Explore the vast range of titles available.

Background Mucopolysaccharidosis (MPS) Type I (MPSI) is caused by mutations in the gene encoding the lysosomal enzyme, α-L-iduronidase (IDUA), and a majority of patients present with severe neurodegeneration and cognitive impairment. Recombinant IDUA does not cross the blood-brain barrier (BBB). To enable BBB transport, IDUA was re-engineered as an IgG-IDUA fusion protein, valanafusp alpha, where the IgG domain targets the BBB human insulin receptor to enable transport of the enzyme into the brain. We report the results of a 52-week clinical trial on the safety and efficacy of valanafusp alpha in pediatric MPSI patients with cognitive impairment. In the phase I trial, 6 adults with attenuated MPSI were administered 0.3, 1, and 3 mg/kg doses of valanafusp alpha by intravenous (IV) infusion. In the phase II trial, 11 pediatric subjects, 2-15 years of age, were treated for 52 weeks with weekly IV infusions of valanafusp alpha at 1, 3, or 6 mg/kg. Assessments of adverse events, cognitive stabilization, and somatic stabilization were made. Outcomes at 52 weeks were compared to baseline. Results Drug related adverse events included infusion related reactions, with an incidence of 1.7%, and transient hypoglycemia, with an incidence of 6.4%. The pediatric subjects had CNS involvement with a mean enrollment Development Quotient (DQ) of 36.1±7.1. The DQ, and the cortical grey matter volume of brain, were stabilized by valanafusp alpha treatment. Somatic manifestations were stabilized, or improved, based on urinary glycosaminoglycan levels, hepatic and spleen volumes, and shoulder range of motion. Conclusion Clinical evidence of the cognitive and somatic stabilization indicates that valanafusp alpha is transported into both the CNS and into peripheral organs due to its dual targeting mechanism via the insulin receptor and the mannose 6-phosphate receptor. This novel fusion protein offers a pharmacologic approach to the stabilization of cognitive function in MPSI. Trial registration Clinical Trials.Gov, NCT03053089 . Retrospectively registered 9 February, 2017; Clinical Trials.Gov, NCT03071341 . Registered 6 March, 2017.

This study assessed the efficacy and safety of a biosimilar Laronidase (CinnaGen Company, Iran), compared to the reference Laronidase (Aldurazyme, BioMarin, USA) in maintaining urinary glycosaminoglycan (uGAG) levels in mucopolysaccharidosis type I (MPS I) patients. In this phase III, open-label, single-sequence, and cross-over study, MPS I patients received Aldurazyme for 12 weeks, followed by Laronidase (CinnaGen) for another 12 weeks. The primary outcome was the assessment of mean uGAG levels at the final visits of each medication administration. The secondary outcomes included the assessment of 6-minute walking test (6MWT), predicted forced vital capacity (FVC), enzyme activity assay, and adverse events (AEs). Twelve patients with mean (standard deviation [SD]) age of 10.25 ± 3.11 years were included in the study. The mean (± SD) uGAG level was 220.47 ± 177.13 CPC unit/g creatinine at the end of Aldurazyme treatment and changed to 270.02 ± 111.55 CPC unit/g creatinine at the end of Laronidase (CinnaGen) treatment, with variable patient responses. The mean 6MWT and predicted FVC improved by almost 30 m and 13%, respectively. Post-infusion enzyme activity levels showed similar patterns between Aldurazyme and Laronidase (CinnaGen), with no detectable activity before the infusion. A total of 30 AEs were reported during the trial. In the first time period (receiving Aldurazyme), AEs were reported for seven patients (58.33%), and in the subsequent time period (receiving Laronidase (CinnaGen)), AEs were reported for six patients (50%). Among all, nasopharyngitis was the most common reported AE. In conclusion, the biosimilar Laronidase was shown to have a comparable efficacy and safety profile compared with the reference Laronidase. Clinical Trial Registration: Clinicaltrials.gov: NCT06406153; First registration: 09/05/2024.

Background Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by deficiency of the enzyme α-L-iduronidase. Laronidase (Aldurazyme ® ) stands as the sole FDA-approved enzyme replacement therapy (ERT) for MPS I to date. In June 2020, a concentrated solution of laronidase for injection received approval for a Chinese bioproduct license, exempted from clinical trials. Compliance with approval requirements mandates post-marketing surveillance (PMS) for laronidase. The objective of this study was to evaluate the safety and efficacy of laronidase treatment at a dosage of 100 U/kg body weight weekly in Chinese patients with MPS I. Methods From October 2021 to July 2023, 12 MPS I patients at four institutions in China received weekly intravenous injections of laronidase at a dose of 100 U/kg of body weight once a week for 26 weeks. The primary efficacy endpoint was the percentage change in urinary glycosaminoglycans (uGAGs) levels at week 26 relative to baseline. Safety endpoints included the incidence of adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESIs, including infusion-related reactions) during the treatment period (TE). Results Laronidase consistently reduced uGAGs levels from baseline to week 26, with a percentage change of -64.61% ± 26.90% (95% CI: -81.70% to -47.52%). There was a revealed reduction following laronidase treatment. The percentage reductions in uGAGs from baseline to weeks 2, 4, 8, 12, and 20 were decreased. The decreases in absolute change of uGAGs were observed at weeks 2, 4, 8, 12, 20, and 26. The percentage reduction in liver volume from baseline to week 26 was − 13.24% ± 7.86% (95% CI: -18.24% to -8.25%). Nine participants (75%) achieved an overall treatment compliance rate ≥80%. Eleven participants (91.7%) experienced treatment-emergent adverse events (TEAEs). Four participants (33.3%) experienced AESIs. Conclusions In Chinese patients with MPS I, laronidase as an enzyme replacement therapy effectively reduces glycosaminoglycan storage and liver volume while demonstrating a favorable safety profile. Clinical trial registration number NCT05134571. Clinical trial registration date 2021-10-21. Name of the registry China Post-marketing Surveillance (PMS) Study of Aldurazyme ® . URL of the trial registry record https://clinicaltrials.gov/search?term=NCT05134571

To evaluate the efficacy and safety of IV laronidase for MPS I. A systematic literature review was performed by searching the ClinicalTrials.gov, MEDLINE/PubMed, EMBASE, LILACS, and Cochrane Library databases, limited to clinical trials published until December 31, 2016. The first inclusion criterion was being a randomized controlled trial (RCT). If < five RCTs were identified, open-label and nonrandomized trials, controlled or uncontrolled (quasi-experimental), including ≥ five patients, and evaluating relevant outcomes defined a priori, would also be included. For meta-analysis, primary inferences were based on random-effects models. Assessment of article quality was performed in accordance with the GRADE criteria. The Cochrane Risk of Bias tool was used to examine the risk of bias for RCTs. The selection phase retrieved 632 articles. During the first phase of selection, 158 had the abstract or full text read for assessment of eligibility, of which nine (two RCTs) were included for qualitative synthesis. Four papers were included in the meta-analysis, which was performed for the following outcomes: occurrence of treatment-emergent or infusion-related adverse events (65%; 95%CI 53, 76), mild in most cases; development of IgG antibodies to laronidase (88%; 95%CI 67, 100); apnea-hypopnea index (not significant-NS), urinary glycosaminoglycans (GAGs) [mean change -65.5 μg/mg creatinine (95%CI -68.8, -62.3)], liver size [mean change -31.03% (95%CI -36.1, -25.9)], left ventricular mass index (LVMI) [mean change -1.8 (95%CI -2.32, -0.25)], and distance covered in the 6-minute walk test (NS). Among the outcomes not included in meta-analysis, we found evidence for benefit of laronidase only on shoulder flexion. Our findings suggest that IV laronidase effectively reduces urinary GAGs excretion, hepatomegaly and LVMI, and can improve shoulder flexion in MPS I patients. Laronidase appears to be safe in the studied population.

BackgroundMucopolysaccharidosis I (MPS IH) is a lysosomal storage disease treated with hematopoietic cell transplantation (HCT) because it stabilizes cognitive deterioration, but is insufficient to alleviate all somatic manifestations. Intravenous laronidase improves somatic burden in attenuated MPS I. It is unknown whether laronidase can improve somatic disease following HCT in MPS IH. The objective of this study was to evaluate the effects of laronidase on somatic outcomes of patients with MPS IH previously treated with HCT.MethodsThis 2-year open-label pilot study of laronidase included ten patients (age 5–13 years) who were at least 2 years post-HCT and donor engrafted. Outcomes were assessed semi-annually and compared to historic controls.ResultsThe two youngest participants had a statistically significant improvement in growth compared to controls. Development of persistent high-titer anti-drug antibodies (ADA) was associated with poorer 6-min walk test (6MWT) performance; when patients with high ADA titers were excluded, there was a significant improvement in the 6MWT in the remaining seven patients.ConclusionsLaronidase seemed to improve growth in participants <8 years old, and 6MWT performance in participants without ADA. Given the small number of patients treated in this pilot study, additional study is needed before definitive conclusions can be made.

Mucopolysaccharidosis I is a lysosomal storage disease caused by a deficiency of α-L-iduronidase, an enzyme that cleaves the terminal α-l-idu-ronic acid residues in the glycosaminoglycans heparan sulfate and dermatan sulfate. 1 , 2 The deficiency blocks the degradation of these glycosaminoglycans, which accumulate in lysosomes. Mucopolysaccharidosis I has a wide spectrum of clinical severity and has been subdivided into three syndromes: Hurler's syndrome (severe), Hurler–Scheie syndrome (intermediate), and Scheie's syndrome (mild). Patients with Hurler's syndrome have many medical problems, including progressive developmental delay, corneal clouding, airway obstruction, cardiac disease, hepatosplenomegaly, and severe joint restriction, and most die by the age of 10 . . .

Enzyme-replacement therapy has been assessed as a treatment for patients who have mucopolysaccharidosis I (α-L-iduronidase deficiency). We aimed to investigate the humoral immune response to recombinant human α-L-iduronidase among these patients. We characterised the antibody titres and specific linear sequence epitope reactivity of serum antibodies to α-L-iduronidase for ten patients with mucopolysaccharidosis I, at the start of treatment and after 6, 12, 26, 52, and 104 weeks. We compared the values for patients' samples with those for samples from normal human controls. Before enzyme-replacement therapy, all patients had low serum antibody titres to recombinant human α-L-iduronidase that were within the control range. Five of the ten patients produced higher-than-normal titres of antibody to the replacement protein during the treatment course (serum antibody titres 130 000–500 000 and high-affinity epitope reactivity). However, by week 26, antibody reactivity was reduced, and by week 104 all patients had low antibody titres and only low-affinity epitope reactivity. Patients who had mucopolysaccharidosis I with antibody titres within the normal range at 6–12 weeks did not subsequently develop immune responses. After 2 years of treatment, patients who initially had an immune reaction developed immune tolerance to α-L-iduronidase. This finding has positive implications for long-term enzyme-replacement therapy in patients who have mucopolysaccharidosis I.

Hurler syndrome is a debilitating genetic disease with a typical life span of 5 to 8 years. Early hematopoietic stem cell transplantation (HSCT) mitigates disease symptoms and improves survival. However, morbidity and mortality associated with HSCT can limit its success. We describe the initial experience with combined use of enzyme replacement therapy (ERT, laronidase) and HSCT in Hurler syndrome. Thirteen transplants were performed in 12 patients. ERT was given at a standard dose of 0.58 mg/kg per week. Transplant conditioning regimen and donor graft source were determined by institutional protocol. The median age at initiation of ERT was 12 months (range, 8 to 18 months). The median duration of pre-HSCT ERT was 12 weeks (range, 4 to 28). All but 1 patient tested showed decrease in urinary GAG excretion during ERT. ERT infusion-related toxicity was limited to mild reactions. Development of antibodies to laronidase did not correlate with infusion reactions or responses in urinary GAG excretion. ERT was given for a median of 7 weeks (range, 3 to 20) after HSCT. After transplantation, eight patients demonstrated complete donor engraftment and four suffered graft failure. Two patients required ventilator support and three developed acute GVHD. Eleven of the 12 patients are surviving with a median follow-up of 3 months (range, 1 to 7 months). In children with Hurler syndrome, ERT with HSCT is feasible and well tolerated. Development of antibodies against exogenous enzyme does not appear to correlate with infusion reactions or response to ERT. A prospective study is needed to determine the effect of concomitant ERT on transplant outcomes.

A 25-year-old female was referred for short stature and joint deformities. Except for previous corneal transplantation, her medical history was unremarkable. Initial physical examination revealed the presence of a coarse facies, short neck, kyphosis, restricted joint movements and deformities, and cardiac murmur besides a normal intellect. Urine glycosaminoglycan levels were high, and blood enzyme assay indicated significantly low alpha-L-iduronidase levels. Mucopolysaccharidosis I (MPS I) was diagnosed and prompted the onset of enzyme replacement therapy (ERT), which significantly improved articular complaints, while cardiac pathology remained stable. At the eighteenth month of ERT, sudden vision loss developed. She spontaneously recovered her vision in a month. MPS I is a progressive disease, in which tissue accummulation of heparan and dermatan sulphate result from defective activity or lack of alpha-L-iduronidase. ERT in MPS I usually presents favourable outcomes or at least stabilization of symptoms. This present case qualifies as the first report ofa MPS I patient developing sudden vision loss under ERT. We suggest that further research studies are warranted for defining the efficiency and possible limitations of ERT.

Purpose Mucopolysaccharidosis I is a genetic disorder caused by alpha-L-iduronidase deficiency. Its primary treatment is enzyme replacement therapy (ERT), which has limitations such as a high cost and a need for repeated infusions over the patient's lifetime. Considering that nanotechnological approaches may enhance enzyme delivery to organs and can reduce the dosage thereby enhancing ERT efficiency and/or reducing its cost, we synthesized laronidase surface-functionalized lipid-core nanocapsules (L-MLNC). Methods L-MLNCs were synthesized by using a metal complex. Size distributions were evaluated by laser diffraction and dynamic light scattering. The kinetic properties, cytotoxicity, cell uptake mechanisms, clearance profile and biodistribution were evaluated. Results Size distributions showed a D[4,3] of 134 nm and a z-average diameter of 71 nm. L-MLNC enhanced the Vmax and Kcat in comparison with laronidase. L-MLNC is not cytotoxic, and nanocapsule uptake by active transport is not only mediated by mannose-6-phosphate receptors. The clearance profile is better for L-MLNC than for laronidase. A biodistribution analysis showed enhanced enzyme activity in different organs within 4 h and 24 h for L-MLNC. Conclusions The use of lipid-core nanocapsules as building blocks to synthesize surface-functionalized nanocapsules represents a new platform for producing decorated soft nanoparticles that are able to modify drug biodistribution.