotrexate, highlighting the importance of monitoring antibody development and exploring alternative therapeutic approaches. CASE PRESENTATION: Patient 1, a 10-month-old female from Bogota, Colombia, presented with generalized hypotonia, macroglossia, hyporeflexia, and mild left ventricular hypertrophy. Diagnostic tests confirmed early-onset Pompe disease, and enzyme replacement therapy was started at 12 months. Due to a lack of improvement and high anti-recombinant human acid alpha-glucosidase IgG antibody titers (1:1800), methotrexate was started at 18 months. After 8 months of combined therapy, antibody titers were negative and significant improvement in motor function was observed using the Gross Motor Function Measure 88. Patient 2, a 7-year-old female from Bogota, Colombia, was diagnosed with early-onset Pompe disease at 12 months and initiated enzyme replacement therapy. At 5 years of age, she experienced frequent falls and grip strength alterations. Functional tests revealed motor development delay, generalized hypotonia, and positive anti-recombinant human acid alpha-glucosidase IgG antibody titers (6400). Methotrexate was initiated, leading to a reduction in falls and antibody titers (3200) after 6 months, with no adverse events or complications. Motor function improvement was assessed using the Motor Function Measurement 32. CONCLUSIONS: The presented cases highlight the importance of monitoring patients for anti-recombinant human acid alpha-glucosidase antibody development during enzyme replacement therapy and the potential benefit of methotrexate as an immunomodulatory agent in early-onset Pompe disease. Early diagnosis and timely initiation of enzyme replacement therapy, combined with prophylactic immune tolerance induction, may improve clinical outcomes and reduce the development of anti-recombinant human acid alpha-glucosidase antibodies. The cases also highlight the importance of objective motor function assessment tools, such as Gross Motor Function Measure 88 and Motor Function Measurement 32, in assessing treatment response. Further research is needed to optimize treatment regimens, monitor long-term effects, and address the current limitations of enzyme replacement therapy in Pompe disease.

Twelve Years of the Gaucher Outcomes Survey (GOS): Insights, Achievements, and Lessons Learned from a Global Patient Registry.

Background: Long-term patient registries are important for evaluating treatment outcomes in patients with rare diseases, and can provide insights into natural disease history and progression in real-world clinical practice. Initiated in 2010, the Gaucher Outcome Survey (GOS) is an ongoing, international, multicenter, observational registry (ClinicalTrials.gov Identifier: NCT03291223) for patients with a diagnosis of Gaucher disease (GD), irrespective of treatment type or status, with a primary objective to monitor safety and long-term effectiveness of velaglucerase alfa. Methods: Here, we evaluated the GOS population 12 years after the registry initiation. Results: As of 25 February 2023, 2084 patients enrolled in the GOS and 1643 received GD-specific treatment. Patients exhibited broad heterogeneity at baseline: age of diagnosis (0 to 85.3 years), hemoglobin concentrations (<80.0 g/L to >150 g/L), platelet counts (<50 × 109/L to >450 × 109/L), and liver and spleen volumes. Most patients treated with enzyme replacement therapy or substrate reduction therapy reported improvements in clinical parameters within 1 year of treatment initiation, maintained over the course of treatment up to 12 years, whereas untreated patients had baseline values closer to standard reference thresholds and showed stability over time. Conclusion: The 12-year data from the GOS confirm the impact of long-term treatment with GD-specific agents and offer insights into disease progression and outcomes in a real-world setting.

Evaluation of a Ground Subsidence Zone in an Urban Area Using Geophysical Methods.

An important geological risk to which many towns in Puglia are exposed is sinking cavities in urban areas. For urban centers, studying, mapping, providing geological and speleological descriptions, classifying, and cataloging the forms and types of cavities is essential because cavities are linked to past local anthropic and natural processes at different sites. These circumstances could lead to the enhancement of existing underground cavities in urban areas through conservation and continuous monitoring. Unfortunately, in many cases, these underground cavities have been used as landfills and subsequently abandoned. In late March 2007, one of these cavities collapsed inside Gallipoli's inhabited center, causing damage to the structures but fortunately not human lives. In the area surrounding the collapsed cavity, a series of geophysical investigations were undertaken using ground penetrating radar in an attempt to delimit the area of collapse and develop possible interventions for restoration. In the same area, these measures were repeated 16 years later in December 2022 due to another collapse. The comparison between data acquired in these two periods shows that there were no strong changes apart from an increased presence of subsoil moisture in 2022.

Patterns of electrical properties change of heavy metal-organic compound contaminated media in soil-groundwater systems: From laboratory experiments to site application.

Differences in electrical properties of media are the basis for determining the type and extent of contamination using geophysical methods. However, differences in heavy metals and organic matter complicate the electrical properties of compound-contaminated media, and existing geophysical methods cannot independently identify compound contamination. Therefore, this study proposes a geophysical detection system that combines electrical resistance tomography (ERT) and induced polarization methods and establishes a solid theory as the basis for the system application through laboratory experiments, model analysis, and site applications. The study reveals that as the organics volume proportion increases, the resistivity and normalized chargeability of contaminated media increased slowly, followed by a rapid increase, and finally reached a stable state. The specific type of compound significantly influences the electrical properties, while the resistivity of different kinds of compound-contaminated media reaches the same maximum value as the organics volume proportion increases. The medium type determines the contaminated media's lower resistivity limit and upper normalized chargeability limit. Additionally, the interplay between heavy metal type, content, and medium complicates the electrical properties of the media, with the compound type exerting a significant impact on resistivity. Archie's law and random forest modeling reveal that the inflection point for resistivity change occurs at 40 % and 80 % organics volume proportions, while the inflection point for normalized chargeability change occurs at 30 % and 70 % organics volume proportions in compound-contaminated media. These inflection points depend on the types of compounds, compositions, proportions, and media, and their importance for the electrical properties of the media changes with the increasing organics volume proportion. Based on the changing patterns of resistivity and normalized chargeability in heavy metal-organic compound contaminated media, the modified geophysical detection system can effectively identify the pollution type and intensity, which provides accurate pollution information to develop effective treatment strategies.

Evidence of Lysosomal ß-Hexosaminidase Enzymatic Activity Associated with Extracellular Vesicles: Potential Applications for the Correction of Sandhoff Disease.

Extracellular vesicles (EVs) can be isolated from biological fluids and cell culture medium. Their nanometric dimension, relative stability, and biocompatibility have raised considerable interest for their therapeutic use as delivery vehicles of macromolecules, namely nucleic acids and proteins. Deficiency in lysosomal enzymes and associated proteins is at the basis of a group of genetic diseases known as lysosomal storage disorders (LSDs), characterized by the accumulation of undigested substrates into lysosomes. Among them, GM2 gangliosidoses are due to a deficiency in the activity of lysosomal enzyme ß-hexosaminidase, leading to the accumulation of the GM2 ganglioside and severe neurological symptoms. Current therapeutic approaches, including enzyme replacement therapy (ERT), have proven unable to significantly treat these conditions. Here, we provide evidence that the lysosomal ß-hexosaminidase enzyme is associated with EVs released by HEK cells and that the EV-associated activity can be increased by overexpressing the α-subunit of ß-hexosaminidase. The delivery of EVs to ß-hexosaminidase-deficient fibroblasts results in a partial cross-correction of the enzymatic defect. Overall findings indicate that EVs could be a source of ß-hexosaminidase that is potentially exploitable for developing therapeutic approaches for currently untreatable LSDs.

Effects of Enzyme Replacement Therapy on Cardiac MRI Findings in Fabry Disease: A Systematic Review and Meta-Analysis.

Purpose To perform a systematic review and meta-analysis to assess the effect of enzyme replacement therapy on cardiac MRI parameters in patients with Fabry disease. Materials and Methods A systematic literature search was conducted from January 1, 2000, through January 1, 2024, in PubMed, ClinicalTrials.gov, Embase, and Cochrane Library databases. Study outcomes were changes in the following parameters: (a) left ventricular wall mass (LVM), measured in grams; (b) LVM indexed to body mass index, measured in grams per meters squared; (c) maximum left ventricular wall thickness (MLVWT), measured in millimeters; (d) late gadolinium enhancement (LGE) extent, measured in percentage of LVM; and (e) native T1 mapping, measured in milliseconds. A random-effects meta-analysis of the pooled mean differences between baseline and follow-up parameters was conducted. The study protocol was registered in PROSPERO (CRD42022336223). Results The final analysis included 11 studies of a total of 445 patients with Fabry disease (mean age ± SD, 41 years ± 11; 277 male, 168 female). Between baseline and follow-up cardiac MRI, the following did not change: T1 mapping (mean difference, 6 msec [95% CI: -2, 15]; two studies, 70 patients, I2 = 88%) and LVM indexed (mean difference, -1 g/m2 [95% CI: -6, 3]; four studies, 290 patients, I2 = 81%). The following measures minimally decreased: LVM (mean difference, -18 g [95% CI: -33, -3]; seven studies, 107 patients, I2 = 96%) and MLVWT (mean difference, -1 mm [95% CI: -2, -0.02]; six studies, 151 patients, I2 = 90%). LGE extent increased (mean difference, 1% [95% CI: 1, 1]; three studies, 114 patients, I2 = 85%). Conclusion In patients with Fabry disease, enzyme replacement therapy was associated with stabilization of LVM, MLVWT, and T1 mapping values, whereas LGE extent mildly increased. Keywords: Fabry Disease, Enzyme Replacement Therapy (ERT), Cardiac MRI, Late Gadolinium Enhancement (LGE) Supplemental material is available for this article. © RSNA, 2024.