RESUMO
Acid sphingomyelinase deficiency (ASMD) is a severe lipid storage disorder caused by the diminished activity of the acid sphingomyelinase enzyme. ASMD is characterized by the accumulation of sphingomyelin in late endosomes and lysosomes leading to progressive neurological dysfunction and hepatosplenomegaly. Our objective was to investigate the utility of synthetic apolipoprotein A-I (ApoA-I) mimetics designed to act as lipid scavengers for the treatment of ASMD. We determined the lead peptide, 22A, could reduce sphingomyelin accumulation in ASMD patient skin fibroblasts in a dose dependent manner. Intraperitoneal administration of 22A formulated as a synthetic high-density lipoprotein (sHDL) nanodisc mobilized sphingomyelin from peripheral tissues into circulation and improved liver function in a mouse model of ASMD. Together, our data demonstrates that apolipoprotein mimetics could serve as a novel therapeutic strategy for modulating the pathology observed in ASMD.
Assuntos
Doença de Niemann-Pick Tipo A , Animais , Camundongos , Humanos , Doença de Niemann-Pick Tipo A/tratamento farmacológico , Doença de Niemann-Pick Tipo A/patologia , Esfingomielinas , Peptídeos/uso terapêutico , Fígado/patologiaRESUMO
ASM deficiency in Niemann-Pick disease type A results in aberrant cellular accumulation of sphingomyelin, neuroinflammation, neurodegeneration, and early death. There is no available treatment because enzyme replacement therapy cannot surmount the blood-brain barrier (BBB). Nanocarriers (NCs) targeted across the BBB via transcytosis might help; yet, whether ASM deficiency alters transcytosis remains poorly characterized. We investigated this using model NCs targeted to intracellular adhesion molecule-1 (ICAM-1), transferrin receptor (TfR), or plasmalemma vesicle-associated protein-1 (PV1) in ASM-normal vs. ASM-deficient BBB models. Disease differentially changed the expression of all three targets, with ICAM-1 becoming the highest. Apical binding and uptake of anti-TfR NCs and anti-PV1 NCs were unaffected by disease, while anti-ICAM-1 NCs had increased apical binding and decreased uptake rate, resulting in unchanged intracellular NCs. Additionally, anti-ICAM-1 NCs underwent basolateral reuptake after transcytosis, whose rate was decreased by disease, as for apical uptake. Consequently, disease increased the effective transcytosis rate for anti-ICAM-1 NCs. Increased transcytosis was also observed for anti-PV1 NCs, while anti-TfR NCs remained unaffected. A fraction of each formulation trafficked to endothelial lysosomes. This was decreased in disease for anti-ICAM-1 NCs and anti-PV1 NCs, agreeing with opposite transcytosis changes, while it increased for anti-TfR NCs. Overall, these variations in receptor expression and NC transport resulted in anti-ICAM-1 NCs displaying the highest absolute transcytosis in the disease condition. Furthermore, these results revealed that ASM deficiency can differently alter these processes depending on the particular target, for which this type of study is key to guide the design of therapeutic NCs.
Assuntos
Doença de Niemann-Pick Tipo A , Doenças de Niemann-Pick , Humanos , Doença de Niemann-Pick Tipo A/tratamento farmacológico , Portadores de Fármacos/química , Barreira Hematoencefálica/metabolismo , Molécula 1 de Adesão Intercelular/metabolismoRESUMO
Olipudase alfa (Xenpozyme™) is an intravenously administered acid sphingomyelinase enzyme replacement therapy indicated to treat non-CNS manifestations of acid sphingomyelinase deficiency (ASMD) in adult and paediatric patients. It is the first and currently the only disease-modifying treatment for ASMD. Olipudase alfa treatment improves hepatosplenomegaly, lung function and platelet counts, along with multiple other pathological features of ASMD in adult and paediatric patients with ASMD. These benefits are sustained through at least 24 months of treatment. Olipudase alfa is generally well tolerated; infusion-associated reactions (mostly mild) were the most common treatment-related adverse events. Other warnings and precautions associated with its use include risks of hypersensitivity reactions (including anaphylaxis) and elevated transaminase levels seen in clinical trials, and foetal malformation based on animal studies. All these risks are generally manageable. A gradual dose escalation of olipudase alfa, followed by a maintenance phase, is required to reduce the risks of toxic sphingomyelin catabolites build up, infusion-associated reactions and transient transaminase elevations.
Sphingomyelin, a fatty substance found in mammalian cell membranes, is broken down by the enzyme acid sphingomyelinase in healthy individuals. Acid sphingomyelinase deficiency (ASMD) is a rare inherited genetic disorder, in which the patient's body does not produce enough of the acid sphingomyelinase enzyme, leading to accumulation of sphingomyelin in major organs such as lungs, liver and spleen. ASMD types A and A/B (but not type B) also involve brain cells. Olipudase alfa (Xenpozyme™) is an enzyme replacement therapy indicated to treat non-CNS manifestations of ASMD in adult and paediatric patients. By reducing sphingomyelin accumulation, olipudase alfa improves lung function, reduces liver and spleen volume, and increases platelet counts, while also correcting other ASMD-related dysfunctions. These benefits are sustained through at least 24 months of treatment. Olipudase alfa is generally well tolerated. It is the first and currently the only disease-modifying treatment for ASMD.
Assuntos
Doença de Niemann-Pick Tipo A , Esfingomielina Fosfodiesterase , Animais , Humanos , Esfingomielina Fosfodiesterase/efeitos adversos , Doença de Niemann-Pick Tipo A/tratamento farmacológico , Terapia de Reposição de EnzimasRESUMO
INTRODUCTION: Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disease. Patients with ASMD type B experience multiple morbidities, potentially leading to early mortality. Before the 2022 approval of olipudase alfa for non-neuronopathic ASMD manifestations, only symptom management was offered. Data on healthcare services used by patients with ASMD type B are limited. This analysis used medical claims data to evaluate real-world healthcare service use by patients with ASMD type B in the United States of America (USA). METHODS: The IQVIA Open Claims patient-level database (2010-2019) was cross-examined. Two patient cohorts were identified: the primary analysis cohort, which included patients with at least two claims associated with ASMD type B (ICD-10 code E75.241) and more total claims with ASMD type B than any other ASMD types, and the sensitivity analysis cohort, which included patients with a high probability of having ASMD type B identified using a validated machine-learning algorithm. Claims for ASMD-associated healthcare services were recorded, including outpatient visits, emergency department (ED) visits, and inpatient hospitalizations. RESULTS: The primary analysis cohort included 47 patients; a further 59 patients made up the sensitivity analysis cohort. Patient characteristics and healthcare service use were similar in both cohorts and were consistent with established characteristics of ASMD type B. Overall, 70% of the primary analysis cohort from this study were aged < 18 years, and the liver, spleen, and lungs were the most frequently affected organs. Cognitive, developmental, and/or emotional problems and respiratory/lung disorders caused most outpatient visits; respiratory/lung disorders accounted for most ED visits and hospitalizations. CONCLUSION: This retrospective analysis of medical claims data identified patients with ASMD type B who had characteristics typical of this condition. A machine-learning algorithm detected further cases with a high probability of having ASMD type B. High use of ASMD-related healthcare services and medications was observed in both cohorts.
Acid sphingomyelinase deficiency (ASMD) type B, historically known as NiemannPick type B, is a rare illness. People with acid sphingomyelinase deficiency type B experience damage to many organs of the body (such as the liver and lungs), which may lead to early death. Until recently, no treatment has been available, and people were only treated for their symptoms. Now, a treatment called olipudase alfa has been approved in Europe, Japan, and the USA. People with ASMD type B may need lots of tests, surgeries, medications, and physician visits; however, we do not know how often these healthcare services are used. This study used medical claims to find out more about the healthcare services used by people with ASMD type B. To find as many people with ASMD type B as possible, we identified two groups of people. The first group included people with diagnosis codes for ASMD type B, the other group was identified as having a high likelihood of ASMD type B. The people in each group were similar in age and the illnesses/symptoms they had. The liver, spleen, and lungs were the most frequently damaged organs, and most physician visits were for mental, developmental, and/or emotional problems, and breathing or lung diseases. Breathing or lung disease and bleeding problems caused the most emergency department visits and hospitalizations. Overall, the use of healthcare services was high in people with ASMD type B. This study shows the need for specific treatments for people with ASMD.
Assuntos
Doença de Niemann-Pick Tipo A , Humanos , Estados Unidos , Doença de Niemann-Pick Tipo A/tratamento farmacológico , Estudos Retrospectivos , Revisão da Utilização de Seguros , Cuidados Paliativos , Atenção à SaúdeRESUMO
Olipudase alfa (XENPOZYME®) is a recombinant human acid sphingomyelinase that has been developed by Sanofi, for the treatment of acid sphingomyelinase deficiency (ASMD). Olipudase alfa catalyses the hydrolysis of sphingomyelin accumulated in hepatocytes and in mononuclear-macrophage cells, such as the lungs, liver, spleen, kidneys and bone marrow. Olipudase alfa was approved in Japan under the SAKIGAKE designation on 28 March 2022 for use in adult and paediatric patients with non-CNS manifestations of ASMD and has received a positive Committee for Medicinal Products for Human Use opinion in the EU. Regulatory review in the USA is underway. This article summarizes the milestones in the development of olipudase alfa leading to this first approval for the treatment of patients with ASMD.
Assuntos
Doença de Niemann-Pick Tipo A , Esfingomielina Fosfodiesterase , Adulto , Criança , Aprovação de Drogas , Terapia de Reposição de Enzimas , Humanos , Doença de Niemann-Pick Tipo A/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Esfingomielina Fosfodiesterase/efeitos adversosRESUMO
Niemann-Pick disease (NPD) type A and type B are part of the spectrum disease of the acid sphingomyelinase deficiency (ASMD). Plasma lipid abnormalities are frequently associated with both NPD-A and NPD-B, and include decreased high-density lipoprotein cholesterol (HDL-C), increased low-density lipoprotein cholesterol (LDL-C), and hypertriglyceridemia. The atherogenic lipid profile has been associated to early atherosclerotic vascular disease and coronary artery disease in NPD-B patients. Thus, early treatment of dyslipidemia in these patients is advisable. We present here a pediatric case of NPD-B with an atherogenic lipid profile not responding to lifestyle changes, low fat diet, and daily supplementation with plant sterols. We reviewed the existing literature about the treatment strategies for dyslipidemia in ASMD patients, with a special focus on the pediatric age. Finally, we speculated on the mechanisms underlying dyslipidemia in this disorder. The clinical experiences in lipid-lowering strategies in NPD-B patients are limited, in particular in the pediatric age. Olipudase alfa appears as the most promising candidate for improving lipid profile. Since olipudase alfa is not yet approved and, due to its costs, it will probably not be available for all patients worldwide, further research is needed to broaden our knowledge on this clinical need and to evaluate the efficacy and the long-term effects of lipid-lowering agents in ASMD patients. A deep understanding of the pathophysiology of dyslipidemia in ASMD may promote the identification of new targets and support the identification of new therapeutic strategies.
Assuntos
Aterosclerose , Doença de Niemann-Pick Tipo A , Doença de Niemann-Pick Tipo B , Doenças de Niemann-Pick , Aterosclerose/tratamento farmacológico , Criança , LDL-Colesterol , Humanos , Doença de Niemann-Pick Tipo A/tratamento farmacológico , Doença de Niemann-Pick Tipo B/tratamento farmacológico , Doenças de Niemann-Pick/induzido quimicamente , Doenças de Niemann-Pick/tratamento farmacológico , Esfingomielina Fosfodiesterase/uso terapêuticoRESUMO
PURPOSE: To assess olipudase alfa enzyme replacement therapy for non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in children. METHODS: This phase 1/2, international, multicenter, open-label trial (ASCEND-Peds/NCT02292654) administered intravenous olipudase alfa every 2 weeks with intrapatient dose escalation to 3 mg/kg. Primary outcome was safety through week 64. Secondary outcomes included pharmacokinetics, spleen and liver volumes, lung diffusing capacity (DLCO), lipid profiles, and height through week 52. RESULTS: Twenty patients were enrolled: four adolescents (12-17 years), nine children (6-11 years), and seven infants/early child (1-5 years). Most adverse events were mild or moderate, including infusion-associated reactions (primarily urticaria, pyrexia, and/or vomiting) in 11 patients. Three patients had serious treatment-related events: one with transient asymptomatic alanine aminotransferase increases, another with urticaria and rash (antidrug antibody positive [ADA+]), and a third with an anaphylactic reaction (ADA+) who underwent desensitization and reached the 3 mg/kg maintenance dose. Mean splenomegaly and hepatomegaly improved by >40% (p < 0.0001). Mean % predicted DLCO improved by 32.9% (p = 0.0053) in patients able to perform the test. Lipid profiles and elevated liver transaminase levels normalized. Mean height Z-scores improved by 0.56 (p < 0.0001). CONCLUSION: In this study in children with chronic ASMD, olipudase alfa was generally well-tolerated with significant, comprehensive improvements in disease pathology across a range of clinically relevant endpoints.
Assuntos
Doença de Niemann-Pick Tipo A , Adolescente , Criança , Pré-Escolar , Terapia de Reposição de Enzimas , Humanos , Lactente , Fígado , Doença de Niemann-Pick Tipo A/tratamento farmacológico , Doença de Niemann-Pick Tipo A/genética , Proteínas Recombinantes/uso terapêutico , Esfingomielina Fosfodiesterase/genéticaRESUMO
Induction of lysosomal exocytosis alleviates lysosomal storage of undigested metabolites in cell models of lysosomal disorders (LDs). However, whether this strategy affects other vesicular compartments, e.g., those involved in endocytosis, is unknown. This is important both to predict side effects and to use this strategy in combination with therapies that require endocytosis for intracellular delivery, such as lysosomal enzyme replacement therapy (ERT). We investigated this using δ-tocopherol as a model previously shown to induce lysosomal exocytosis and cell models of type A Niemann-Pick disease, a LD characterized by acid sphingomyelinase (ASM) deficiency and sphingomyelin storage. δ-Tocopherol and derivative CF3-T reduced net accumulation of fluid phase, ligands, and polymer particles via phagocytic, caveolae-, clathrin-, and cell adhesion molecule (CAM)-mediated pathways, yet the latter route was less affected due to receptor overexpression. In agreement, δ-tocopherol lowered uptake of recombinant ASM by deficient cells (known to occur via the clathrin pathway) and via targeting intercellular adhesion molecule-1 (associated to the CAM pathway). However, the net enzyme activity delivered and lysosomal storage attenuation were greater via the latter route. Data suggest stimulation of exocytosis by tocopherols is not specific of lysosomes and affects endocytic cargo. However, this effect was transient and became unnoticeable several hours after tocopherol removal. Therefore, induction of exocytosis in combination with therapies requiring endocytic uptake, such as ERT, may represent a new type of drug interaction, yet this strategy could be valuable if properly timed for minimal interference.
Assuntos
Endocitose/efeitos dos fármacos , Terapia de Reposição de Enzimas/métodos , Doença de Niemann-Pick Tipo A/tratamento farmacológico , Esfingomielina Fosfodiesterase/uso terapêutico , Tocoferóis/farmacologia , Animais , Moléculas de Adesão Celular/metabolismo , Células Cultivadas , Terapia Combinada , Interações Medicamentosas , Exocitose/efeitos dos fármacos , Humanos , Nanopartículas , Proteínas Recombinantes/farmacocinética , Esfingomielina Fosfodiesterase/administração & dosagem , Esfingomielina Fosfodiesterase/farmacocinéticaRESUMO
Olipudase alfa, a recombinant human acid sphingomyelinase (ASM), is an enzyme replacement therapy for the treatment of nonneurologic manifestations of acid sphingomyelinase deficiency (ASMD). This ongoing, open-label, long-term study (NCT02004704) assessed safety and efficacy of olipudase alfa following 30 months of treatment in five adult patients with ASMD. There were no deaths, serious or severe events, or discontinuations during 30 months of treatment. The majority of adverse events were mild and included headache, nausea, and abdominal pain. No patient developed anti-drug antibodies and there were no clinically significant adverse changes in vital signs, hematology, or cardiac safety parameters. Statistically significant reductions in liver (31%) and spleen (39%) volumes were maintained through 30 months of treatment. There was a mean increase in lung diffusing capacity of 35%, and clinically relevant improvements in infiltrative lung disease parameters. Lipid profiles improved in all patients. Improvements in bone mineral density of the spine were observed in some patients. Chitotriosidase in serum and lyso-sphingomyelin in dried blood spots decreased with olipudase alfa treatment, suggesting utility as biomarkers for monitoring treatment efficacy. Olipudase alfa is the first etiology-specific treatment in development for ASMD. This study demonstrates that treatment with olipudase alfa for 30 months is well-tolerated and associated with life-transforming sustained improvements in relevant disease clinical measures.
Assuntos
Doença de Niemann-Pick Tipo A/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Esfingomielina Fosfodiesterase/uso terapêutico , Adulto , Biomarcadores/sangue , Densidade Óssea/efeitos dos fármacos , Terapia de Reposição de Enzimas , Feminino , Hexosaminidases/sangue , Humanos , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Fosforilcolina/análogos & derivados , Fosforilcolina/sangue , Proteínas Recombinantes/efeitos adversos , Esfingomielina Fosfodiesterase/efeitos adversos , Esfingosina/análogos & derivados , Esfingosina/sangue , Baço/efeitos dos fármacos , Baço/patologia , Resultado do TratamentoRESUMO
Acid sphingomyelinase deficiency (ASMD; Niemann-Pick disease type A and B) is a lysosomal storage disorder characterized by abnormal intracellular sphingomyelin (SM) accumulation. Prominent liver involvement results in hepatomegaly, fibrosis/cirrhosis, abnormal liver chemistries, and a proatherogenic lipid profile. Olipudase alfa (recombinant human ASM) is in clinical development as an investigational enzyme replacement therapy for the non-neurological manifestations of ASMD. In a phase 1b study conducted to evaluate the safety and tolerability of within-patient dose escalation with olipudase alfa, measurement of SM levels in liver biopsies was used as a pharmacodynamic biomarker of substrate burden. Five adult patients with non neuronopathic ASMD received escalating doses of olipudase alfa every 2 weeks for 26 weeks. Liver biopsies obtained at baseline and 26 weeks after treatment were evaluated for SM storage by histomorphometric analysis, biochemistry, and electron microscopy. Biopsies were also assessed for inflammation and fibrosis, and for the association of SM levels with liver volume, liver function tests, and lipid profiles. At baseline, SM storage present in Kupffer cells and hepatocytes ranged from 9.8% to 53.8% of the microscopic field. After 26 weeks of treatment, statistically significant reductions in SM (P<0.0001) measured by morphometry were seen in 4 patients with evaluable liver biopsies. The 26-week biopsy of the fifth patient was insufficient for morphometric quantitation. Posttreatment SM levels ranged from 1.2% to 9.5% of the microscopic field, corresponding to an 84% to 92% relative reduction from baseline. Improvements in liver volume, liver function tests, and lipid profiles were also observed. This study illustrates the utility of SM assessment by liver biopsy as a pharmacodynamic biomarker of disease burden in these patients.
Assuntos
Fígado/metabolismo , Doença de Niemann-Pick Tipo A/tratamento farmacológico , Doença de Niemann-Pick Tipo B/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Esfingomielina Fosfodiesterase/uso terapêutico , Esfingomielinas/metabolismo , Adulto , Idoso , Relação Dose-Resposta a Droga , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Imuno-Histoquímica , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Microscopia Eletrônica de Transmissão , Pessoa de Meia-IdadeRESUMO
PURPOSE: Enzyme replacement therapy with olipudase alfa (recombinant human acid sphingomyelinase) is being developed for Niemann-Pick disease type B (NPD B). METHODS: A single-center, open-label, nonrandomized, single-ascending-dose trial evaluated the safety of intravenous olipudase alfa (0.03-1.0 mg/kg) in 11 adults with NPD B. Patients were monitored in the hospital for 72 h after infusion and had follow-up visits on days 14 and 28. RESULTS: Plasma ceramide, a product of sphingomyelin catabolism by olipudase alfa, showed dose-dependent elevations by 6 h postdose, or postinfusion. No serious adverse drug reactions (ADRs) occurred during the study. Acute phase reaction-type ADRs, as evidenced by elevated inflammatory biomarkers (high-sensitivity C-reactive protein, interleukin-8, and calcitonin) and constitutional symptoms (fever, pain, nausea, and/or vomiting) emerged 12-24 h following doses ≥0.3 mg/kg olipudase alfa. Three patients experienced hyperbilirubinemia. The study was terminated after a patient dosed at 1 mg/kg exhibited severe hyperbilirubinemia; he was subsequently diagnosed with Gilbert syndrome. CONCLUSION: The maximum tolerated dose of olipudase alfa in adults with NPD B was 0.6 mg/kg. First-dose ADRs were likely induced by elevated concentrations of ceramide (or its downstream derivatives) generated by the catabolism of accumulated sphingomyelin. Within-patient dose escalation to slowly catabolize sphingomyelin stores may be a strategy to mitigate first-dose ADRs in patients with NPD B.Genet Med 18 1, 34-40.
Assuntos
Doença de Niemann-Pick Tipo A/tratamento farmacológico , Doença de Niemann-Pick Tipo B/tratamento farmacológico , Proteínas Recombinantes/efeitos adversos , Esfingomielina Fosfodiesterase/efeitos adversos , Adulto , Proteína C-Reativa/metabolismo , Relação Dose-Resposta a Droga , Terapia de Reposição de Enzimas/efeitos adversos , Terapia de Reposição de Enzimas/métodos , Feminino , Humanos , Hiperbilirrubinemia , Interleucina-8/metabolismo , Masculino , Pessoa de Meia-Idade , Doença de Niemann-Pick Tipo A/enzimologia , Doença de Niemann-Pick Tipo B/enzimologia , Proteínas Recombinantes/administração & dosagem , Esfingomielina Fosfodiesterase/administração & dosagem , Esfingomielina Fosfodiesterase/deficiênciaRESUMO
Nonsense mutations are quite prevalent in inherited diseases. Readthrough drugs could provide a therapeutic option for any disease caused by this type of mutation. Geneticin (G418) and gentamicin were among the first to be described. Novel compounds have been generated, but only a few have shown improved results. PTC124 is the only compound to have reached clinical trials. Here we first investigated the readthrough effects of gentamicin on fibroblasts from one patient with Sanfilippo B, one with Sanfilippo C, and one with Maroteaux-Lamy. We found that ARSB activity (Maroteaux-Lamy case) resulted in an increase of 2-3 folds and that the amount of this enzyme within the lysosomes was also increased, after treatment. Since the other two cases (Sanfilippo B and Sanfilippo C) did not respond to gentamicin, the treatments were extended with the use of geneticin and five non-aminoglycoside (PTC124, RTC13, RTC14, BZ6 and BZ16) readthrough compounds (RTCs). No recovery was observed at the enzyme activity level. However, mRNA recovery was observed in both cases, nearly a two-fold increase for Sanfilippo B fibroblasts with G418 and around 1.5 fold increase for Sanfilippo C cells with RTC14 and PTC124. Afterwards, some of the products were assessed through in vitro analyses for seven mutations in genes responsible for those diseases and, also, for Niemann-Pick A/B. Using the coupled transcription/translation system (TNT), the best results were obtained for SMPD1 mutations with G418, reaching a 35% recovery at 0.25 µg/ml, for the p.W168X mutation. The use of COS cells transfected with mutant cDNAs gave positive results for most of the mutations with some of the drugs, although to a different extent. The higher enzyme activity recovery, of around two-fold increase, was found for gentamicin on the ARSB p.W146X mutation. Our results are promising and consistent with those of other groups. Further studies of novel compounds are necessary to find those with more consistent efficacy and fewer toxic effects.
Assuntos
Códon de Terminação/genética , Gentamicinas/uso terapêutico , Mucopolissacaridose III/genética , Mucopolissacaridose VI/genética , Animais , Células COS , Linhagem Celular , Chlorocebus aethiops , Códon sem Sentido/efeitos dos fármacos , Códon sem Sentido/genética , Códon de Terminação/efeitos dos fármacos , Fibroblastos/citologia , Humanos , Lisossomos/metabolismo , Mucopolissacaridose III/tratamento farmacológico , Mucopolissacaridose VI/tratamento farmacológico , Doença de Niemann-Pick Tipo A/tratamento farmacológico , Doença de Niemann-Pick Tipo A/genética , Doença de Niemann-Pick Tipo B/tratamento farmacológico , Doença de Niemann-Pick Tipo B/genética , RNA Mensageiro/genéticaRESUMO
BACKGROUND: Olipudase alfa, a recombinant human acid sphingomyelinase (rhASM), is an investigational enzyme replacement therapy (ERT) for patients with ASM deficiency [ASMD; Niemann-Pick Disease (NPD) A and B]. This open-label phase 1b study assessed the safety and tolerability of olipudase alfa using within-patient dose escalation to gradually debulk accumulated sphingomyelin and mitigate the rapid production of metabolites, which can be toxic. Secondary objectives were pharmacokinetics, pharmacodynamics, and exploratory efficacy. METHODS: Five adults with nonneuronopathic ASMD (NPD B) received escalating doses (0.1 to 3.0 mg/kg) of olipudase alfa intravenously every 2 weeks for 26 weeks. RESULTS: All patients successfully reached 3.0mg/kg without serious or severe adverse events. One patient repeated a dose (2.0 mg/kg) and another had a temporary dose reduction (1.0 to 0.6 mg/kg). Most adverse events (97%) were mild and all resolved without sequelae. The most common adverse events were headache, arthralgia, nausea and abdominal pain. Two patients experienced single acute phase reactions. No patient developed hypersensitivity or anti-olipudase alfa antibodies. The mean circulating half-life of olipudase alfa ranged from 20.9 to 23.4h across doses without accumulation. Ceramide, a sphingomyelin catabolite, rose transiently in plasma after each dose, but decreased over time. Reductions in sphingomyelin storage, spleen and liver volumes, and serum chitotriosidase activity, as well as improvements in infiltrative lung disease, lipid profiles, platelet counts, and quality of life assessments, were observed. CONCLUSIONS: This study provides proof-of-concept for the safety and efficacy of within-patient dose escalation of olipudase alfa in patients with nonneuronopathic ASMD.
Assuntos
Doença de Niemann-Pick Tipo A/tratamento farmacológico , Proteínas Recombinantes/administração & dosagem , Esfingomielina Fosfodiesterase/uso terapêutico , Adolescente , Adulto , Idoso , Biomarcadores/metabolismo , Relação Dose-Resposta a Droga , Terapia de Reposição de Enzimas , Feminino , Humanos , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Esfingomielina Fosfodiesterase/administração & dosagem , Esfingomielina Fosfodiesterase/efeitos adversos , Esfingomielinas/farmacocinética , Adulto JovemRESUMO
Recombinant human acid sphingomyelinase (rhASM) is being developed as an enzyme replacement therapy for patients with acid sphingomyelinase deficiency (Niemann-Pick disease types A and B), which causes sphingomyelin to accumulate in lysosomes. In the acid sphingomyelinase knock-out (ASMKO) mouse, intravenously administered rhASM reduced tissue sphingomyelin levels in a dose-dependent manner. When rhASM was administered to normal rats, mice, and dogs, no toxicity was observed up to a dose of 30mg/kg. However, high doses of rhASM≥10mg/kg administered to ASMKO mice resulted in unexpected toxicity characterized by cardiovascular shock, hepatic inflammation, adrenal hemorrhage, elevations in ceramide and cytokines (especially IL-6, G-CSF, and keratinocyte chemoattractant [KC]), and death. The toxicity could be completely prevented by the administration of several low doses (3mg/kg) of rhASM prior to single or repeated high doses (≥20mg/kg). These results suggest that the observed toxicity involves the rapid breakdown of large amounts of sphingomyelin into ceramide and/or other toxic downstream metabolites, which are known signaling molecules with cardiovascular and pro-inflammatory effects. Our results suggest that the nonclinical safety assessment of novel therapeutics should include the use of specific animal models of disease whenever feasible.
Assuntos
Cães , Terapia de Reposição de Enzimas , Doença de Niemann-Pick Tipo A/tratamento farmacológico , Esfingomielina Fosfodiesterase/administração & dosagem , Esfingomielina Fosfodiesterase/deficiência , Administração Intravenosa , Glândulas Suprarrenais , Animais , Ceramidas/sangue , Ceramidas/metabolismo , Citocinas/sangue , Citocinas/imunologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Fígado/metabolismo , Fígado/patologia , Lisossomos/metabolismo , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Doença de Niemann-Pick Tipo A/metabolismo , Ratos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/toxicidade , Esfingomielina Fosfodiesterase/toxicidade , Esfingomielinas/metabolismoRESUMO
Niemann-Pick disease type A (NPDA) is a fatal disease due to mutations in the acid sphingomyelinase (ASM) gene, which triggers the abnormal accumulation of sphingomyelin (SM) in lysosomes and the plasma membrane of mutant cells. Although the disease affects multiple organs, the impact on the brain is the most invalidating feature. The mechanisms responsible for the cognitive deficit characteristic of this condition are only partially understood. Using mice lacking the ASM gene (ASMko), a model system in NPDA research, we report here that high sphingomyelin levels in mutant neurons lead to low synaptic levels of phosphoinositide PI(4,5)P2 and reduced activity of its hydrolyzing phosphatase PLCγ, which are key players in synaptic plasticity events. In addition, mutant neurons have reduced levels of membrane-bound MARCKS, a protein required for PI(4,5)P2 membrane clustering and hydrolysis. Intracerebroventricular infusion of a peptide that mimics the effector domain of MARCKS increases the content of PI(4,5)P2 in the synaptic membrane and ameliorates behavioral abnormalities in ASMko mice.
Assuntos
Encéfalo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/uso terapêutico , Proteínas de Membrana/uso terapêutico , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/etiologia , Doença de Niemann-Pick Tipo A/complicações , Doença de Niemann-Pick Tipo A/tratamento farmacológico , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Injeções Intraventriculares , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Força Muscular/efeitos dos fármacos , Força Muscular/genética , Mutação/genética , Substrato Quinase C Rico em Alanina Miristoilada , Doença de Niemann-Pick Tipo A/metabolismo , Doença de Niemann-Pick Tipo A/patologia , Fosfolipase C gama/metabolismo , Esfingomielina Fosfodiesterase/genética , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismoRESUMO
Understanding the role of lipids in synapses and the aberrant molecular mechanisms causing the cognitive deficits that characterize most lipidosis is necessary to develop therapies for these diseases. Here we describe sphingomyelin (SM) as a key modulator of the dendritic spine actin cytoskeleton. We show that increased SM levels in neurons of acid sphingomyelinase knock out mice (ASMko), which mimic Niemann Pick disease type A (NPA), result in reduced spine number and size and low levels of filamentous actin. Mechanistically, SM accumulation decreases the levels of metabotropic glutamate receptors type I (mGluR1/5) at the synaptic membrane impairing membrane attachment and activity of RhoA and its effectors ROCK and ProfilinIIa. Pharmacological enhancement of the neutral sphingomyelinase rescues the aberrant molecular and morphological phenotypes in vitro and in vivo and improves motor and memory deficits in ASMko mice. Altogether, these data demonstrate the influence of SM and its catabolic enzymes in dendritic spine physiology and contribute to our understanding of the cognitive deficits of NPA patients, opening new perspectives for therapeutic interventions.
Assuntos
Espinhas Dendríticas/efeitos dos fármacos , Doença de Niemann-Pick Tipo A/tratamento farmacológico , Doença de Niemann-Pick Tipo A/patologia , Citoesqueleto de Actina/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Espinhas Dendríticas/metabolismo , Dexametasona/farmacologia , Modelos Animais de Doenças , Feminino , Memória de Curto Prazo/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Doença de Niemann-Pick Tipo A/metabolismo , Esfingomielina Fosfodiesterase/deficiência , Esfingomielina Fosfodiesterase/genética , Esfingomielina Fosfodiesterase/metabolismo , Esfingomielinas/toxicidadeRESUMO
Niemann-Pick A (NPA) disease is a lysosomal storage disorder (LSD) caused by a deficiency in acid sphingomyelinase (ASM) activity. Previously, we showed that the storage pathology in the ASM knockout (ASMKO) mouse brain could be corrected by intracerebral injections of cell, gene and protein based therapies. However, except for instances where distal areas were targeted with viral vectors, correction of lysosomal storage pathology was typically limited to a region within a few millimeters from the injection site. As NPA is a global neurometabolic disease, the development of delivery strategies that maximize the distribution of the enzyme throughout the CNS is likely necessary to arrest or delay progression of the disease. To address this challenge, we evaluated the effectiveness of intracerebroventricular (ICV) delivery of recombinant human ASM into ASMKO mice. Our findings showed that ICV delivery of the enzyme led to widespread distribution of the hydrolase throughout the CNS. Moreover, a significant reduction in lysosomal accumulation of sphingomyelin was observed throughout the brain and also within the spinal cord and viscera. Importantly, we demonstrated that repeated ICV infusions of ASM were effective at improving the disease phenotype in the ASMKO mouse as indicated by a partial alleviation of the motor abnormalities. These findings support the continued exploration of ICV delivery of recombinant lysosomal enzymes as a therapeutic modality for LSDs such as NPA that manifests substrate accumulation within the CNS.
Assuntos
Doença de Niemann-Pick Tipo A/tratamento farmacológico , Esfingomielina Fosfodiesterase/administração & dosagem , Animais , Encéfalo/metabolismo , Colesterol/metabolismo , Modelos Animais de Doenças , Humanos , Injeções Intraventriculares/métodos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Camundongos , Camundongos Knockout , Doença de Niemann-Pick Tipo A/genética , Doença de Niemann-Pick Tipo A/patologia , Esfingomielina Fosfodiesterase/deficiência , Esfingomielina Fosfodiesterase/metabolismo , Esfingomielinas/metabolismo , Fatores de TempoRESUMO
Niemann-Pick A disease (NPD-A) is caused by a deficiency of acid sphingomyelinase (ASM) leading to the intracellular accumulation of sphingomyelin and cholesterol in lysosomes. We evaluated the effects of direct intraparenchymal brain injections of purified recombinant human ASM (hASM) at correcting the storage pathology in a mouse model of NPD-A (ASMKO). Different doses (0.1 ng to 10 mug of hASM) were injected into the right hemisphere of the hippocampus and thalamus of 12- to 14-week-old ASMKO mice. Immunohistochemical analysis after 1 week indicated that animals treated with greater than 1 mug hASM/site showed detectable levels of enzyme around the injected regions. However, localized clearance of sphingomyelin and cholesterol storage were observed in animals administered lower doses of enzyme, starting at 100 ng hASM/site. Areas of correction were also noted at distal sites such as in the contralateral hemispheres. Indications of storage re-accumulation were seen after 2 weeks post-injection. Injections of hASM did not cause any significant cell infiltration, astrogliosis, or microglial activation. These results indicate that intraparenchymal injection of hASM is associated with minimal toxicity and can lead to regional reductions in storage pathology in the ASMKO mouse.