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1.
Mol Ther ; 31(1): 7-23, 2023 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-36196048

RESUMO

Krabbe disease (KD) is a lysosomal storage disease (LSD) caused by mutations in the galc gene. There are over 50 monogenetic LSDs, which largely impede the normal development of children and often lead to premature death. At present, there are no cures for LSDs and the available treatments are generally insufficient, short acting, and not without co-morbidities or long-term side effects. The last 30 years have seen significant advances in our understanding of LSD pathology as well as treatment options. Two gene therapy-based clinical trials, NCT04693598 and NCT04771416, for KD were recently started based on those advances. This review will discuss how our knowledge of KD got to where it is today, focusing on preclinical investigations, and how what was discovered may prove beneficial for the treatment of other LSDs.


Assuntos
Leucodistrofia de Células Globoides , Doenças por Armazenamento dos Lisossomos , Criança , Humanos , Leucodistrofia de Células Globoides/genética , Leucodistrofia de Células Globoides/terapia , Leucodistrofia de Células Globoides/patologia , Terapia Combinada , Mutação , Doenças por Armazenamento dos Lisossomos/genética , Doenças por Armazenamento dos Lisossomos/terapia
2.
Proc Natl Acad Sci U S A ; 117(16): 9032-9041, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32253319

RESUMO

Lysosomal storage diseases (LSDs) are typically caused by a deficiency in a soluble acid hydrolase and are characterized by the accumulation of undegraded substrates in the lysosome. Determining the role of specific cell types in the pathogenesis of LSDs is a major challenge due to the secretion and subsequent uptake of lysosomal hydrolases by adjacent cells, often referred to as "cross-correction." Here we create and validate a conditional mouse model for cell-autonomous expression of galactocerebrosidase (GALC), the lysosomal enzyme deficient in Krabbe disease. We show that lysosomal membrane-tethered GALC (GALCLAMP1) retains enzyme activity, is able to cleave galactosylsphingosine, and is unable to cross-correct. Ubiquitous expression of GALCLAMP1 fully rescues the phenotype of the GALC-deficient mouse (Twitcher), and widespread deletion of GALCLAMP1 recapitulates the Twitcher phenotype. We demonstrate the utility of this model by deleting GALCLAMP1 specifically in myelinating Schwann cells in order to characterize the peripheral neuropathy seen in Krabbe disease.


Assuntos
Galactosilceramidase/metabolismo , Leucodistrofia de Células Globoides/patologia , Lisossomos/enzimologia , Proteínas Recombinantes de Fusão/metabolismo , Células de Schwann/patologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Feminino , Fibroblastos , Galactosilceramidase/genética , Técnicas de Silenciamento de Genes , Humanos , Membranas Intracelulares/metabolismo , Leucodistrofia de Células Globoides/diagnóstico , Leucodistrofia de Células Globoides/genética , Proteínas de Membrana Lisossomal/genética , Proteínas de Membrana Lisossomal/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Cultura Primária de Células , Proteínas Recombinantes de Fusão/genética
3.
Mol Ther ; 29(5): 1883-1902, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33508430

RESUMO

Neonatal AAV9-gene therapy of the lysosomal enzyme galactosylceramidase (GALC) significantly ameliorates central and peripheral neuropathology, prolongs survival, and largely normalizes motor deficits in Twitcher mice. Despite these therapeutic milestones, new observations identified the presence of multiple small focal demyelinating areas in the brain after 6-8 months. These lesions are in stark contrast to the diffuse, global demyelination that affects the brain of naive Twitcher mice. Late-onset lesions exhibited lysosomal alterations with reduced expression of GALC and increased psychosine levels. Furthermore, we found that lesions were closely associated with the extravasation of plasma fibrinogen and activation of the fibrinogen-BMP-SMAD-GFAP gliotic response. Extravasation of fibrinogen correlated with tight junction disruptions of the vasculature within the lesioned areas. The lesions were surrounded by normal appearing white matter. Our study shows that the dysregulation of therapeutic GALC was likely driven by the exhaustion of therapeutic AAV episomal DNA within the lesions, paralleling the presence of proliferating oligodendrocyte progenitors and glia. We believe that this is the first demonstration of diminishing expression in vivo from an AAV gene therapy vector with detrimental effects in the brain of a lysosomal storage disease animal model. The development of this phenotype linking localized loss of GALC activity with relapsing neuropathology in the adult brain of neonatally AAV-gene therapy-treated Twitcher mice identifies and alerts to possible late-onset reductions of AAV efficacy, with implications to other genetic leukodystrophies.


Assuntos
Galactosilceramidase/genética , Terapia Genética/métodos , Leucodistrofia de Células Globoides/patologia , Substância Branca/patologia , Animais , Animais Recém-Nascidos , Células Cultivadas , Dependovirus/genética , Modelos Animais de Doenças , Feminino , Fibrinogênio/metabolismo , Galactosilceramidase/metabolismo , Vetores Genéticos/administração & dosagem , Leucodistrofia de Células Globoides/sangue , Leucodistrofia de Células Globoides/genética , Leucodistrofia de Células Globoides/terapia , Masculino , Camundongos , Recidiva
4.
Mol Ther ; 29(2): 691-701, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33388420

RESUMO

Infantile globoid cell leukodystrophy (GLD, Krabbe disease) is a demyelinating disease caused by the deficiency of the lysosomal enzyme galactosylceramidase (GALC) and the progressive accumulation of the toxic metabolite psychosine. We showed previously that central nervous system (CNS)-directed, adeno-associated virus (AAV)2/5-mediated gene therapy synergized with bone marrow transplantation and substrate reduction therapy (SRT) to greatly increase therapeutic efficacy in the murine model of Krabbe disease (Twitcher). However, motor deficits remained largely refractory to treatment. In the current study, we replaced AAV2/5 with an AAV2/9 vector. This single change significantly improved several endpoints primarily associated with motor function. However, nearly all (14/16) of the combination-treated Twitcher mice and all (19/19) of the combination-treated wild-type mice developed hepatocellular carcinoma (HCC). 10 out of 10 tumors analyzed had AAV integrations within the Rian locus. Several animals had additional integrations within or near genes that regulate cell growth or death, are known or potential tumor suppressors, or are associated with poor prognosis in human HCC. Finally, the substrate reduction drug L-cycloserine significantly decreased the level of the pro-apoptotic ceramide 18:0. These data demonstrate the value of AAV-based combination therapy for Krabbe disease. However, they also suggest that other therapies or co-morbidities must be taken into account before AAV-mediated gene therapy is considered for human therapeutic trials.


Assuntos
Dependovirus/genética , Terapia Genética/efeitos adversos , Vetores Genéticos/genética , Leucodistrofia de Células Globoides/complicações , Leucodistrofia de Células Globoides/terapia , Animais , Transplante de Medula Óssea/métodos , Carcinoma Hepatocelular/etiologia , Terapia Combinada , Modelos Animais de Doenças , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Neoplasias Hepáticas/etiologia , Camundongos
5.
Proc Natl Acad Sci U S A ; 116(40): 20097-20103, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31527255

RESUMO

Infantile globoid cell leukodystrophy (GLD, Krabbe disease) is a fatal demyelinating disorder caused by a deficiency in the lysosomal enzyme galactosylceramidase (GALC). GALC deficiency leads to the accumulation of the cytotoxic glycolipid, galactosylsphingosine (psychosine). Complementary evidence suggested that psychosine is synthesized via an anabolic pathway. Here, we show instead that psychosine is generated catabolically through the deacylation of galactosylceramide by acid ceramidase (ACDase). This reaction uncouples GALC deficiency from psychosine accumulation, allowing us to test the long-standing "psychosine hypothesis." We demonstrate that genetic loss of ACDase activity (Farber disease) in the GALC-deficient mouse model of human GLD (twitcher) eliminates psychosine accumulation and cures GLD. These data suggest that ACDase could be a target for substrate reduction therapy (SRT) in Krabbe patients. We show that pharmacological inhibition of ACDase activity with carmofur significantly decreases psychosine accumulation in cells from a Krabbe patient and prolongs the life span of the twitcher (Twi) mouse. Previous SRT experiments in the Twi mouse utilized l-cycloserine, which inhibits an enzyme several steps upstream of psychosine synthesis, thus altering the balance of other important lipids. Drugs that directly inhibit ACDase may have a more acceptable safety profile due to their mechanistic proximity to psychosine biogenesis. In total, these data clarify our understanding of psychosine synthesis, confirm the long-held psychosine hypothesis, and provide the impetus to discover safe and effective inhibitors of ACDase to treat Krabbe disease.


Assuntos
Ceramidase Ácida/genética , Deleção de Genes , Leucodistrofia de Células Globoides/genética , Leucodistrofia de Células Globoides/metabolismo , Psicosina/metabolismo , Animais , Linhagem Celular Tumoral , Citocinas/metabolismo , Metilação de DNA , Modelos Animais de Doenças , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Leucodistrofia de Células Globoides/tratamento farmacológico
6.
Mol Genet Metab ; 133(2): 185-192, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33839004

RESUMO

Mucopolysaccharidosis IIIB (MPS IIIB, Sanfilippo syndrome type B) is caused by a deficiency in α-N-acetylglucosaminidase (NAGLU) activity, which leads to the accumulation of heparan sulfate (HS). MPS IIIB causes progressive neurological decline, with affected patients having an expected lifespan of approximately 20 years. No effective treatment is available. Recent pre-clinical studies have shown that intracerebroventricular (ICV) ERT with a fusion protein of rhNAGLU-IGF2 is a feasible treatment for MPS IIIB in both canine and mouse models. In this study, we evaluated the biochemical efficacy of a single dose of rhNAGLU-IGF2 via ICV-ERT in brain and liver tissue from Naglu-/- neonatal mice. Twelve weeks after treatment, NAGLU activity levels in brain were 0.75-fold those of controls. HS and ß-hexosaminidase activity, which are elevated in MPS IIIB, decreased to normal levels. This effect persisted for at least 4 weeks after treatment. Elevated NAGLU and reduced ß-hexosaminidase activity levels were detected in liver; these effects persisted for up to 4 weeks after treatment. The overall therapeutic effects of single dose ICV-ERT with rhNAGLU-IGF2 in Naglu-/- neonatal mice were long-lasting. These results suggest a potential benefit of early treatment, followed by less-frequent ICV-ERT dosing, in patients diagnosed with MPS IIIB.


Assuntos
Acetilglucosaminidase/genética , Terapia de Reposição de Enzimas , Fator de Crescimento Insulin-Like II/genética , Mucopolissacaridose III/terapia , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Cães , Heparitina Sulfato/metabolismo , Humanos , Infusões Intraventriculares , Camundongos , Camundongos Knockout , Mucopolissacaridose III/enzimologia , Mucopolissacaridose III/genética , Mucopolissacaridose III/patologia , Doenças do Sistema Nervoso , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/farmacologia
7.
Proc Natl Acad Sci U S A ; 114(29): E5920-E5929, 2017 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-28673981

RESUMO

Infantile neuronal ceroid lipofuscinosis (INCL, or CLN1 disease) is an inherited neurodegenerative storage disorder caused by a deficiency of the lysosomal enzyme palmitoyl protein thioesterase 1 (PPT1). It was widely believed that the pathology associated with INCL was limited to the brain, but we have now found unexpectedly profound pathology in the human INCL spinal cord. Similar pathological changes also occur at every level of the spinal cord of PPT1-deficient (Ppt1-/- ) mice before the onset of neuropathology in the brain. Various forebrain-directed gene therapy approaches have only had limited success in Ppt1-/- mice. Targeting the spinal cord via intrathecal administration of an adeno-associated virus (AAV) gene transfer vector significantly prevented pathology and produced significant improvements in life span and motor function in Ppt1-/- mice. Surprisingly, forebrain-directed gene therapy resulted in essentially no PPT1 activity in the spinal cord, and vice versa. This leads to a reciprocal pattern of histological correction in the respective tissues when comparing intracranial with intrathecal injections. However, the characteristic pathological features of INCL were almost completely absent in both the brain and spinal cord when intracranial and intrathecal injections of the same AAV vector were combined. Targeting both the brain and spinal cord also produced dramatic and synergistic improvements in motor function with an unprecedented increase in life span. These data show that spinal cord pathology significantly contributes to the clinical progression of INCL and can be effectively targeted therapeutically. This has important implications for the delivery of therapies in INCL, and potentially in other similar disorders.


Assuntos
Encéfalo/patologia , Terapia Genética/métodos , Proteínas de Membrana/farmacologia , Lipofuscinoses Ceroides Neuronais/terapia , Medula Espinal/patologia , Tioléster Hidrolases/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Criança , Modelos Animais de Doenças , Vetores Genéticos/administração & dosagem , Vetores Genéticos/farmacologia , Humanos , Injeções Intraventriculares/métodos , Injeções Espinhais , Proteínas de Membrana/administração & dosagem , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Neuroglia/patologia , Lipofuscinoses Ceroides Neuronais/patologia , Neurônios/patologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacologia , Medula Espinal/efeitos dos fármacos , Tioléster Hidrolases/administração & dosagem , Tioléster Hidrolases/genética , Tioléster Hidrolases/metabolismo
8.
Liver Transpl ; 25(7): 1034-1042, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30980599

RESUMO

The hepatic venous pressure gradient (HVPG) measurement is known to correlate with the severity of portal hypertension in patients with liver cirrhosis. This retrospective study investigated the clinical value of preoperative measurement of HVPG in patients who underwent adult-to-adult living donor liver transplantation (LDLT) and its predictive value for hepatic hemodynamics after graft reperfusion. For this study, 75 patients who underwent adult-to-adult LDLT were divided into 2 groups (HVPG <16 mm Hg or HVPG ≥16 mm Hg) to investigate the correlation between preoperative HVPG and characteristics and surgical outcomes of the patients, including portal vein flow (PVF) and hepatic artery flow (HAF) after graft reperfusion. In total, 35 (46.7%) patients had an HVPG ≥16 mm Hg. These patients had significantly higher international normalized ratio values, serum creatinine levels, and Model for End-Stage Liver Disease scores compared with the 40 patients with HVPG <16 mm Hg. They also had higher rates of variceal bleeding, encephalopathy, and intractable ascites as well as lower serum albumin levels and platelet counts compared with those patients with HVPG <16 mm Hg. Portal inflow modulation (PIM) was frequently performed in the patients with HVPG ≥16 mm Hg compared with those with HVPG <16 mm Hg. No significant differences in surgical outcomes after LDLT were found between these 2 groups except for postoperative ascites. Preoperative HVPG showed a positive correlation with PVF and a negative correlation with HAF after graft reperfusion (false discovery rate [FDR] P = 0.08 and FDR P = 0.08, respectively). In linear regression analyses, preoperative HVPG was independently associated with PVF after graft reperfusion. In conclusion, our findings indicate that preoperative HVPG is associated with hepatic hemodynamics after graft implantation in LDLT. HVPG as a routine preoperative evaluation may be helpful for surgical planning of PIM.


Assuntos
Rejeição de Enxerto/epidemiologia , Hipertensão Portal/diagnóstico , Cirrose Hepática/cirurgia , Transplante de Fígado/efeitos adversos , Pressão na Veia Porta/fisiologia , Disfunção Primária do Enxerto/epidemiologia , Adulto , Idoso , Aloenxertos/irrigação sanguínea , Feminino , Seguimentos , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/fisiopatologia , Sobrevivência de Enxerto/fisiologia , Artéria Hepática/fisiopatologia , Humanos , Hipertensão Portal/etiologia , Hipertensão Portal/fisiopatologia , Fígado/irrigação sanguínea , Cirrose Hepática/complicações , Cirrose Hepática/fisiopatologia , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Veia Porta/fisiopatologia , Valor Preditivo dos Testes , Disfunção Primária do Enxerto/etiologia , Disfunção Primária do Enxerto/fisiopatologia , Fluxo Sanguíneo Regional , Estudos Retrospectivos , Medição de Risco/métodos , Índice de Gravidade de Doença , Adulto Jovem
9.
Immunology ; 153(3): 387-396, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28992358

RESUMO

Asthma is a chronic inflammatory respiratory disease characterized by airway inflammation, airway hyperresponsiveness and reversible airway obstruction. Understanding the mechanisms that underlie the various endotypes of asthma could lead to novel and more personalized therapies for individuals with asthma. Using a tissue inhibitor of metalloproteinases 1 (TIMP-1) knockout murine allergic asthma model, we previously showed that TIMP-1 deficiency results in an asthma phenotype, exhibiting airway hyperreactivity, enhanced eosinophilic inflammation and T helper type 2 cytokine gene and protein expression following sensitization with ovalbumin. In the current study, we compared the expression of Galectins and other key cytokines in a murine allergic asthma model using wild-type and TIMP-1 knockout mice. We also examined the effects of Galectin-3 (Gal-3) inhibition on a non-T helper type 2 cytokine interleukin-17 (IL-17) to evaluate the relationship between Gal-3 and the IL-17 axis in allergic asthma. Our results showed a significant increase in Gal-3, IL-17 and transforming growth factor-ß1 gene expression in lung tissue isolated from an allergic asthma murine model using TIMP-1 knockout. Gal-3 gene and protein expression levels were also significantly higher in lung tissue from an allergic asthma murine model using TIMP-1 knockout. Our data show that Gal-3 may regulate the IL-17 axis and play a pivotal role in the modulation of inflammation during experimental allergic asthma.


Assuntos
Asma/metabolismo , Hiper-Reatividade Brônquica/metabolismo , Galectina 3/metabolismo , Pneumonia/metabolismo , Hipersensibilidade Respiratória/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Células A549 , Animais , Linhagem Celular Tumoral , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Pulmão , Camundongos , Camundongos Knockout , Células Th2/metabolismo
10.
Biomed Chromatogr ; 32(7): e4235, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29516569

RESUMO

Deficiencies of galactosylceramidase and glucocerebrosidase result in the accumulation of galactosylsphingosine (GalSph) and glucosylsphingosine (GluSph) in Krabbe and Gaucher diseases, respectively. GalSph and GluSph are useful biomarkers for both diagnosis and monitoring of treatment effects. We have developed and validated a sensitive, accurate, high-throughput assay for simultaneous determination of the concentration of GalSph and GluSph in mouse serum. GalSph and GluSph and their deuterated internal standards were extracted by protein precipitation in quantitative recoveries, baseline separated by hydrophilic interaction chromatography and detected by positive-ion electrospray mass spectrometry in multiple reaction monitoring mode. Total run time was 7 min. The lower limit of quantification was 0.2 ng/mL for both GalSph and GluSph. Sample stability, assay precision and accuracy, and method robustness were demonstrated. This method has been successfully applied to measurement of these lipid biomarkers in a natural history study in twitcher (Krabbe) mice.


Assuntos
Biomarcadores/sangue , Cromatografia Líquida/métodos , Doença de Gaucher/sangue , Psicosina/análogos & derivados , Psicosina/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Modelos Animais de Doenças , Doença de Gaucher/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Modelos Lineares , Camundongos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
11.
J Vasc Interv Radiol ; 28(10): 1371-1377, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28689934

RESUMO

PURPOSE: To compare overall survival and toxicities after yttrium-90 (90Y) radioembolization and chemoembolization with drug-eluting embolics (DEE) in patients with infiltrative hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Retrospective review of 50 patients with infiltrative HCC without main portal vein invasion who were treated with 90Y radioembolization (n = 26) or DEE chemoembolization (n = 24) between March 2007 and August 2012 was completed. Infiltrative tumors were defined by cross-sectional imaging as masses that lacked well-demarcated boundaries, and treatment allocations were made by a multidisciplinary tumor board. Median age was 63 years; median tumor diameter was 9.0 cm; and there were no significant differences between groups in performance status, severity of liver disease, or HCC stage. Toxicities were graded by Common Terminology Criteria for Adverse Events v4.03. Overall survival from treatment was assessed by Kaplan-Meier analysis, with analysis of potential predictors of survival with log-rank test. RESULTS: There was no difference in the average number of procedures performed in each treatment group (DEE, 1.5 ± 1.1; 90Y, 1.6 ± 0.5; P = .97), and technical success was achieved in all cases. Abdominal pain (73% vs 33%; P = .004) and fever (38% vs 8%; P = .01) were more frequent after DEE chemoembolization. There was no significant difference in median overall survival between treatment groups after treatment (DEE, 9.9 months; 90Y, 8.1 months; P = .11). CONCLUSIONS: 90Y radioembolization and DEE chemoembolization provided similar overall survival in the treatment of infiltrative HCC without main portal vein invasion. Abdominal pain and fever were more frequent after DEE chemoembolization.


Assuntos
Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Biópsia , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/radioterapia , Quimioembolização Terapêutica , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/radioterapia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento , Radioisótopos de Ítrio
12.
Dig Dis Sci ; 62(2): 534-542, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27154510

RESUMO

BACKGROUND: It is not known whether transjugular intrahepatic porto-systemic shunt (TIPS) is safe in patients with advanced liver cirrhosis. The aim of our study was to evaluate the impact of TIPS on transplant-free survival in patients with liver cirrhosis and MELD score ≥15. METHODS: All adult patients who underwent TIPS at our institution between 2004 and 2011 were identified (N = 470). A total of 144 patients had MELD ≥15 at the time of TIPS. These patients were matched 1:1 to patients with liver cirrhosis who did not undergo TIPS based on age and MELD score using the greedy algorithm. Patients were followed up until time of death or liver transplantation. Kaplan-Meier curves and log-rank tests were used to test for differences in survival outcome between the two groups. RESULTS: A total of 288 patients with liver cirrhosis were included, of whom 144 underwent TIPS and 144 did not. The two groups were matched based on age and MELD score and were comparable with regard to gender and ethnicity. Mean MELD and Child-Pugh scores in the study population were 20.9 ± 6.5 and 10.5 ± 1.8, respectively. The most common indication for TIPS was varices (49 %), followed by refractory ascites (42 %). In the first 2 months post-TIPS, there was increased mortality or liver transplantation in patients who had TIPS compared to those who did not, but this did not reach statistical significance (p = 0.07). However, after 2 months, TIPS is associated with 56 % lower risk of dying or needing liver transplantation (p < 0.01) than cirrhotic patients who did not undergo TIPS. CONCLUSION: In patients with liver cirrhosis and MELD ≥15, TIPS might improve transplant-free survival for patients who live for at least 2 months after the procedure.


Assuntos
Ascite/cirurgia , Varizes Esofágicas e Gástricas/cirurgia , Hemorragia Gastrointestinal/cirurgia , Hipertensão Portal/cirurgia , Cirrose Hepática/fisiopatologia , Derivação Portossistêmica Transjugular Intra-Hepática , Adulto , Idoso , Ascite/etiologia , Doença Hepática Terminal , Varizes Esofágicas e Gástricas/etiologia , Feminino , Hemorragia Gastrointestinal/etiologia , Humanos , Hipertensão Portal/complicações , Estimativa de Kaplan-Meier , Cirrose Hepática/complicações , Cirrose Hepática/mortalidade , Cirrose Hepática/cirurgia , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Taxa de Sobrevida , Resultado do Tratamento
13.
J Med Genet ; 53(6): 403-18, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26908836

RESUMO

BACKGROUND: Mucopolysaccharidosis VII (MPS VII) is an ultra-rare disease characterised by the deficiency of ß-glucuronidase (GUS). Patients' phenotypes vary from severe forms with hydrops fetalis, skeletal dysplasia and mental retardation to milder forms with fewer manifestations and mild skeletal abnormalities. Accurate assessments on the frequency and clinical characteristics of the disease have been scarce. The aim of this study was to collect such data. METHODS: We have conducted a survey of physicians to document the medical history of patients with MPS VII. The survey included anonymous information on patient demographics, family history, mode of diagnosis, age of onset, signs and symptoms, severity, management, clinical features and natural progression of the disease. RESULTS: We collected information on 56 patients from 11 countries. Patients with MPS VII were classified based on their phenotype into three different groups: (1) neonatal non-immune hydrops fetalis (NIHF) (n=10), (2) Infantile or adolescent form with history of hydrops fetalis (n=13) and (3) Infantile or adolescent form without known hydrops fetalis (n=33). Thirteen patients with MPS VII who had the infantile form with history of hydrops fetalis and survived childhood, had a wide range of clinical manifestations from mild to severe. Five patients underwent bone marrow transplantation and one patient underwent enzyme replacement therapy with recombinant human GUS. CONCLUSIONS: MPS VII is a pan-ethnic inherited lysosomal storage disease with considerable phenotypical heterogeneity. Most patients have short stature, skeletal dysplasia, hepatosplenomegaly, hernias, cardiac involvement, pulmonary insufficiency and cognitive impairment. In these respects it resembles MPS I and MPS II. In MPS VII, however, one unique and distinguishing clinical feature is the unexpectedly high proportion of patients (41%) that had a history of NIHF. Presence of NIHF does not, by itself, predict the eventual severity of the clinical course, if the patient survives infancy.


Assuntos
Mucopolissacaridose VII/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Glucuronidase/metabolismo , Humanos , Lactente , Doenças por Armazenamento dos Lisossomos/metabolismo , Doenças por Armazenamento dos Lisossomos/patologia , Masculino , Mucopolissacaridose VII/metabolismo , Fenótipo , Inquéritos e Questionários , Adulto Jovem
14.
J Neurosci ; 35(16): 6495-505, 2015 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-25904800

RESUMO

Globoid cell leukodystrophy (GLD, Krabbe disease) is a lysosomal storage disease (LSD) caused by a deficiency in galactocerebrosidase (GALC) activity. In the absence of GALC activity, the cytotoxic lipid, galactosylsphingosine (psychosine), accumulates in the CNS and peripheral nervous system. Oligodendrocytes and Schwann cells are particularly sensitive to psychosine, thus leading to a demyelinating phenotype. Although hematopoietic stem-cell transplantation provides modest benefit in both presymptomatic children and the murine model (Twitcher), there is no cure for GLD. In addition, GLD has been relatively refractory to virtually every experimental therapy attempted. Here, Twitcher mice were simultaneously treated with CNS-directed gene therapy, substrate reduction therapy, and bone marrow transplantation to target the primary pathogenic mechanism (GALC deficiency) and two secondary consequences of GALC deficiency (psychosine accumulation and neuroinflammation). Simultaneously treating multiple pathogenic targets resulted in an unprecedented increase in life span with improved motor function, persistent GALC expression, nearly normal psychosine levels, and decreased neuroinflammation. Treating the primary pathogenic mechanism and secondary targets will likely improve therapeutic efficacy for other LSDs with complex pathological and clinical presentations.


Assuntos
Transplante de Medula Óssea , Ciclosserina/uso terapêutico , Galactosilceramidase/genética , Terapia Genética , Leucodistrofia de Células Globoides/terapia , Animais , Peso Corporal/efeitos dos fármacos , Peso Corporal/genética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Terapia Combinada , Citocinas/metabolismo , Feminino , Galactosilceramidase/metabolismo , Leucodistrofia de Células Globoides/tratamento farmacológico , Leucodistrofia de Células Globoides/genética , Leucodistrofia de Células Globoides/patologia , Masculino , Camundongos , Camundongos Endogâmicos , Destreza Motora/efeitos dos fármacos , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/fisiologia , Psicosina/metabolismo , Nervo Isquiático/metabolismo
15.
J Neurosci Res ; 94(11): 1126-37, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27638598

RESUMO

Globoid cell leukodystrophy (GLD) is an autosomal recessive neurodegenerative disorder caused by a deficiency of the lysosomal enzyme galactocerebrosidase (GALC). GALC is responsible for catabolism of certain glycolipids, including the toxic compound galactosylsphingosine (psychosine). Histological signs of disease include the widespread loss of myelin in the central and peripheral nervous systems, profound neruroinflammation, and axonal degeneration. Patients suffering from GLD also display neurological deterioration. Many different individual therapies have been investigated in the murine model of the GLD, the Twitcher mouse, with minimal success. The current standard of care for GLD patients, hematopoietic stem cell transplantation, serves only to delay disease progression and is not an effective cure. However, combination therapies that target different pathogenic mechanisms/pathways have been more effective at reducing histological signs of disease, delaying disease onset, prolonging life span, and improving behavioral/cognitive functions in rodent models of Krabbe's disease. In some cases, dramatic synergy between the various therapies has been observed. © 2016 Wiley Periodicals, Inc.


Assuntos
Terapia Combinada/métodos , Leucodistrofia de Células Globoides/terapia , Animais , Anti-Inflamatórios/uso terapêutico , Transplante de Medula Óssea , Ciclosserina/uso terapêutico , Modelos Animais de Doenças , Terapia de Reposição de Enzimas , Galactosilceramidase/deficiência , Terapia Genética , Humanos , Leucodistrofia de Células Globoides/genética , Leucodistrofia de Células Globoides/metabolismo
16.
J Neurosci Res ; 94(11): 1152-68, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27638600

RESUMO

Currently, presymtomatic hematopoietic stem and progenitor cell transplantation (HSPCT) is the only therapeutic modality that alleviates Krabbe's disease (KD)-induced central nervous system damage. However, all HSPCT-treated patients exhibit severe deterioration in peripheral nervous system function characterized by major motor and expressive language pathologies. We hypothesize that a combination of several mechanisms contribute to this phenomenon, including 1) nonoptimal conditioning protocols with consequent inefficient engraftment and biodistribution of donor-derived cells and 2) insufficient uptake of donor cell-secreted galactocerebrosidease (GALC) secondary to a naturally low expression level of the cation-independent mannose 6-phosphate-receptor (CI-MPR). We have characterized the effects of a busulfan (Bu) based conditioning regimen on the efficacy of HSPCT in prolonging twi mouse average life span. There was no correlation between the efficiency of bone marrow engraftment of donor cells and twi mouse average life span. HSPCT prolonged the average life span of twi mice, which directly correlated with the aggressiveness of the Bu-mediated conditioning protocols. HSPC transduced with lentiviral vectors carrying the GALC cDNA under control of cell-specific promoters were efficiently engrafted in twi mouse bone marrow. To facilitate HSPCT-mediated correction of GALC deficiency in target cells expressing low levels of CI-MPR, a novel GALC fusion protein including the ApoE1 receptor was developed. Efficient cellular uptake of the novel fusion protein was mediated by a mannose-6-phosphate-independent mechanism. The novel findings described here elucidate some of the cellular mechanisms that impede the cure of KD patients by HSPCT and concomitantly open new directions to enhance the therapeutic efficacy of HSPCT protocols for KD. © 2016 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc.


Assuntos
Terapia Genética , Transplante de Células-Tronco Hematopoéticas , Leucodistrofia de Células Globoides/terapia , Animais , Antígenos CD/metabolismo , Antimetabólitos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Bussulfano/farmacologia , Linhagem Celular Transformada , Ciclosserina/uso terapêutico , Modelos Animais de Doenças , Feminino , Fibroblastos/metabolismo , Fibroblastos/fisiologia , Galactosilceramidase/genética , Galactosilceramidase/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Terapia Genética/tendências , Vetores Genéticos/fisiologia , Transplante de Células-Tronco Hematopoéticas/tendências , Humanos , Imunossupressores/uso terapêutico , Leucodistrofia de Células Globoides/tratamento farmacológico , Leucodistrofia de Células Globoides/metabolismo , Leucodistrofia de Células Globoides/patologia , Receptor IGF Tipo 2/metabolismo , Receptores de Somatomedina/metabolismo
17.
Mol Genet Metab ; 117(2): 210-6, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26597320

RESUMO

Infantile neuronal ceroid lipofuscinosis (INCL, Infantile Batten disease) is an invariably fatal neurodegenerative pediatric disorder caused by an inherited mutation in the PPT1 gene. Patients with INCL lack the lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1, EC 3.1.2.22), resulting in intracellular accumulation of autofluorescent storage material and subsequent neuropathology. The Ppt1(-/-) mouse is deficient in PPT1 activity and represents a useful animal model of INCL that recapitulates most of the clinical and pathological aspects of the disease. Preclinical therapeutic experiments performed in the INCL mouse include CNS-directed gene therapy and recombinant enzyme replacement therapy; both seek to re-establish therapeutic levels of the deficient enzyme. We present a novel method for the histochemical localization of PPT1 activity in the Ppt1(-/-) mouse. By utilizing the substrate CUS-9235, tissues known to be positive for PPT1 activity turn varying intensities of blue. Presented here are histochemistry data showing the staining pattern in Ppt1(-/-), wild type, and Ppt1(-/-) mice treated with enzyme replacement therapy or AAV2/9-PPT1-mediated gene therapy. Results are paired with quantitative biochemistry data that confirm the ability of CUS-9235 to detect and localize PPT1 activity. This new method complements the current tools for the study of INCL and evaluation of effective therapies.


Assuntos
Tioléster Hidrolases/metabolismo , Animais , Feminino , Terapia Genética , Humanos , Rim/enzimologia , Fígado/enzimologia , Masculino , Camundongos Knockout , Miocárdio/enzimologia , Lipofuscinoses Ceroides Neuronais/terapia , Especificidade de Órgãos , Tioléster Hidrolases/genética
18.
Ann Allergy Asthma Immunol ; 116(2): 106-11, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26522253

RESUMO

OBJECTIVE: To provide an evidence-based review of common safety concerns and emerging potential benefits deriving from the regular use of electronic cigarettes (ECs) and thus improve counseling between physicians and their patients with asthma and allergy using or intending to use ECs. DATA SOURCES: Peer-reviewed articles from the National Center for Biotechnology Information's PubMed about ECs, risk reduction, and harm reversal were appraised. STUDY SELECTION: Keywords used in the search were smoking cessation, electronic cigarette, counseling, asthma, allergy, nicotine, tobacco harm reduction, and harm reversal. RESULTS: Vapor toxicology is far less problematic compared with combustible cigarettes, with exclusive EC users having substantial lower risk of exposure to tobacco smoke toxicants and carcinogens compared with cigarette smokers. Moreover, there is emerging evidence that switching to regular EC use could produce significant respiratory health gains. CONCLUSION: Inaccurate and inconsistent information about EC safety and efficacy, tobacco harm reduction, and nicotine toxicity is being offered to smokers and EC users. In particular, most health care professionals cannot communicate a clear and consistent message to their patients with respiratory problems and allergy who use or intend to use ECs. Therefore, it is important for the medical community to take an active role in considering all the pathways available to a smoking patient and recommend those that provide the greatest probability of eliminating exposure to tobacco smoke, including ECs.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Hipersensibilidade , Relações Médico-Paciente , Aconselhamento , Sistemas Eletrônicos de Liberação de Nicotina/efeitos adversos , Medicina Baseada em Evidências , Humanos , Fumar/efeitos adversos , Abandono do Hábito de Fumar
19.
J Ultrasound Med ; 35(7): 1393-400, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27208197

RESUMO

OBJECTIVES: To retrospectively investigate the role of Doppler sonography in the early detection of splenic steal syndrome. METHODS: Fifty cases of splenic steal syndrome after orthotopic liver transplantation were identified. A control group was matched to the splenic steal syndrome group. Information was collected about the clinical presentation, liver enzyme levels, Doppler sonographic results, and follow-up after patients underwent splenic artery embolization. RESULTS: A persistent hepatic arterial diastolic reversal waveform was observed in 25 patients with splenic steal syndrome versus 0 control patients. The mean hepatic arterial resistive index (RI) values ± SD were 0.95 ± 0.09 in patients with splenic steal syndrome and 0.80 ± 0.10 in control patients (P < .0001). One week after orthotopic liver transplantation, the area under the receiver operating characteristic curve for the RI was 0.884 (95% confidence interval, 0.793-0.975; P = .001) for splenic steal syndrome diagnosis. After splenic artery embolization, there was normalization of the reversal waveform, with an average RI of 0.77 ± 0.11 (P < .0001). CONCLUSIONS: Dynamic changes in the hepatic arterial waveform and RI are keys to detecting splenic steal syndrome with Doppler sonography.


Assuntos
Artéria Hepática/diagnóstico por imagem , Artéria Hepática/fisiopatologia , Transplante de Fígado , Complicações Pós-Operatórias/diagnóstico por imagem , Ultrassonografia Doppler/métodos , Doenças Vasculares/diagnóstico por imagem , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Diagnóstico Precoce , Feminino , Humanos , Circulação Hepática , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/fisiopatologia , Estudos Retrospectivos , Síndrome , Doenças Vasculares/fisiopatologia , Adulto Jovem
20.
Pediatr Endocrinol Rev ; 13 Suppl 1: 689-96, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27491217

RESUMO

Krabbe disease (globoid cell leukodystrophy, GLD) is an inherited disease caused by a deficiency in the lysosomal enzyme galactocerebrosidase (GALC). The major galactosylated lipid degraded by GALC is galactosylceramide. However, GALC is also responsible for the degradation of galactosylsphingosine (psychosine), a highly cytotoxic glycolipid. It has been hypothesized that GALC-deficiency leads to psychosine accumulation that preferentially kills oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system. Krabbe disease has traditionally been considered a white matter disease characterized by the loss and disorganization of myelin, infiltration of multinucleated monocytes/macrophages (globoid cells) and lymphocytes, and dysregulation of pro-inflammatory cytokines and chemokines. However, new studies have revealed unexpected neuronal deficiencies. Infantile Krabbe disease is believed to be the most common and aggressive form. However, juvenile and adult onset forms have been described. Children affected with infantile Krabbe disease present with motor dysfunction, cognitive decline, intractable seizures, and premature death between two to five years of age. Murine, canine, and primate models of GALC deficiency have been described and have played an important role in our understanding of this invariably fatal disease. Although there is no cure for Krabbe disease, hematopoietic stem cell transplantation can slow the progression of disease. Recent pre-clinical data indicate that simulataneously targeting multiple pathogenic mechanisms greatly increases efficacy in the murine model of Krabbe disease. A better understanding of the underlying pathogenesis will identify new therapeutic targets that may further increase efficacy.


Assuntos
Transplante de Medula Óssea , Terapia de Reposição de Enzimas , Galactosilceramidase/uso terapêutico , Terapia Genética , Transplante de Células-Tronco Hematopoéticas , Leucodistrofia de Células Globoides/terapia , Acetilcisteína/uso terapêutico , Animais , Antimetabólitos/uso terapêutico , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiopatologia , Ciclosserina/uso terapêutico , Modelos Animais de Doenças , Sequestradores de Radicais Livres/uso terapêutico , Galactosilceramidase/genética , Humanos , Leucodistrofia de Células Globoides/genética , Leucodistrofia de Células Globoides/fisiopatologia , Fenótipo , Inibidores de Fosfodiesterase/uso terapêutico , Piridinas/uso terapêutico
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