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1.
Cells ; 8(4)2019 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-31010158

RESUMO

Parkinson's disease (PD) is the second most common degenerative disorder. Although the disease was described more than 200 years ago, its pathogenetic mechanisms have not yet been fully described. In recent years, the discovery of the association between mutations of the GBA gene (encoding for the lysosomal enzyme glucocerebrosidase) and PD facilitated a better understating of this disorder. GBA mutations are the most common genetic risk factor of the disease. However, mutations of this gene can be found in different phenotypes, such as Gaucher's disease (GD), PD, dementia with Lewy bodies (DLB) and rapid eye movements (REM) sleep behavior disorders (RBDs). Understanding the pathogenic role of this mutation and its different manifestations is crucial for geneticists and scientists to guide their research and to select proper cohorts of patients. Moreover, knowing the implications of the GBA mutation in the context of PD and the other associated phenotypes is also important for clinicians to properly counsel their patients and to implement their care. With the present review we aim to describe the genetic, clinical, and therapeutic features related to the mutation of the GBA gene.


Assuntos
Doença de Gaucher/genética , Glucosilceramidase/genética , Doença de Parkinson/genética , Doença de Gaucher/terapia , Humanos , Doença por Corpos de Lewy/genética , Mutação , Doença de Parkinson/terapia , Fenótipo , Fatores de Risco
2.
Rev Med Interne ; 40(5): 313-322, 2019 May.
Artigo em Francês | MEDLINE | ID: mdl-30638965

RESUMO

Gaucher disease is a rare autosomal recessive genetic disease, caused by a deficiency of the lysosomal enzyme, glucocerebrosidase that leads to the accumulation of its substrate (glucosylceramide) in lysosomal macrophages. In the general population, its incidence varies between 0.4 and 5.8/100,000 inhabitants. Type 1 Gaucher disease is the most frequent and is characterized by its extreme heterogeneity including asymptomatic or more severe presentations. The most frequent symptoms are anemia, thrombocytopenia, splenomegaly, and/or hepatomegaly, and a potentially severe bone involvement. Type 2 and type 3 Gaucher diseases are associated with neurological involvement that can be severe. Diagnosis is confirmed by demonstrating a deficiency of glucocerebrosidase activity in leucocytes, and by the identification of biallelic pathogenic variants in GBA1 gene. Type 1 Gaucher disease is associated with a higher risk of Parkinson disease, some solid cancers, and hematologic diseases in particularly multiple myeloma. Specific treatment, such as enzyme replacement therapy or substrate reduction therapy is indicated in symptomatic type 1 Gaucher disease. Only enzyme replacement therapy is indicated in type 3 Gaucher disease. Treatment improves quality of life and prognosis. The rarity of Gaucher disease and its wide variability in clinical presentations lead to diagnosis delays. There is a strong need for a better knowledge of its symptoms among physicians, to reduce irreversible complications.


Assuntos
Doença de Gaucher/diagnóstico , Diagnóstico Diferencial , Terapia de Reposição de Enzimas/normas , Doença de Gaucher/complicações , Doença de Gaucher/epidemiologia , Doença de Gaucher/terapia , Glucosilceramidase/uso terapêutico , Humanos , Monitorização Fisiológica/métodos , Monitorização Fisiológica/normas , Prognóstico
3.
Childs Nerv Syst ; 35(1): 191-194, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30094495

RESUMO

BACKGROUND: Gaucher disease is a rare hereditary glycolipid storage disease. One of the rare complications is neurodeficits due to vertebral involvement. CASE PRESENTATION: An 18-year-old female patient presented to the outpatient clinic with cauda equina syndrome due to sacral involvement of type 1 GD. Bilateral laminectomy via posterior approach without posterior stabilization was performed. CONCLUSION: Maximum excision of the mass avoiding destabilization of the spinal column can provide long-term vertebral stability and improvement in neurodeficits.


Assuntos
Síndrome da Cauda Equina/etiologia , Doença de Gaucher/complicações , Adolescente , Síndrome da Cauda Equina/diagnóstico por imagem , Síndrome da Cauda Equina/cirurgia , Descompressão Cirúrgica , Terapia de Reposição de Enzimas/métodos , Feminino , Doença de Gaucher/cirurgia , Doença de Gaucher/terapia , Humanos , Laminectomia/métodos , Imagem por Ressonância Magnética , Procedimentos Neurocirúrgicos/métodos , Resultado do Tratamento
4.
J Pediatr Hematol Oncol ; 41(1): 38-41, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30080752

RESUMO

The delay in platelet recovery after hematopoietic stem cell transplantation (HSCT) is closely related to the overall survival rate of transplanted children. The use of platelet-producing agents such as eltrombopag and romiplostim has made great progress in treating diseases such as immune thrombocytopenia and aplastic anemia. However, the use of such drugs in patients with thrombocytopenia after transplantation, especially in children, is rare. This study aimed to report eltrombopag treatment for 3 children with primary platelet engraftment failure and secondary thrombocytopenia after allogeneic HSCT. Of these patients, 2 had platelets stabilized at ≥50×10/L after eltrombopag treatment and subsequent withdrawal of eltrombopag. All 3 patients showed no clear adverse reactions. The results indicated a wide application prospect of eltrombopag treatment in children with thrombocytopenia after allogeneic HSCT.


Assuntos
Benzoatos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Hidrazinas/administração & dosagem , Pirazóis/administração & dosagem , Recuperação de Função Fisiológica/efeitos dos fármacos , Trombocitopenia , Adolescente , Aloenxertos , Anemia Aplástica/sangue , Anemia Aplástica/terapia , Criança , Doença de Gaucher/sangue , Doença de Gaucher/terapia , Humanos , Masculino , Contagem de Plaquetas , Receptores Fc/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Trombocitopenia/sangue , Trombocitopenia/tratamento farmacológico , Trombocitopenia/etiologia , Trombopoetina/administração & dosagem
6.
J Inherit Metab Dis ; 41(6): 1259-1265, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30066229

RESUMO

Preliminary data suggest a positive effect of taliglucerase alfa on the bone marrow infiltration of Gaucher cells. In this investigator-initiated study, we report the impact of taliglucerase alfa on the bone marrow fat fraction (FF) in 26 patients assessed by quantitative chemical shift imaging (QCSI). Of 15 treatment-naïve patients (median age 48 [range 24-68] years), eight had baseline FF ≤ 0.3, six of those with a FF ≤ 0.23 ('bone at risk'). All significantly improved from a median baseline FF of 0.24 (0.15-0.32) to 1st year FF of 0.37 (0.25-0.54) and 2nd year FF of 0.42 (0.27-0.59) (p = 0.01). Among the 11 'switch-over' patients (median age 42 [range 33-69] years; median imiglucerase exposure 8 [range 1-17] years), eight had baseline FF ≤ 0.3, five of those with FF < 0.23. All, but one, significantly improved from a median baseline FF of 0.17 (0.08-0.28) to 1st year FF of 0.3 (0.05-0.34) and 2nd year FF of 0.34 (0.08-0.44) (p = 0.03). Two elderly female patients (age 43 and 58 years, with 17 years imiglucerase exposure) who remained at the same enzyme replacement therapy dose, increased from baseline FF of 0.13 and 0.19 to 0.26 at 1 year. Although the number of observations is small, we hypothesize that switching to taliglucerase may result in an improved bone marrow response. A larger study is needed to assess the early benefit of taliglucerase alfa in adult patients with type 1 Gaucher disease on the bone marrow compartment.


Assuntos
Medula Óssea/metabolismo , Terapia de Reposição de Enzimas , Doença de Gaucher/terapia , Glucosilceramidase/uso terapêutico , Tecido Adiposo/metabolismo , Adulto , Idoso , Medula Óssea/efeitos dos fármacos , Feminino , Glucosilceramidase/imunologia , Humanos , Israel , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
7.
Nat Med ; 24(9): 1317-1323, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30013199

RESUMO

For inherited genetic diseases, fetal gene therapy offers the potential of prophylaxis against early, irreversible and lethal pathological change. To explore this, we studied neuronopathic Gaucher disease (nGD), caused by mutations in GBA. In adult patients, the milder form presents with hepatomegaly, splenomegaly and occasional lung and bone disease; this is managed, symptomatically, by enzyme replacement therapy. The acute childhood lethal form of nGD is untreatable since enzyme cannot cross the blood-brain barrier. Patients with nGD exhibit signs consistent with hindbrain neurodegeneration, including neck hyperextension, strabismus and, often, fatal apnea1. We selected a mouse model of nGD carrying a loxP-flanked neomycin disruption of Gba plus Cre recombinase regulated by the keratinocyte-specific K14 promoter. Exclusive skin expression of Gba prevents fatal neonatal dehydration. Instead, mice develop fatal neurodegeneration within 15 days2. Using this model, fetal intracranial injection of adeno-associated virus (AAV) vector reconstituted neuronal glucocerebrosidase expression. Mice lived for up to at least 18 weeks, were fertile and fully mobile. Neurodegeneration was abolished and neuroinflammation ameliorated. Neonatal intervention also rescued mice but less effectively. As the next step to clinical translation, we also demonstrated the feasibility of ultrasound-guided global AAV gene transfer to fetal macaque brains.


Assuntos
Feto/metabolismo , Terapia Genética , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/terapia , Animais , Doença de Gaucher/genética , Doença de Gaucher/terapia , Humanos , Lactente , Injeções Intravenosas , Injeções Intraventriculares , Camundongos Endogâmicos C57BL
8.
Acta Haematol ; 139(4): 240-242, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29945135

RESUMO

BACKGROUND: Gaucher disease (GD) and primary myelofibrosis (PMF) share similar clinical and laboratory features, such as cytopenia, hepatosplenomegaly, and marrow fibrosis, often resulting in a misdiagnosis. CASE REPORT: We report here the case of a young woman with hepatosplenomegaly, leukopenia, and thrombocytopenia. Based on bone marrow (BM) findings and on liver biopsy showing extramedullary hematopoiesis, an initial diagnosis of PMF was formulated. The patient refused stem cell transplantation from an HLA-identical sibling. Low-dose melphalan was given, without any improvement. Two years later, a BM evaluation showed Gaucher cells. Low glucocerebrosidase and high chitotriosidase levels were indicative for GD. Molecular analysis revealed N370S/complex I mutations. Enzyme replacement therapy with imiglucerase was commenced, resulting in clinical and hematological improvements. Due to an unexpected and persistent organomegaly, PMF combined with GD were suspected. JAK2V617F, JAK2 exon 12, MPL, calreticulin, and exon 9 mutations were negative, and BM examination showed no marrow fibrosis. PMF was excluded. Twenty years after starting treatment, the peripheral cell count and liver size were normal, whereas splenomegaly persisted. CONCLUSION: In order to avoid a misdiagnosis, a diagnostic algorithm for patients with hepatosplenomegaly combined with cytopenia is suggested.


Assuntos
Doença de Gaucher/diagnóstico , Mielofibrose Primária/diagnóstico , Adulto , Algoritmos , Biomarcadores , Biópsia , Análise Mutacional de DNA , Diagnóstico Diferencial , Erros de Diagnóstico , Gerenciamento Clínico , Terapia de Reposição de Enzimas , Feminino , Doença de Gaucher/terapia , Humanos , Imagem por Ressonância Magnética , Mielofibrose Primária/terapia , Avaliação de Sintomas , Ultrassonografia
9.
Br J Haematol ; 182(4): 467-480, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29808905

RESUMO

Treatment of Gaucher Disease (GD) is now beset with the abundance of therapeutic options for an individual patient, making the choice of therapy complex for both expert and non-expert clinicians. The pathogenesis of all disease manifestations is a gene mutation-driven deficiency of glucocerebrosidase, but the clinical expression and response of each of the clinical manifestations to different therapies can be difficult to predict. Enzyme replacement therapy has been available since 1991 and is well-established, with known efficacy and minimal toxicity. Of interest, the three available enzymes are distinct molecules and were registered as new products, not biosimilars. Oral substrate reduction therapy has undergone a revitalisation with a newly approved agent in this class for which some efficacy and toxicity questions have been raised. Herein we present our approach to the management of GD in the era of choices, including a new algorithm for how to manage a newly diagnosed patient.


Assuntos
Doença de Gaucher , Glucosilceramidase/uso terapêutico , Terapia de Reposição de Enzimas , Doença de Gaucher/diagnóstico , Doença de Gaucher/genética , Doença de Gaucher/terapia , Humanos
10.
Indian Pediatr ; 55(2): 143-153, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29503270

RESUMO

JUSTIFICATION: Gaucher disease (GD) is amongst the most frequently occurring lysosomal storage disorder in all ethnicities. The clinical manifestations and natural history of GD is highly heterogeneous with extreme geographic and ethnic variations. The literature on GD has paucity of information and optimal management guidelines for Indian patients. PROCESS: Gaucher Disease Task Force was formed under the auspices of the Society for Indian Academy of Medical Genetics. Invited experts from various specialties formulated guidelines for the management of patients with GD. A writing committee was formed and the draft guidelines were circulated by email to all members for comments and inputs. The guidelines were finalized in December 2016 at the annual meeting of the Indian Academy of Medical Genetics. OBJECTIVES: These guidelines are intended to serve as a standard framework for treating physicians and the health care systems for optimal management of Gaucher disease in India and to define unique needs of this patient population. RECOMMENDATIONS: Manifestations of GD are protean and a high index of suspicion is essential for timely diagnosis. Patients frequently experience diagnostic delays during which severe irreversible complications occur. Leucocyte acid b-glucosidase activity is mandatory for establishing the diagnosis of Gaucher disease; molecular testing can help identify patients at risk of neuronopathic disease. Enzyme replacement therapy for type 1 and type 3 Gaucher disease is the standard of care. Best outcomes are achieved by early initiation of therapy before onset of irreversible complications. However, in setting of progressive neurological symptoms such as seizures and or/ neuroregression, ERT is not recommended, as it cannot cross the blood brain barrier. The recommendations herein are for diagnosis, for initiation of therapy, therapeutic goals, monitoring and follow up of patients. We highlight that prevention of recurrence of the disease through genetic counseling and prenatal diagnosis is essential in India, due to uniformly severe phenotypes encountered in our population.


Assuntos
Doença de Gaucher/diagnóstico , Doença de Gaucher/terapia , Adolescente , Adulto , Criança , Pré-Escolar , Consenso , Terapia de Reposição de Enzimas , Aconselhamento Genético , Humanos , Índia , Lactente , Recém-Nascido , Guias de Prática Clínica como Assunto , Adulto Jovem
11.
J Med Case Rep ; 12(1): 19, 2018 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-29373994

RESUMO

BACKGROUND: Intravenous enzyme replacement therapy is a first-line therapy for Gaucher disease type 1, and substrate reduction therapy represents an oral treatment alternative. Both enzyme replacement therapy and substrate reduction therapy are generally used as monotherapies in Gaucher disease. However, one randomized study and several case reports have described combination therapy over short time periods. CASE PRESENTATION: We report two female Gaucher disease type 1 patients of mainly Anglo-Saxon descent, where combined enzyme replacement therapy and miglustat substrate reduction therapy were administered to overcome refractory clinical symptoms. The first patient was diagnosed at age 17 and developed Gaucher disease-related bone manifestations that worsened despite starting imiglucerase enzyme replacement therapy. After switching to miglustat substrate reduction therapy, her bone symptoms improved, but she developed tremors and eventually switched back to enzyme replacement therapy. Miglustat was later recommenced in combination with ongoing enzyme replacement therapy due to continued bone pain, and her bone symptoms improved along with maintained visceral manifestations. Enzyme replacement therapy was subsequently tapered off and the patient has since been successfully maintained on miglustat. The second patient was diagnosed aged 3, and commenced imiglucerase enzyme replacement therapy aged 15. After 9 years on enzyme replacement therapy she switched to miglustat substrate reduction therapy and her core symptoms were maintained/stable for 3 years. Imiglucerase enzyme replacement therapy was later added as a boost to therapy and her symptoms were subsequently maintained over a 2.3-year period. However, miglustat was discontinued due to her relocation, necessitating an increase in enzyme replacement therapy dose. Overall, both patients benefited from combination therapy. CONCLUSION: While the majority of Gaucher disease type 1 patients will not need treatment with both substrate reduction therapy and enzyme replacement therapy, the current case reports demonstrate that judicious use of combination therapy may be of benefit in some cases.


Assuntos
1-Desoxinojirimicina/análogos & derivados , Inibidores Enzimáticos/administração & dosagem , Terapia de Reposição de Enzimas/métodos , Doença de Gaucher/terapia , Glucosilceramidase/administração & dosagem , 1-Desoxinojirimicina/administração & dosagem , Adulto , Pré-Escolar , Terapia Combinada , Quimioterapia Combinada , Feminino , Hexosaminidases/sangue , Humanos , Trombocitopenia/sangue
12.
Blood Cells Mol Dis ; 68: 203-208, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28274788

RESUMO

Gaucher Disease type 1 (GD1) is a lysosomal disorder that affects many systems. Therapy improves the principal manifestations of the condition and, as a consequence, many patients show a modified phenotype which reflects manifestations of their disease that are refractory to treatment. More generally, it is increasingly recognised that information as to how a patient feels and functions [obtained by patient- reported outcome measurements (PROMs)] is critical to any comprehensive evaluation of treatment. A new set of management goals for GD1 in which both trends are reflected is needed. To this end, a modified Delphi procedure among 25 experts was performed. Based on a literature review and with input from patients, 65 potential goals were formulated as statements. Consensus was considered to be reached when ≥75% of the participants agreed to include that specific statement in the management goals. There was agreement on 42 statements. In addition to the traditional goals concerning haematological, visceral and bone manifestations, improvement in quality of life, fatigue and social participation, as well as early detection of long-term complications or associated diseases were included. When applying this set of goals in medical practice, the clinical status of the individual patient should be taken into account.


Assuntos
Doença de Gaucher/complicações , Doença de Gaucher/terapia , Qualidade de Vida , Consenso , Gerenciamento Clínico , Europa (Continente)/epidemiologia , Doença de Gaucher/epidemiologia , Doença de Gaucher/psicologia , Humanos
13.
Blood Cells Mol Dis ; 68: 66-73, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-27842801

RESUMO

Gaucher disease (GD), one of the most prevalent lysosomal storage diseases, is associated with glucocerebroside accumulation in cells of the monocyte-macrophage system in various organs, including the liver. Evaluating and managing liver disease in patients with Gaucher disease may be challenging. While hepatic involvement is common in Gaucher disease, its severity, and clinical significance span a wide spectrum, ranging from sub-clinical involvement to liver cirrhosis with its associated complications including portal hypertension. Apart from liver involvement in Gaucher disease, patients with may also suffer from other comorbidities involving the liver. That Gaucher disease itself can mimic hepatic lesions, affect laboratory tests used to characterize liver disease, and may be associated with non-cirrhotic portal hypertension, complicates the diagnostic approach even more. Better understanding of liver involvement in Gaucher disease can spare patients unnecessary invasive testing, and assist physicians in decision making when evaluating patients with Gaucher disease suspected for significant liver disease. This review describes the various clinical manifestations, laboratory and imaging abnormalities that may be encountered when following patients with Gaucher disease for liver involvement. The mechanism for liver disease are discussed, as well as the possible hepato-protective effect of glucocerebroside, and the a diagnostic and treatment approaches.


Assuntos
Doença de Gaucher/complicações , Doença de Gaucher/patologia , Hepatopatias/complicações , Hepatopatias/patologia , Fígado/patologia , Animais , Doença de Gaucher/sangue , Doença de Gaucher/terapia , Glucosilceramidas/sangue , Humanos , Hepatopatias/sangue , Hepatopatias/terapia
14.
Joint Bone Spine ; 85(1): 71-77, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28034821

RESUMO

OBJECTIVES: Type 1 Gaucher disease may be related to the presence of autoantibodies. Their clinical significance is questioned. Primary endpoint was to compare the prevalence of autoantibodies in type 1 Gaucher disease patients with healthy subjects, seeking correlations with autoimmune characteristics. Secondary endpoints were to determine whether patients with autoantibodies reported autoimmunity-related symptoms and if genotype, splenectomy or treatment influenced autoantibodies presence. METHODS: Type 1 Gaucher disease patients and healthy volunteers were included in this national multicenter exploratory study. Autoantibodies presence was compared in both groups and assessed regarding to genotype, splenectomy, Gaucher disease treatment and autoimmunity-related symptoms. RESULTS: Twenty healthy subjects and 40 type 1 Gaucher disease patients were included. Of the studied group: 15 patients undergone splenectomy, 37 were treated either with enzyme replacement therapy (34) or with substrate reduction therapy (3), 25 were homozygous/heterozygous for the N370S mutation. In type 1 Gaucher disease group (studied group), 52% had positive autoantibodies versus 26% in control group. Antiphospholipid antibodies were more frequent in the studied group (30% vs. 5%), but without correlation to thrombosis, osteonecrosis or bone infarcts. In the studied group, antinuclear antibodies were more frequent (25% vs. 16%). None of the patients with autoantibodies had clinical manifestations of autoimmune diseases. Autoantibodies were not correlated with treatment, genotype, or splenectomy, except for anticardiolipid, more frequent in splenectomized patients. CONCLUSIONS: In type 1 Gaucher disease, autoantibodies were more frequent compared to a healthy population. However, they were not associated with an increased prevalence of clinical active autoimmune diseases.


Assuntos
Autoanticorpos/imunologia , Doenças Autoimunes/imunologia , Autoimunidade , Doença de Gaucher/imunologia , Adulto , Idoso , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/terapia , Terapia de Reposição de Enzimas , Europa (Continente)/epidemiologia , Feminino , Doença de Gaucher/epidemiologia , Doença de Gaucher/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Esplenectomia
15.
Biol Chem ; 399(5): 447-452, 2018 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-29272250

RESUMO

Gaucher disease (GD) is a lysosomal storage disorder, caused by an impaired function of ß-glucocerebrosidase, which results in accumulation of glucocerebroside in cells, and altered membrane ordering. Using electron paramagnetic resonance spin labeling, a statistically significant difference in the order parameter between the peripheral blood mononuclear cell membranes of GD patients and healthy controls was observed. Moreover, the results show that the introduction of the enzyme replacement therapy leads to the restoration of the physiological membrane fluidity. Accordingly, this simple method could serve as a preliminary test for GD diagnosis and therapy efficiency.


Assuntos
Membrana Celular/patologia , Doença de Gaucher/diagnóstico , Leucócitos Mononucleares/patologia , Fluidez de Membrana , Adulto , Espectroscopia de Ressonância de Spin Eletrônica , Doença de Gaucher/sangue , Doença de Gaucher/terapia , Glucosilceramidase/administração & dosagem , Humanos , Infusões Intravenosas
16.
Bioconjug Chem ; 29(3): 649-656, 2018 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-29285931

RESUMO

Enzymes are attractive as immunotherapeutics because they can catalyze shifts in the local availability of immunostimulatory and immunosuppressive signals. Clinical success of enzyme immunotherapeutics frequently hinges upon achieving sustained biocatalysis over relevant time scales. The time scale and location of biocatalysis are often dictated by the location of the substrate. For example, therapeutic enzymes that convert substrates distributed systemically are typically designed to have a long half-life in circulation, whereas enzymes that convert substrates localized to a specific tissue or cell population can be more effective when designed to accumulate at the target site. This Topical Review surveys approaches to improve enzyme immunotherapeutic efficacy via chemical modification, encapsulation, and immobilization that increases enzyme accumulation at target sites or extends enzyme half-life in circulation. Examples provided illustrate "replacement therapies" to restore deficient enzyme function, as well as "enhancement therapies" that augment native enzyme function via supraphysiologic doses. Existing FDA-approved enzyme immunotherapies are highlighted, followed by discussion of emerging experimental strategies such as those designed to enhance antitumor immunity or resolve inflammation.


Assuntos
Terapia Enzimática/métodos , Imunoterapia/métodos , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/química , Antineoplásicos/imunologia , Antineoplásicos/uso terapêutico , Asparaginase/química , Asparaginase/imunologia , Asparaginase/uso terapêutico , Biocatálise , Enzimas Imobilizadas/química , Enzimas Imobilizadas/imunologia , Enzimas Imobilizadas/uso terapêutico , Doença de Fabry/imunologia , Doença de Fabry/terapia , Doença de Gaucher/imunologia , Doença de Gaucher/terapia , Glucosilceramidase/química , Glucosilceramidase/imunologia , Glucosilceramidase/uso terapêutico , Glicosilação , Humanos , Imunoconjugados/química , Imunoconjugados/imunologia , Imunoconjugados/uso terapêutico , Inflamação/imunologia , Inflamação/terapia , Doenças por Armazenamento dos Lisossomos/imunologia , Doenças por Armazenamento dos Lisossomos/terapia , Neoplasias/imunologia , Neoplasias/terapia , alfa-Galactosidase/química , alfa-Galactosidase/imunologia , alfa-Galactosidase/uso terapêutico
17.
Santiago; MINSAL; 2018. tab.
Não convencional em Espanhol | BRISA/RedTESA | ID: biblio-1021790

RESUMO

INTRODUCCIÓN: La enfermedad de Gaucher es considerada la enfermedad por depósito lisosomal más frecuente. Se produce por el déficit de la enzima lisosomal glucocerebrosidasa, y se transmite de manera autosómica recesiva. La frecuencia aproximada es de 1: 60.000 recién nacidos en el mundo. La enfermedad de Gaucher se caracteriza por presentar compromiso visceral, hematológico y óseo y por la ausencia de compromiso neurológico primario en la mayoría de las personas (95%). Generalmente inician la presentación de síntomas desde una etapa temprana, presentando epistaxis a repetición, hematomas o equimosis frecuentes y otras manifestaciones asociadas a trombocitopenia. Luego aparecen la esplenomegalia, hepatomegalia y las crisis de dolor óseo. En Chile, se ha reportado una prevalencia de 1 en 100 mil habitantes para la enfermedad de Gaucher. Este informe evalúa Velaglucerasa Alfa para pacientes con la Enfermedad de Gaucher Tipo 1, los cuales no están cubiertos por la Ley 20.850. TECNOLOGÍAS SANITARIA DE INTERÉS: Velaglucerasa Alfa es una terapia de reemplazo enzimático a largo plazo (ERT) en pacientes pediátricos y adultos con enfermedad de Gaucher tipo I. EFICACIA DE LOS TRATAMIENTOS: En relación a la efectividad del tratamiento, la certeza de la evidencia es muy baja, por lo que no se continúa con la evaluación. Por lo tanto, dado el no efecto y/o lo informado en la evidencia y, en conformidad con el Título III De las Evaluaciones Favorables de la Norma Técnica N° 0192 del Ministerio de Salud, sobre el proceso de evaluación científica de la Evidencia establecido en el artículo 7° de la ley N°20.850. ALTERNATIVAS DISPONIBLES: La terapia de reemplazo enzimático es la primera terapia específica para el tratamiento de las personas que presentan Enfermedad de Gaucher. En el primer decreto de la Ley Ricarte Soto, se incluyeron para la enfermedad de Gaucher tipo I, la terapia de reemplazo enzimática con Taliglucerasa o Imiglucerasa (enzimas recombinantes). Por otro lado, se pueden considerar dos opciones terapéuticas para disminuir la acumulación de glucosilceramida: terapia de reemplazo enzimático y terapia de reducción de sustrato. El enfoque de tratamiento con reducción de sustrato más reciente se puede usar en pacientes estables con enfermedad de Gaucher tipo 1 que están levemente afectados y no pueden o no desean continuar con la terapia de reemplazo enzimático, lo que significa que no todos los pacientes pueden utilizar esta otra alternativa. RESULTADOS DE LA BÚSQUEDA DE EVIDENCIA: Se identificaron dos revisiones sistemáticas, las cuales incluyen un ensayo comparando directamente la intervención contra un comparador adecuado. CONCLUSIÓN: Para dar cumplimiento al artículo 28° del Reglamento que establece el proceso destinado a determinar los diagnósticos y tratamientos de alto costo con Sistema de Protección Financiera, según lo establecido en los artículos 7°y 8° de la ley N°20.850, aprobado por el decreto N°13 del Ministerio de Salud, se concluye que el presente informe de evaluación se considera no favorable, de acuerdo a lo establecido en el Título III. de las Evaluaciones Favorables de la Norma Técnica N° 0192 de este mismo ministerio.


Assuntos
Humanos , Terapia de Reposição de Enzimas , Doença de Gaucher/terapia , Avaliação da Tecnologia Biomédica , Análise Custo-Benefício
18.
Analyst ; 142(18): 3380-3387, 2017 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-28812093

RESUMO

Gaucher disease (GD) is caused by mutations on the GBA1 gene leading to deficiency in acid ß-glucosidase (GCase) and subsequent accumulation of its substrates, glucosylceramide (GlcC) and glucosylsphingosine (GlcS). GlcS in plasma has been proposed as a highly sensitive and specific biomarker for the diagnosis of GD and for monitoring disease progression and response to therapy. Here we report a novel robust and accurate hydrophilic interaction liquid chromatography tandem mass spectrometric method (HILIC-MS/MS) for the direct measurement of glucosylsphingosine (GlcS) in dried plasma spots (DPS). The method was also capable of resolving the isomeric pair, glucosylsphingosine and galactosylsphingosine, the latter of which was proposed as a promising biomarker for Krabbe disease. The method was fully validated and applied to the analysis of 19 GD patients and carriers. The GlcS levels in 9 GD type I patients who have been on enzyme replacement therapy (ERT) were reduced to a mean of 31.0 nM, much lower compared to a pre-treated specimen at a level of 85.8 nM, but still significantly elevated compared to healthy controls. GlcS concentrations in three treated type III GD patients were much lower compared to an untreated patient. In our preclinical GD studies, 4L;C* mice (subacute nGD model) exhibited comparable levels of plasma GlcS, but had much higher GlcS accumulation in the brain than those of 9V/null mice (chronic neuropathic GD model). Our method for the measurement of GlcS in DPS proved to be a very convenient approach for sample collection, storage and shipping nationwide and internationally.


Assuntos
Cromatografia Líquida , Teste em Amostras de Sangue Seco , Doença de Gaucher/diagnóstico , Doença de Gaucher/terapia , Glucosilceramidase/sangue , Espectrometria de Massas em Tandem , Animais , Biomarcadores/sangue , Progressão da Doença , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
20.
Int J Mol Sci ; 18(4)2017 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-28430167

RESUMO

Gaucher's disease (GD) is the most frequently inherited lysosomal storage disease, presenting both visceral and neurologic symptoms. Mutations in acid ß-glucocerebrosidase disrupt the sphingolipid catabolic pathway promoting glucosylceramide (GlcCer) accumulation in lysosomes. Current treatment options are enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). However, neither of these approaches is effective in treating the neurological aspect of the disease. The use of small pharmacological compounds that act as molecular chaperones is a promising approach that is still experimental. In recent years, an association between GD and Parkinson like synucleinopathies has been discovered. Since 1992, a number of mouse models of GD have been the developed and partially reproduce phenotype of the disease. More recently, the discovery of direct reprograming has allowed the derivation of induced pluripotent stem cells (iPSc) from fibroblasts obtained from GD patients. iPSc can be expanded indefinitely in vitro and differentiated to macrophages and neurons, the main relevant cell types involved in GD. In this work, we review iPSc models of GD and summarize what we have learned from this system.


Assuntos
Doença de Gaucher/terapia , Células-Tronco Pluripotentes Induzidas/metabolismo , Animais , Diferenciação Celular , Reprogramação Celular , Descoberta de Drogas , Terapia de Reposição de Enzimas , Doença de Gaucher/metabolismo , Doença de Gaucher/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Modelos Biológicos , Neurônios/citologia , Neurônios/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia
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