The diagnosis and management of mucopolysaccharidosis type II.

Mucopolysaccharidosis type II (MPS II) is a rare X-linked recessive inherited lysosomal storage disease. With pathogenic variants of the IDS gene, the activity of iduronate-2-sulfatase (IDS) is reduced or lost, causing the inability to degrade glycosaminoglycans (GAGs) in cells and influencing cell function, eventually resulting in multisystemic manifestations, such as a coarse face, dysostosis multiplex, recurrent respiratory tract infections, and hernias. Diagnosing MPS II requires a combination of clinical manifestations, imaging examinations, urinary GAGs screening, enzyme activity, and genetic testing. Currently, symptomatic treatment is the main therapeutic approach. Owing to economic and drug availability issues, only a minority of patients opt for enzyme replacement therapy or hematopoietic stem cell transplantation. The limited awareness of the disease, the lack of widespread detection technology, and uneven economic development contribute to the high rates of misdiagnosis and missed diagnosis in China.

Therapeutic delivery of recombinant glucocerebrosidase enzyme-containing extracellular vesicles to human cells from Gaucher disease patients.

BACKGROUND: Gaucher disease (GD) is one of the most common types of lysosomal storage diseases (LSDs) caused by pathogenic variants of lysosomal ß-glucocerebrosidase gene (GBA1), resulting in the impairment of Glucocerebrosidase (GCase) enzyme function and the accumulation of a glycolipid substrate, glucosylceramide (GlcCer) within lysosomes. Current therapeutic approaches such as enzyme replacement therapy and substrate reduction therapy cannot fully rescue GD pathologies, especially neurological symptoms. Meanwhile, delivery of lysosomal enzymes to the endocytic compartment of affected human cells is a promising strategy for treating neuropathic LSDs. RESULT: Here, we describe a novel approach to restore GCase enzyme in cells from neuropathic GD patients by producing extracellular vesicle (EVs)-containing GCase from cells overexpressing GBA1 gene. Lentiviral vectors containing modified GBA1 were introduced into HEK293T cells to produce a stable cell line that provides a sustainable source of functional GCase enzyme. The GBA1-overexpressing cells released EV-containing GCase enzyme, that is capable of entering into and localizing in the endocytic compartment of recipient cells, including THP-1 macrophage, SH-SY5Y neuroblastoma, and macrophages and neurons derived from induced pluripotent stem cells (iPSCs) of neuropathic GD patients. Importantly, the recipient cells exhibit higher GCase enzyme activity. CONCLUSION: This study presents a promising therapeutic strategy to treat severe types of LSDs. It involves delivering lysosomal enzymes to the endocytic compartment of human cells affected by conditions such as GDs with neurological symptoms, as well as potentially other neurological disorders impacting lysosomes.

[Pharmacological Chaperone Therapy for Fabry Disease].

Pharmacological chaperone therapy (PCT) structurally stabilizes mutant enzyme proteins and increases their activity. Although ease of oral administration and effectiveness in patients with central nervous system disorders serve as advantages, PCT is effective only for patients with amenable mutations because its efficacy depends on gene mutations. PCT, which prevents progression of Fabry cardiomyopathy and nephropathy, was approved in Japan in 2018. It is expected that PCT will also be developed for lysosomal diseases that cause central nervous system disorders in the future.

Production of active human iduronate-2-sulfatase (IDS) enzyme in Nicotiana benthamiana.

Many strategies have been developed to produce high levels of biologically active recombinant proteins in plants for biopharmaceutical purposes. However, the production of an active form of human iduronate-2-sulfatase (hIDS) for the treatment of Hunter syndrome by enzyme replacement therapy (ERT) is challenging due to the requirement for cotranslational modification by a formylglycine-producing enzyme encoded by sulfatase modifying factor 1 (hSUMF1) at the Cys84 residue, which converts it to C(alpha)-formylglycine. In this study, we have shown that hIDS can be highly expressed in N. benthamiana by using different constructs. Among them, BiP-GB1-L-dCBD1-2L-8xHis-L-6xHis-3L-EK-hIDS-HDEL (GB1-CBD1-hIDS) showed a high expression level when transiently co-expressed with the turnip crinkle virus gene silencing suppressor P38 and GB1-fused human calreticulin (GB1-CRT1) as a folding enhancer. The hSUMF1 was co-expressed with hIDS for cotranslational modification. The full-length recombinant proteins were purified using Ni2+-NTA affinity resin followed by enterokinase treatment to obtain tag-free hIDS. The N-terminal fragment was removed using microcrystalline cellulose (MCC) beads. The purified active form of hIDS can successfully cleave the sulfate group from an artificial substrate, 4-nitrocatechol sulfate, at a similar level to commercial hIDS expressed in animal cells. These results suggest that plants could be a promising platform for the production of recombinant hIDS.

Significance of early diagnosis and treatment of adult late-onset Pompe disease on the effectiveness of enzyme replacement therapy in improving muscle strength and respiratory function: a case report.

BACKGROUND: Pompe disease, a rare autosomal recessive disorder, is caused by mutations in the acid α-glucosidase gene. Pompe disease is a congenital metabolic disorder that affects all organs, particularly the striated muscle and nerve cells. Diagnosis is typically confirmed through enzyme assays that reveal reduced acid α-glucosidase activity. Enzyme replacement therapy utilizing human α-glucosidase is an available treatment option. Timely diagnosis and treatment in the early stages of the disease significantly impact the effectiveness of enzyme replacement therapy in enhancing patient condition. Here, we present a case of a patient with Pompe disease diagnosed 20 years after the onset of clinical symptoms. CASE PRESENTATION: A 38-year-old Iranian Baloch woman referred to our rheumatology clinic with progressive muscle weakness presents with a complex medical history. On mechanical ventilation for 12 years, she has endured fatigue and limb weakness since the age of 16, exacerbated following an abortion at 19. Despite undergoing corticosteroid and azathioprine therapies, the suspected diagnosis of inflammatory myopathy did not yield improvement. Hospitalization at 23 due to respiratory failure post-pregnancy led to her continued reliance on a ventilator. A dried blood spot test indicated reduced GAA enzyme activity, confirming a diagnosis of Pompe disease through genetic testing. Treatment with myozyme for 2 years demonstrated limited efficacy, as the patient experienced improved breathing but no significant overall improvement in limb-girdle muscular weakness. This case underscores the challenges and complexities involved in diagnosing and managing rare neuromuscular disorders like Pompe disease. CONCLUSION: Early intervention with enzyme replacement therapy plays a crucial role in halting further muscle loss and disease progression in Pompe disease patients. It is important to note that treatment during advanced stages of the disease may not yield substantial benefits. Nevertheless, enzyme instability and denaturation due to temperature and neutral pH levels, along with limited delivery to disease-relevant tissues, can pose challenges in treatment. However, timely diagnosis of Pompe disease is paramount for its effective management and improved outcomes.

[Lysosomal storage disorders - Fabry disease and Gaucher disease]. / Lysosomale Speicherkrankheiten ­ Morbus Fabry und Morbus Gaucher.

Lysosomal storage disorders (LSD) are a heterogenous group of inborn errors of metabolism due to lysosomal malfunction. LSDs affect 1 in 5000 live births, albeit every LSD itself has a low incidence. The most common LSDs are Fabry disease and Gaucher disease. The underlying cause mainly is an enzyme deficiency but may also be due to defects in transport or activation proteins, which result in progressive intra- and extra-lysosomal accumulation of undegraded storage material. The lysosomes play a key role in degradation and cellular recycling of macromolecules. Besides disturbance of cellular function, substrate accumulation may result in secondary toxic and/or inflammatory processes. For treatment of Fabry and Gaucher disease, several therapeutic approaches are approved including enzyme replacement therapy, chaperon therapy for Fabry disease and substrate reduction therapy for Gaucher disease.

Living with Pompe disease: results from a qualitative interview study with children and adolescents and their caregivers.

BACKGROUND: Children and adolescents with Pompe disease (PD) face chronic and progressive myopathy requiring time-intensive enzyme replacement therapy (ERT). Little is known about their perspectives on the disease and its treatment. This study explored their perceptions of disease symptoms and functioning status, and more subjective feelings about the impacts on their lives as part of developing a disease-specific questionnaire. METHODS: Eleven pediatric patients aged 8-18 years and 26 caregivers from six children's hospitals in Germany, Austria, and Switzerland underwent semi-structured interviews. Data were recorded, transcribed using MAXQDA software, and analyzed using qualitative content analysis. A system of meaningful categories was developed. RESULTS: Sixteen main categories were derived across four major thematic areas: perceptions of symptoms and limitations, experiences to do with the biopsychosocial impact of PD, treatment experiences, and general emotional well-being/burden. Participants demonstrated broad heterogeneity in symptom perceptions such as muscle weakness, breathing difficulties, pain, and fatigue. Emotional appraisals of limitations were not directly proportional to their severity, and even comparatively minor impairments were often experienced as highly frustrating, particularly for social reasons. The main psychosocial topics were social exclusion vs. inclusion and experiences to do with having a disease. The main finding regarding treatment was that switching ERT from hospital to home was widely viewed as a huge relief, reducing the impact on daily life and the burden of infusions. Emotional well-being ranged from not burdened to very happy in most children and adolescents, including the most severely affected. CONCLUSION: This study provided qualitative insights into the perceptions and experiences of pediatric PD patients. Interestingly, biopsychosocial burden was not directly related to disease severity, and tailored psychosocial support could improve health-related quality of life. The present findings ensure the content validity of a novel questionnaire to be tested as a screening tool to identify patients in need of such support.

Neurological glycogen storage diseases and emerging therapeutics.

Glycogen storage diseases (GSDs) comprise a group of inherited metabolic disorders characterized by defects in glycogen metabolism, leading to abnormal glycogen accumulation in multiple tissues, most notably affecting the liver, skeletal muscle, and heart. Recent findings have uncovered the importance of glycogen metabolism in the brain, sustaining a myriad of physiological functions and linking its perturbation to central nervous system (CNS) pathology. This link resulted in classification of neurological-GSDs (n-GSDs), a group of diseases with shared deficits in neurological glycogen metabolism. The n-GSD patients exhibit a spectrum of clinical presentations with common etiology while requiring tailored therapeutic approaches from the traditional GSDs. Recent research has elucidated the genetic and biochemical mechanisms and pathophysiological basis underlying different n-GSDs. Further, the last decade has witnessed some promising developments in novel therapeutic approaches, including enzyme replacement therapy (ERT), substrate reduction therapy (SRT), small molecule drugs, and gene therapy targeting key aspects of glycogen metabolism in specific n-GSDs. This preclinical progress has generated noticeable success in potentially modifying disease course and improving clinical outcomes in patients. Herein, we provide an overview of current perspectives on n-GSDs, emphasizing recent advances in understanding their molecular basis, therapeutic developments, underscore key challenges and the need to deepen our understanding of n-GSDs pathogenesis to develop better therapeutic strategies that could offer improved treatment and sustainable benefits to the patients.

Comparing the efficacy of cipaglucosidase alfa plus miglustat with other enzyme replacement therapies for late-onset Pompe disease: a network meta-analysis utilizing patient-level and aggregate data.

Aim: Late-onset Pompe disease is characterized by progressive loss of muscular and respiratory function. Until recently, standard of care was enzyme replacement therapy (ERT) with alglucosidase alfa. Second-generation ERTs avalglucosidase alfa (aval) and cipaglucosidase alfa with miglustat (cipa+mig) are now available. Without head-to-head trials comparing aval with cipa+mig, an indirect treatment comparison is informative and timely for understanding potential clinical differentiation. Materials & methods: A systematic literature review was performed to identify relevant studies on cipa+mig and aval. Using patient-level and aggregate published data from randomized controlled trials (RCTs) and phase I/II and open-label extension (OLE) trials, a multi-level network meta-regression was conducted, adjusting for various baseline covariates, including previous ERT duration, to obtain relative effect estimates on 6-minute walk distance (6MWD, meters [m]) and forced vital capacity (FVC, % predicted [pp]). Analyses of two networks were conducted: Network A, including only RCTs, and network B, additionally including single-arm OLE and phase I/II studies. Results: Network B (full evidence analysis) showed that cipa+mig was associated with a relative increase in 6MWD (mean difference 28.93 m, 95% credible interval [8.26-50.11 m]; Bayesian probability 99.7%) and FVC (2.88 pp [1.07-4.71 pp]; >99.9%) compared with aval. The comparison between cipa+mig and aval became more favorable for cipa+mig with increasing previous ERT duration for both end points. Analysis of network A showed that cipa+mig was associated with a relative decrease in 6MWD (-10.02 m [-23.62 to 4.00 m]; 91.8%) and FVC (-1.45 pp [-3.01 to 0.07 pp]; 96.8%) compared with aval. Conclusion: Cipa+mig showed a favorable effect versus aval when all available evidence was used in the analysis.

Allergic reactions to enzyme replacement therapy in children with lysosomal storage diseases and their management.

OBJECTIVES: Human recombinant enzyme replacement therapy, given to compensate for genetic enzyme deficiency in lysosomal storage diseases, delays the progression of the disease and improves the quality of life. However, enzyme replacement therapy may cause hypersensitivity reactions. Within the scope of this research, we aimed to elucidate the frequency and clinical features of hypersensitivity reactions against enzyme replacement therapy in children with lysosomal storage diseases and clarify the management of these reactions. METHODS: Medical records of pediatric patients with lysosomal storage disease and receiving enzyme replacement therapy were retrospectively reviewed, and patients who experienced allergic reactions were included in the study. The demographic characteristics of the patients, their diagnosis, the responsible enzyme, the time at which the reaction started and at what dose, the signs and symptoms associated with the reaction, diagnostic tests, the management of the reaction, and the protocol applied for the maintenance of enzyme replacement therapy after the reaction were recorded. RESULTS: Hypersensitivity reactions developed in 18 of 71 patients (25.3 %) who received enzyme replacement therapy. The most common cutaneous findings were observed. Anaphylaxis developed in 6 of 18 patients. Patients who experienced recurrent hypersensitivity reactions with premedication or a slower infusion rate, those with positive skin test results, and patients who developed anaphylaxis were given enzyme replacement therapy with desensitization. CONCLUSIONS: HSR may develop during enzyme replacement therapy, which are vital in lysosomal storage diseases, and discontinuation of enzyme replacement therapy is a significant loss for patients with metabolic disorders. These reactions can be treated with premedication and long-term infusions, but some patients may require desensitization protocols for continued treatment.

Inflammatory cytokine expression in Fabry disease: impact of disease phenotype and alterations under enzyme replacement therapy.

Objectives: The aim of this study is to explore the expression of inflammatory cytokines (ICs) in Fabry disease (FD), the correlation between ICs and FD phenotypes, and the impact of enzyme replacement therapy (ERT) on IC expression. Methods: We recruited 67 FD patients and 44 healthy controls (HCs) and detected concentrations of the following ICs: interferon-γ, interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12P70, IL-17A, IL-17F, IL-22, tumor necrosis factor (TNF)-α, and TNF-ß. We also analyzed the impact of ERT on IC expression in FD patients and the relationship between IC expression and sex, genotype, phenotype, disease burden, and biomarkers. Results: Most ICs were significantly higher in FD patients than in HCs. A number of ICs were positively correlated with clinical aspects, including disease burden (Mainz Severity Score Index [MSSI]) and cardiac and renal markers. IL-8 was higher in the high MSSI (P-adj=0.026*) than in the low MSSI. Conclusions: ICs were upregulated in FD patients, indicating the role of the innate immune process in FD etiology. ERT ameliorated FD-related inflammatory activation, at least to some extent. IC expression was positively correlated with disease burden and clinical markers in FD. Our findings indicated that the inflammatory pathway may be a promising therapeutic target for FD.

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.

Association between under-dose of enzyme replacement therapy and quality of life in adults with late-onset Pompe disease in China: A retrospective matched cohort study.

BACKGROUND: Due to the high cost of enzyme replacement therapy (ERT), most of adults with late-onset Pompe disease (LOPD) who received ERT used the medication with insufficient dosefs in China. OBJECTIVE: To compare the change in quality of life (QoL) between adults with LOPD receiving under-dose ERT and no ERT, and identify factors associated with the change of QoL. METHODS: A retrospective matched cohort study was conducted among adult patients with LOPD in a nationwide Pompe registry in China. Eligible participants were those who completed two investigations, and didn't expose to ERT at baseline or before. The treated group were those who used ERT during follow-up; the untreated group received general care. The treated and untreated group were matched with a ratio of 1:2. QoL was assessed by the SF-12 and EQ-5D-5L. The dose of ERT was evaluated by the ratio of actual vials patients used divided by the indicated vials patients should use. The treated patients were further classified into mild and severe under-dose users by the median ratio. Multivariate linear regression analyses were performed to estimate the average treatment effect in the treated groups and identify factors associated with the changes of QoL scores. RESULTS: The study sample included 5 mild under-dose users, 6 severe under-dose users, and 22 untreated participants. Compared with the untreated group, mild under-dose ERT had no significant effect on the changes of QoL scores. In contrast, severe under-dose ERT was associated with a decline of physical QoL (ß = -6.19, p = 0.001), but an increase of overall health state (ß = 19.69, p = 0.032). A higher score of physical QoL (ß = -0.74, p = 0.001) and overall health state (ß = -0.69, p<0.001) at baseline was associated with decline in corresponding scores at follow-up. Being female was a contributor to the worsening of the overall health state (ß = -22.79, p = 0.002), while being employed or at school was a predictor of improvement in mental QoL (ß = 5.83, p = 0.002). CONCLUSIONS: A Pompe-disease specific instrument based on patient experiences is warranted to closely monitor changes in QoL on a routine basis. It is desirable for patients with severe under-dose ERT to discuss with physicians whether to adjust treatment strategies.

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.

Safety, pharmacokinetics, and pharmacodynamics of efzimfotase alfa, a second-generation enzyme replacement therapy: phase 1, dose-escalation study in adults with hypophosphatasia.

Hypophosphatasia (HPP) is a rare, inherited metabolic disease caused by deficient activity of tissue-nonspecific alkaline phosphatase (TNSALP). Efzimfotase alfa (ALXN1850) is a second-generation TNSALP enzyme replacement therapy in development for HPP. This first-in-human open-label, dose-escalating phase 1 trial evaluated efzimfotase alfa safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity. Fifteen adults (5/cohort) with HPP received efzimfotase alfa in doses of 15 mg (cohort 1), 45 mg (cohort 2), or 90 mg (cohort 3) as one intravenous (i.v.) dose followed by 3 weekly subcutaneous (s.c.) doses. The primary objective was to assess safety and tolerability. Secondary objectives included pharmacokinetics, pharmacodynamics of ALP substrates known to be biomarkers of disease (inorganic pyrophosphate [PPi] and pyridoxal 5'-phosphate [PLP]) and immunogenicity. Treatment-emergent adverse events (TEAEs) occurred in 12 (80%) participants. Eight (53%) participants had injection site reactions (ISRs), observed after 10 of 41 (24%) s.c. injections. Most ISR TEAEs were mild and resolved within 1-2 d. Peak and total exposures of efzimfotase alfa increased in a greater-than-dose proportional manner over the range of 15-90 mg after i.v. and s.c. dosing. The arithmetic mean elimination half-life was approximately 6 d; absolute bioavailability was 28.6%-36.8% over the s.c. dose range of 15-90 mg. Dose-dependent reductions in plasma concentrations of PPi and PLP relative to baseline reached nadir in the first week after i.v. dosing and were sustained for 3-4 wk after the last s.c. dose. Four (27%) participants tested positive for antidrug antibodies (ADAs), 3 of whom were ADA positive before the first dose of efzimfotase alfa. ADAs had no apparent effect on efzimfotase alfa pharmacokinetics/pharmacodynamics. No participants had neutralizing antibodies. Efzimfotase alfa demonstrated acceptable safety, tolerability, and pharmacokinetic profiles and was associated with sustained reductions in biomarkers of disease in adults with HPP, supporting further evaluation in adult and pediatric patients. Registration: ClinicalTrials.gov NCT04980248 (https://clinicaltrials.gov/study/NCT04980248).

Hypophosphatasia (HPP) is a rare metabolic disease caused by low activity of tissue nonspecific alkaline phosphatase (TNSALP), which is an enzyme involved in the formation and healing of bone and function of other body systems. People with HPP experience fractures, difficulty moving and walking, muscle weakness, pain, fatigue (tiredness), and teeth problems. Babies with HPP often have life-threatening breathing problems, craniosynostosis (early closure of skull bones), seizures that respond to treatment with vitamin B6, failure to thrive (inability to gain weight), and weak and abnormally shaped bones. Enzyme replacement therapy (ERT) for HPP was developed to supplement defective TNSALP with active enzyme, thus improving bone health and the symptoms of HPP. Asfotase alfa, the first ERT approved for the treatment of HPP, is given by subcutaneous injection either 3 or 6 times per week. Efzimfotase alfa is a second-generation ERT that is being developed for the treatment of HPP. Although similar to asfotase alfa, efzimfotase alfa has incorporated several changes that have the potential to require lower doses and reduce injection volume and dosing frequency, thereby potentially improving the treatment experience for patients. This first-in-human study investigated the safety, tolerability, pharmacokinetics (how a drug is absorbed into, distributed throughout, and removed from the body), pharmacodynamics (effects of the drug within the body), and immunogenicity (ability of a drug to provoke an undesirable immune response) of 4 injections of efzimfotase alfa when given by intravenous and subcutaneous routes of administration to adults with HPP. Our results showed that efzimfotase alfa has acceptable safety and pharmacokinetics and is effective for reducing biomarkers (measurable substances that reflect underlying disease) when given once weekly by subcutaneous injection, supporting further evaluation of efzimfotase alfa in planned clinical trials in adult and pediatric patients with HPP.

Efficacy and safety of asfotase alfa in patients with hypophosphatasia: A systematic review.

BACKGROUND: Hypophosphatasia (HPP) is a rare genetic disorder characterized by defective bone mineralization, leading to skeletal abnormalities and systemic complications. Asfotase alfa, a recombinant human tissue-nonspecific alkaline phosphatase (TNSALP) enzyme replacement therapy, has emerged as a promising treatment for HPP. However, a comprehensive evaluation of its efficacy and safety is warranted to guide clinical practice effectively. METHODS: The study followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was registered in Prospective Register of Systematic Reviews (PROSPERO). A search strategy across databases found studies on asfotase alfa for HPP. Two researchers independently extracted and assessed data. This systematic review examined how the drug impacted clinical outcomes such as survival rates, musculoskeletal symptoms, respiratory function, growth measurements, dental health, quality of life, and laboratory results. RESULTS: This systematic review included 15 articles with a total of 455 HPP patients. Asfotase alfa was predominantly administered at a dose of 6 mg per kg per week among the reviewed studies. Notable findings included enhanced survival rates, relief from musculoskeletal pain, improvements in respiratory outcomes, growth parameters, dental health, and quality of life. Changes in laboratory variables indicated positive responses to treatment, including changes such as increase in alkaline phosphatase (ALP), decline in pyridoxal 5'-phosphate (PLP) and inorganic pyrophosphate (PPi) levels. CONCLUSION: Asfotase alfa demonstrates efficacy in improving clinical outcomes and safety in patients with HPP. Its therapeutic benefits extend across various domains. However, Larger, age-stratified comparative studies are needed to further investigate the drug's effects in HPP patients.

Clinical and preclinical insights into high-dose ambroxol therapy for Gaucher disease type 2 and 3: A comprehensive systematic review.

RATIONALE: Gaucher disease (GD), an autosomal recessive lysosomal storage disease, results from GBA1 variants causing glucocerebrosidase (GCase) deficiency. While enzyme replacement therapy (ERT) helps with systemic symptoms, neurological complications in GD2 and GD3 persist due to the blood-brain-barrier (BBB) limiting ERT efficacy. Ambroxol, a BBB-permeable chaperone, enhances GCase activity. Our review explores high-dose ambroxol's therapeutic potential, both preclinical and clinical, in GD2 and GD3. METHODS: PubMed was searched for studies published before March 2023, including clinical, animal, and in vitro studies focusing on the effect of high-dose ambroxol in GD2 and GD3. A narrative synthesis was performed. RESULTS: Nine in vitro, three animal, and eight clinical studies were included, demonstrating varied responses to ambroxol across diverse outcome measures. In vitro and animal studies demonstrated reduced endoplasmatic reticulum stress due to the relocation of GCase from the ER to the lysosomes. In vitro cell lines exhibited varying degrees of increased GCase activity. Clinical trials observed reduced lyso-GL1 levels in plasma (41-89%) and cerebrospinal fluid (CSF) (26-97%), alongside increased GCase activity in GD3 patients. Ambroxol exhibited varying effects on neurological outcomes and development. No severe adverse events were reported. CONCLUSION: High-dose ambroxol shows promise in managing neurological manifestations in GD3, albeit with uncertainties resulting from genetic heterogeneity and variable response. Further clinical trials, are essential for elucidating dosage-response relationships and refining treatment outcomes and strategies for neuronopathic GD.

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.

Clinical outcomes in elderly patients receiving agalsidase alfa treatment in the Fabry Outcome Survey.

BACKGROUND AND OBJECTIVES: Treatment with agalsidase alfa in patients with Fabry disease is most effective when initiated early in the disease course; however, the clinical benefits in elderly patients are less well established. This analysis assesses outcomes in patients aged 65 years or older from the Fabry Outcome Survey (FOS) who were treated with agalsidase alfa. METHODS: FOS data were extracted for adult patients aged 65 years or older who received agalsidase alfa, had baseline data and at least 3 years of post-baseline data, and had undergone no renal transplantation and/or dialysis before treatment. The data of patients who had undergone renal transplantation and/or dialysis during follow-up were excluded from estimated glomerular filtration rate (eGFR) analysis after the date of the renal transplantation and/or dialysis. Adult patients were stratified into two groups: those who started treatment before 65 years of age and who were still being treated when aged 65 years or older (group A), and those who started treatment when aged 65 years or older (group B). Mean annual changes in left ventricular mass index (LVMI), eGFR and proteinuria were assessed in group A (before and after the age of 65 years to understand if there was an age-related effect once patients turned 65 years of age) and in group B. RESULTS: Estimated mean (standard error [SE]) annual changes in LVMI were 0.46 (0.26) g/m2.7 and 0.21 (0.42) g/m2.7 in patients in group A when they were younger than 65 years and when they were aged 65 years or older, respectively, and 0.12 (0.65) g/m2.7 in patients in group B. For eGFR, mean (SE) annual changes were 0.83 (2.12) mL/min/1.73 m2 and 2.64 (2.18) mL/min/1.73 m2 in patients in group A when they were younger than 65 years and when they were aged 65 years or older, respectively, and 2.31 (1.44) mL/min/1.73 m2 in patients in group B. Proteinuria remained relatively stable in both subgroups of group A (before and after the age of 65 years) and group B. CONCLUSIONS: Continuation and initiation of agalsidase alfa treatment in patients aged 65 years or older with Fabry disease were associated with stabilization of proteinuria and minimal increases in cardiac (LVMI) and renal (eGFR) outcomes.