RESUMO
Fabry disease (FD) is a multisystem lysosomal storage disorder induced by genetic variants in the alpha-galactosidase A (αGalA) gene. Some FD patients have GLA variants with a reduction in overall αGalA enzymatic activity due to mutated proteins with reduced stability, caused by protein misfolding and premature degradation, but the αGalA catalytic activity remains conserved ("amenable" genetic variants). To correct this misfolding and to prevent premature degradation, migalastat, a small iminosugar molecule was developed. We report the clinical characteristics of FD "amenable" cohort patients from Argentina, prior to starting treatment with migalastat. Seventeen Fabry adult patients were recruited from 13 Argentinian Centers; 8 males (47.1%) and 9 females (52.9%) were included. All genotypes included were missense-type "amenables" mutations. Some classic FD typical early manifestations were more frequent in patients with "classic" versus "late-onset" FD phenotype (pain, p=0.002; cornea verticillata, p=0.019). There was a statistically significant difference in estimated glomerular filtration rate in the "classic" versus "late-onset" phenotype (p=0.026) but no difference between genders (p=0.695). Left ventricular mass was similar between genders (p=0.145) and phenotypes (p=0.303). Cardiovascular risk factors were present among "late-onset" females (obesity 50% and smoke 25%). In patients who started "de novo" migalastat, the main indications were (i) heart disease, (ii) kidney damage, and (iii) pain, while in "switched from prior enzyme replacement therapy" patients, the most frequent indication was "patient decision;" this coincides with publications by other authors.
Assuntos
1-Desoxinojirimicina/análogos & derivados , Doença de Fabry , Adulto , Humanos , Masculino , Feminino , Doença de Fabry/epidemiologia , Doença de Fabry/genética , Doença de Fabry/tratamento farmacológico , 1-Desoxinojirimicina/uso terapêutico , alfa-Galactosidase/genética , alfa-Galactosidase/metabolismo , alfa-Galactosidase/uso terapêutico , Dor/induzido quimicamente , Dor/tratamento farmacológicoRESUMO
OBJECTIVE: Gaucher disease (GD) is a rare disorder linked to the absence/deficiency of glucocerebrosidase. GD can be treated by enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). The aim of this systematic review (SR) is to assess the effectiveness of drugs used for GD treatment. DATA SOURCES: Searches were conducted in PubMed and Scopus, in April 2021. The search strategies encompassed the name of the disease and of the drug treatments. Manual search was also conducted. STUDY SELECTION AND DATA EXTRACTION: Observational and interventional longitudinal studies evaluating ERT and SRT for GD were included. Single mean meta-analyses were conducted for each drug using R. DATA SYNTHESIS: The initial search retrieved 2246 articles after duplicates were removed. Following screening and eligibility assessment, 68 reports were included. The studies evaluated imiglucerase, velaglucerase alfa, taliglucerase alfa, miglustat, and eliglustat. The results showed that ERT is effective as a treatment in both naïve and experienced patients. Miglustat did not significantly improve blood outcomes in naïve patients and resulted in a decrease in the platelet levels of experienced patients. Eliglustat was mainly assessed for experienced patients and resulted in stable outcome values. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This extensive SR confirms the effectiveness of GD treatments in short- and long-term follow-ups. CONCLUSIONS: The results were favorable for all ERTs and for eliglustat. Based on the assessed evidence, miglustat did not achieved expressive results. However, all evidence should be interpreted considering its limitations and does not replace well-conducted randomized trials.
Assuntos
Doença de Gaucher , Humanos , Doença de Gaucher/tratamento farmacológico , Doença de Gaucher/diagnóstico , Glucosilceramidase/uso terapêutico , Glucosilceramidase/efeitos adversos , 1-Desoxinojirimicina/uso terapêutico , Plaquetas , Terapia de Reposição de Enzimas/métodosRESUMO
GM2 gangliosidoses are a group of pathologies characterized by GM2 ganglioside accumulation into the lysosome due to mutations on the genes encoding for the ß-hexosaminidases subunits or the GM2 activator protein. Three GM2 gangliosidoses have been described: Tay-Sachs disease, Sandhoff disease, and the AB variant. Central nervous system dysfunction is the main characteristic of GM2 gangliosidoses patients that include neurodevelopment alterations, neuroinflammation, and neuronal apoptosis. Currently, there is not approved therapy for GM2 gangliosidoses, but different therapeutic strategies have been studied including hematopoietic stem cell transplantation, enzyme replacement therapy, substrate reduction therapy, pharmacological chaperones, and gene therapy. The blood-brain barrier represents a challenge for the development of therapeutic agents for these disorders. In this sense, alternative routes of administration (e.g., intrathecal or intracerebroventricular) have been evaluated, as well as the design of fusion peptides that allow the protein transport from the brain capillaries to the central nervous system. In this review, we outline the current knowledge about clinical and physiopathological findings of GM2 gangliosidoses, as well as the ongoing proposals to overcome some limitations of the traditional alternatives by using novel strategies such as molecular Trojan horses or advanced tools of genome editing.
Assuntos
Proteína Ativadora de G(M2)/genética , Gangliosidoses GM2/patologia , beta-N-Acetil-Hexosaminidases/genética , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/uso terapêutico , Barreira Hematoencefálica , Ensaios Clínicos como Assunto , Dieta Cetogênica , Gangliosídeo G(M2)/metabolismo , Gangliosidoses GM2/genética , Gangliosidoses GM2/metabolismo , Gangliosidoses GM2/terapia , Terapia Genética , Humanos , Mutação , Pirimetamina/uso terapêutico , Transplante de Células-TroncoAssuntos
Proteínas de Transporte/genética , Colestanóis/sangue , Filipina/química , Glicoproteínas/genética , Hexosaminidases/sangue , Glicoproteínas de Membrana/genética , Doença de Niemann-Pick Tipo C/diagnóstico , Coloração e Rotulagem , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/uso terapêutico , Brasil , Hexosaminidases/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteína C1 de Niemann-Pick , Doença de Niemann-Pick Tipo C/sangue , Doença de Niemann-Pick Tipo C/tratamento farmacológico , Doença de Niemann-Pick Tipo C/genética , Proteínas de Transporte VesicularRESUMO
Niemann-Pick type C (NPC) is a rare neurodegenerative disorder biochemically characterized by the accumulation of cholesterol and glycosphingolipids in late endosomes and lysosomes of the affected patients. N-butyl-deoxynojirimycin is the only approved drug for patients with NPC disease. It inhibits glycosphingolipid synthesis, therefore reducing intracellular lipid storage. Although the mechanisms underlying the neurologic damage in the NPC disease are not yet well established, in vitro and in vivo studies suggest an involvement of reactive species in the pathophysiology of this disease. In this work we aimed to evaluate parameters of lipid and protein oxidation, measured by thiobarbituric acid-reactive species (TBA-RS) and protein carbonyl formation, respectively, as well as the enzymatic and non-enzymatic antioxidant defenses in plasma, erythrocytes and fibroblasts from NPC1 patients, at diagnosis and during treatment with N-butyl-deoxynojirimycin. We found a significant increase of TBA-RS in plasma and fibroblasts, as well as increased protein carbonyl formation and decreased total antioxidant status (TAS) in plasma of untreated NPC1 patients as compared to the control group. In addition, erythrocyte glutathione peroxidase (GSH-Px) activity was increased, whereas CAT and SOD activities were normal in these patients. We also observed that patients treated with N-butyl-deoxynojirimycin normalized plasma TBA-RS and TAS, as well as erythrocyte GSH-Px activity. Taken together, the present data indicate that oxidative stress is increased in patients with NPC1 disease and that treatment with N-butyl-deoxynojirimycin is able to confer protection against this pathological process.
Assuntos
1-Desoxinojirimicina/análogos & derivados , Inibidores Enzimáticos/uso terapêutico , Doença de Niemann-Pick Tipo C/tratamento farmacológico , Doença de Niemann-Pick Tipo C/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , 1-Desoxinojirimicina/farmacologia , 1-Desoxinojirimicina/uso terapêutico , Adolescente , Adulto , Antioxidantes/metabolismo , Catalase/metabolismo , Criança , Inibidores Enzimáticos/farmacologia , Eritrócitos/efeitos dos fármacos , Feminino , Fibroblastos/efeitos dos fármacos , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Humanos , Lactente , Estudos Longitudinais , Masculino , Doença de Niemann-Pick Tipo C/sangue , Doença de Niemann-Pick Tipo C/patologia , Plasma/efeitos dos fármacos , Carbonilação Proteica/efeitos dos fármacos , Estatísticas não Paramétricas , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Adulto JovemRESUMO
OBJECTIVE: To evaluate the efficacy and safety of oral miglustat treatment in patients with mucopolysaccharidosis type III. The primary outcome was efficacy with improvement or stabilization in at least two domains of Vineland Adaptative Behavior Scales at 6 months. The secondary outcome measured the evolution of other cognitive tests at 12 months. The safety and tolerability were assessed throughout the study. STUDY DESIGN: This was a randomized, double-blind, placebo-controlled, monocenter, institutional, phase IIb to III study. In case of efficacy at 6 months, the study would go on for another 6 months on an open design with all patients receiving miglustat. In the absence of efficacy at 6 months, the trial had to be continued for 6 more months with the initial design. RESULTS: After 6 months, efficacy was not superior in patients with miglustat. The independent review board confirmed continuing the study until 12 months. CONCLUSION: Miglustat treatment was not associated with any improvement/stabilization in behavior problems in patients with mucopolysaccharidosis type III. Miglustat has an acceptable safety profile. However, the study has confirmed that miglustat is able to pass through the blood-brain barrier without significantly decreasing ganglioside levels.
Assuntos
1-Desoxinojirimicina/análogos & derivados , Inibidores Enzimáticos/uso terapêutico , Mucopolissacaridose III/tratamento farmacológico , 1-Desoxinojirimicina/sangue , 1-Desoxinojirimicina/líquido cefalorraquidiano , 1-Desoxinojirimicina/uso terapêutico , Encéfalo/patologia , Criança , Pré-Escolar , Cognição/efeitos dos fármacos , Método Duplo-Cego , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/líquido cefalorraquidiano , Feminino , Inibidores de Glicosídeo Hidrolases , Humanos , Imageamento por Ressonância Magnética , Masculino , Testes Neuropsicológicos , Transtornos do Sono-Vigília/tratamento farmacológico , alfa-Glucosidases/líquido cefalorraquidianoRESUMO
Fabry disease is an X-linked lysosomal storage disorder (LSD) due to deficiency of the enzyme α-galactosidase A (GLA). Absent or reduced enzyme activity leads to impaired catabolism of neutral glycosphingolipids, particularly globotriaosylceramide (Gb3), resulting in intracellular deposition of such lipids. Clinical manifestations in hemizygote males include angiokeratoma, hypohydrosis, acroparesthesia, abdominal pain, proteinuria, renal insufficiency, left ventricular hypertrophy and cerebrovascular accidents. Heterozygote women may present with mild to severe signs and symptoms. Since year 2001, enzyme replacement therapy (ERT) is the only specific treatment for Fabry disease. The beneficial effect of ERT on different organs/systems has been extensively evaluated, and an improvement in renal function, cardiac mass and quality of life has been reported. Different treatment approaches are currently on development. One of them implies the use of the active-site-specific chaperone 1-deoxygalactonojirimycin that acts facilitating folding of mutant GLA in the endoplasmic reticulum and increasing its lysosomal residual activity. Reduction of Gb3 deposits has been shown in lymphoblasts from Fabry patients with missense mutations and transgenic mouse model expressing a missense mutation GLA. Gene therapy has been also developed as a potential option for treatment of Fabry disease. This review will discuss these novel therapeutic options along with their advantages and limitations.
Assuntos
Terapia de Reposição de Enzimas/métodos , Doença de Fabry/terapia , Terapia Genética/métodos , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/uso terapêutico , Animais , Doença de Fabry/tratamento farmacológico , Doença de Fabry/enzimologia , Doença de Fabry/genética , Humanos , Mutação de Sentido Incorreto , alfa-Galactosidase/genéticaRESUMO
Niemann-Pick disease type C (NPC) is an autosomal recessive neurovisceral lysosomal lipid storage disorder that leads to variable symptoms that include cognitive decline, ataxia, dystonia, cataplexy, vertical supranuclear gaze palsy, and seizures. Currently, there is no specific treatment for NPC other than palliative care. Substrate reduction therapy represents a potential strategy for treating this debilitating neurodegenerative disorder. Miglustat (Zavesca) is a reversible inhibitor of the enzyme glucosylceramide synthase, which catalyses the first step in the biosynthesis of most glycosphingolipids. Miglustat has pharmacokinetic properties that allow it to cross the blood-brain barrier, thus making it a potential therapeutic agent for treating neurological symptoms in NPC patients. We present here a case report of a Brazilian child treated with miglustat. Before treatment, the patient presented with difficulties walking and swallowing, slurred speech, moderate cognitive impairments, ataxia, ptosis, and vertical supranuclear ophthalmoplegia. On a disability scale, the patient obtained a score of 15 before treatment and 8 after treatment. Following 12 months of treatment, the patient remained stable with improvements in speech, ptosis, ophthalmoplegia, ataxia, hypotonia and seizures. The Child Behavior Checklist (CBCL) was used to assess psychopathological, behavioural and social problems before and after treatment. The CBCL showed that indices for depression, affective and attention problems were all in the normal range following treatment. Thus, for this individual miglustat was an effective, well-tolerated and efficacious medication for treatment of NPC symptoms. Follow-up maintenance studies are vital to establish whether both the efficacy and safety of miglustat persist with time.