Assuntos
1-Desoxinojirimicina , Doença de Depósito de Glicogênio Tipo II , alfa-Glucosidases , Humanos , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/uso terapêutico , 1-Desoxinojirimicina/administração & dosagem , 1-Desoxinojirimicina/efeitos adversos , Adulto , Terapia de Reposição de Enzimas , Quimioterapia Combinada , Aprovação de Drogas , Idade de InícioAssuntos
1-Desoxinojirimicina , Terapia de Reposição de Enzimas , Doença de Depósito de Glicogênio Tipo II , Manosefosfatos , Animais , Camundongos , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/administração & dosagem , 1-Desoxinojirimicina/uso terapêutico , Terapia de Reposição de Enzimas/métodos , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , alfa-Glucosidases/metabolismo , Humanos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologiaRESUMO
We thank Dr. Weimer and her colleagues for their comments related to our recent work (Anding et al., 2023) and are grateful for the opportunity to further discuss the importance of efficient lysosomal targeting of enzyme-replacement therapies (ERT) for the treatment of Pompe disease. Patients with Pompe disease have mutations in the gene that encodes for acid α glucosidase (GAA), a lysosomal enzyme necessary for the breakdown of glycogen. The first-generation ERT, alglucosidase alfa, provides a lifesaving therapy for the severe form of the disease (infantile onset Pompe disease) and improves or stabilizes respiratory and motor function in patients with less severe disease (late onset Pompe disease). Despite these gains, significant unmet need remains, particularly in patients who display respiratory and motor decline following years of treatment. Poor tissue uptake and lysosomal targeting via inefficient binding of the cation-independent mannose-6-phosphate (M6P) receptor (CIMPR) in skeletal muscle contributed to this suboptimal treatment response, prompting the development of new ERTs with increased levels of M6P.
Assuntos
1-Desoxinojirimicina , Terapia de Reposição de Enzimas , Doença de Depósito de Glicogênio Tipo II , Manosefosfatos , alfa-Glucosidases , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Animais , Terapia de Reposição de Enzimas/métodos , Manosefosfatos/metabolismo , Camundongos , alfa-Glucosidases/uso terapêutico , alfa-Glucosidases/metabolismo , alfa-Glucosidases/administração & dosagem , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/administração & dosagem , 1-Desoxinojirimicina/uso terapêutico , Humanos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismoRESUMO
The phase III double-blind PROPEL study compared the novel two-component therapy cipaglucosidase alfa + miglustat (cipa + mig) with alglucosidase alfa + placebo (alg + pbo) in adults with late-onset Pompe disease (LOPD). This ongoing open-label extension (OLE; NCT04138277) evaluates long-term safety and efficacy of cipa + mig. Outcomes include 6-min walk distance (6MWD), forced vital capacity (FVC), creatine kinase (CK) and hexose tetrasaccharide (Hex4) levels, patient-reported outcomes and safety. Data are reported as change from PROPEL baseline to OLE week 52 (104 weeks post-PROPEL baseline). Of 118 patients treated in the OLE, 81 continued cipa + mig treatment from PROPEL (cipa + mig group; 61 enzyme replacement therapy [ERT] experienced prior to PROPEL; 20 ERT naïve) and 37 switched from alg + pbo to cipa + mig (switch group; 29 ERT experienced; 8 ERT naive). Mean (standard deviation [SD]) change in % predicted 6MWD from baseline to week 104 was + 3.1 (8.1) for cipa + mig and - 0.5 (7.8) for the ERT-experienced switch group, and + 8.6 (8.6) for cipa + mig and + 8.9 (11.7) for the ERT-naïve switch group. Mean (SD) change in % predicted FVC was - 0.6 (7.5) for cipa + mig and - 3.8 (6.2) for the ERT-experienced switch group, and - 4.8 (6.5) and - 3.1 (6.7), respectively, in ERT-naïve patients. CK and Hex4 levels improved in both treatment groups by week 104 with cipa + mig treatment. Three patients discontinued the OLE due to infusion-associated reactions. No new safety signals were identified. Cipa + mig treatment up to 104 weeks was associated with overall maintained improvements (6MWD, biomarkers) or stabilization (FVC) from baseline with continued durability, and was well tolerated, supporting long-term benefits for patients with LOPD.Trial registration number: NCT04138277; trial start date: December 18, 2019.
Assuntos
1-Desoxinojirimicina , 1-Desoxinojirimicina/análogos & derivados , Terapia de Reposição de Enzimas , Doença de Depósito de Glicogênio Tipo II , Humanos , Masculino , Feminino , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Pessoa de Meia-Idade , Adulto , 1-Desoxinojirimicina/administração & dosagem , 1-Desoxinojirimicina/efeitos adversos , 1-Desoxinojirimicina/uso terapêutico , Método Duplo-Cego , Terapia de Reposição de Enzimas/métodos , alfa-Glucosidases/efeitos adversos , alfa-Glucosidases/administração & dosagem , alfa-Glucosidases/uso terapêutico , Quimioterapia Combinada , Resultado do Tratamento , Idoso , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversosRESUMO
Background: Juvenile Yoshitomi tilapia is often infected by pathogens and results in low-level survival rate. Bacillus subtilis, as a probiotic, may have beneficial effects on Y. tilapia with compound 1-deoxynojirimycin (DNJ), which has antibacterial activities. The effects of dietary probiotic supplementation on Y. tilapias were evaluated. Results: Juvenile Y. tilapia was fed with B. subtilis for 56 d. Y. tilapia was infected by Aeromonas hydrophila and survival rate was compared. Dietary B. subtilis increased weight gain rate, specific growth, food conversion ratios and food intake rate of Y. tilapia. The diet improved the cumulative survival rate (CSR) of juvenile Y. tilapia when the concentration of B. subtilis was more than 2.05 × 1010 cfu/kg and CSR reached a maximum rate when the concentration of bacillus was 4.23 × 1010 (P b 0.05). Meanwhile, B. subtilis improved total antioxidant capacity (TAC), spleen index, the activities of serum lysozyme, alkaline phosphatase (ALP), superoxide dismutase (SOD) and catalase (CAT) (P b 0.05). In contrast, B. subtilis reduced serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), malondialdehyde (MDA) and C3 complement (P b 0.05). DNJ was isolated from secondary metabolisms and proved to increase the levels of SOD, CAT and reduce the levels of AST, ALT and MDA at cell levels. After A. hydrophila infection, DNJ prevented the reduction in survival rate of Y. tilapia (P b 0.05). Conclusions: 1-Deoxynojirimycin from Bacillus subtilis can be used to improve the growth performance of juvenile Y. tilapia by affecting its antioxidant and antibacterial activities.