RESUMO
Most lysosomal storage disorders (LSDs) cause progressive neurodegeneration leading to early death. While the genetic defects that cause these disorders impact all cells of the body, neurons are particularly affected. This vulnerability may be explained by neuronal cells' critical dependence on the lysosomal degradative capacity, as they cannot use division to eliminate their waste. However, mounting evidence supports the extension of storage beyond lysosomes to other cellular compartments (mitochondria, plasma membrane and synapses) as a key event in pathogenesis. Impaired energy supply, oxidative stress, calcium imbalance, synaptic failure and glial alterations may all contribute to neuronal death and thus could be suitable therapeutic targets for these disorders. Here we review the pathological mechanisms underlying neurodegeneration in Niemann Pick diseases and therapeutic strategies developed in animal models and patients suffering from these devastating disorders. This article is part of the special issue entitled 'The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders'.
Assuntos
Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/patologia , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/terapia , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/terapia , Doenças de Niemann-Pick/patologia , Doenças de Niemann-Pick/terapia , Animais , Humanos , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/metabolismo , Doenças Neurodegenerativas/metabolismo , Doenças de Niemann-Pick/metabolismoRESUMO
Inborn errors of metabolism (IEM) are caused by mutations in genes coding for enzymes and other proteins involved in cell metabolism. Many IEM can be treated effectively. Although IEM have usually been considered pediatric diseases, they can present at any age, mostly with neurological and psychiatric symptoms, and therefore constitute an integral subspeciality of neurology. However, although they are increasingly being recognized, IEM remain rare, and the care for patients should be optimized in specialized reference centers. Since the number of different diseases is very large, the diagnostic approach needs to be rigorous, starting at the clinics and calling upon the additional help of neuroradiology, biochemistry and molecular biology. In practice, it is important for the neurologist to recognize: (1) when to start suspecting an IEM; and (2) how to correlate a given clinical presentation with one of the five major groups of diseases affecting the nervous system. These five groups may be classified as: (a) energy metabolism disorders such as respiratory chain disorders, pyruvate dehydrogenase deficiency, GLUT1 deficiency, fatty-acid ß-oxidation defects, and disorders involving key cofactors such as electron transfer flavoprotein, thiamine, biotin, riboflavin, vitamin E and coenzyme Q10; (b) intoxication syndromes such as porphyrias, urea-cycle defects, homocystinurias, organic acidurias and amino acidopathies; (c) lipid-storage disorders such as lysosomal storage disorders (Krabbe disease, metachromatic leukodystrophy, Niemann - Pick disease type C, Fabry disease and Gaucher's disease), peroxisomal disorders (adrenomyeloneuropathy, Refsum disease, disorders of pristanic acid metabolism, peroxisome biogenesis disorders), Tangier disease and cerebrotendinous xanthomatosis; (d) metal-storage diseases such as iron, copper and manganese metabolic disorders; and (e) neurotransmitter metabolism defects, including defects of serotonin, dopamine and glycine metabolism.
Assuntos
Erros Inatos do Metabolismo/terapia , Doenças do Sistema Nervoso/terapia , Adulto , Encefalopatias Metabólicas Congênitas/genética , Encefalopatias Metabólicas Congênitas/terapia , Metabolismo Energético/genética , Metabolismo Energético/fisiologia , Humanos , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/terapia , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/genética , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/terapia , Erros Inatos do Metabolismo/classificação , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo dos Metais/genética , Erros Inatos do Metabolismo dos Metais/terapia , Doenças do Sistema Nervoso/classificação , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/genética , Neurotransmissores/metabolismoRESUMO
The recent hypothesis that postnatal microglia are maintained independently of circulating monocytes by local precursors that colonize the brain before birth has relevant implications for the treatment of various neurological diseases, including lysosomal storage disorders (LSDs), for which hematopoietic cell transplantation (HCT) is applied to repopulate the recipient myeloid compartment, including microglia, with cells expressing the defective functional hydrolase. By studying wild-type and LSD mice at diverse time-points after HCT, we showed the occurrence of a short-term wave of brain infiltration by a fraction of the transplanted hematopoietic progenitors, independently from the administration of a preparatory regimen and from the presence of a disease state in the brain. However, only the use of a conditioning regimen capable of ablating functionally defined brain-resident myeloid precursors allowed turnover of microglia with the donor, mediated by local proliferation of early immigrants rather than entrance of mature cells from the circulation.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/terapia , Microglia/citologia , Condicionamento Pré-Transplante/métodos , Análise de Variância , Animais , Diferenciação Celular/fisiologia , Movimento Celular/fisiologia , Citometria de Fluxo , Proteínas de Fluorescência Verde/metabolismo , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos KnockoutRESUMO
Lysosomal storage disorders are inherited metabolic diseases in which a mutation in a gene encoding a lysosomal enzyme or lysosome-related protein results in the intra-cellular accumulation of substrate and reduced cell/tissue function. Few patients with neurodegenerative lysosomal storage disorders have access to safe and effective treatments although many therapeutic strategies have been or are presently being studied in vivo thanks to the availability of a large number of animal models. This review will describe the comparative advancement of a variety of therapeutic strategies through the 'research pipeline'. Our goal is to provide information for clinicians, researchers and patients/families alike on the leading therapeutic candidates at this point in time, and also to provide information on emerging approaches that may provide a safe and effective treatment in the future. The length of the pipeline represents the significant and sustained effort required to move a novel concept from the laboratory into the clinic.
Assuntos
Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/terapia , Doenças Neurodegenerativas/terapia , Terapias em Estudo/métodos , Terapias em Estudo/tendências , Animais , Transplante de Células/métodos , Formação de Conceito/fisiologia , Terapia de Reposição de Enzimas/métodos , Prática Clínica Baseada em Evidências , Terapia Genética/métodos , Humanos , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/complicações , Modelos Biológicos , Doenças Neurodegenerativas/etiologiaRESUMO
Lysosomal storage disorders (LSD) are monogenic diseases caused by the deficiency of different lysosomal enzymes that degrade complex substrates such as glycosaminoglycans, sphingolipids, and others. As a consequence there is multisystemic storage of these substrates. Most treatments for these disorders are based in the fact that most of these enzymes are soluble and can be internalized by adjacent cells via mannose-6-phosphate receptor. In that sense, these disorders are good candidates to be treated by somatic gene therapy based on cell microencapsulation. Here, we review the existing data about this approach focused on the LSD treatments, the advantages and limitations faced by these studies.
Assuntos
Transplante de Células/métodos , Composição de Medicamentos/estatística & dados numéricos , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/terapia , Animais , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/uso terapêutico , Transplante de Células/instrumentação , Composição de Medicamentos/métodos , Técnicas de Transferência de Genes , Terapia Genética/instrumentação , Terapia Genética/métodos , Humanos , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/genética , Modelos BiológicosAssuntos
Pesquisa Biomédica/tendências , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso , Humanos , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/genética , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/fisiopatologia , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/terapiaRESUMO
Microglia activation and neuroinflammation play a pivotal role in the pathogenesis of lysosomal storage disorders (LSD) affecting the central nervous system (CNS), which are amenable to treatment by hematopoietic stem cell transplantation (HSCT). HSCT efficacy relies on replacing the intra- and extra-vascular hematopoietic cell compartments, including CNS microglia, with a cell population expressing the functional enzyme. Non-invasive and quantitative assessment of microglia activation and of its reduction upon HSCT might allow for evaluation of disease evolution and response to treatment in LSD. We here demonstrate that microglia activation can be quantified ex vivo and in vivo by PET using the peripheral benzodiazepine receptor ligand PK11195 in two models of LSD. Furthermore, we show a differential PBR binding following microglia replacement by donor cells in mice undergoing HSCT. Our data indicates that PBR ligands constitute valuable tools for monitoring the evolution and the response to treatment of LSD with CNS involvement, and enable us to evaluate whether the turnover between endogenous and donor microglia following HSCT could be adequate enough to delay disease progression.
Assuntos
Doenças do Sistema Nervoso Central/fisiopatologia , Transplante de Células-Tronco Hematopoéticas , Isoquinolinas/metabolismo , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/fisiopatologia , Microglia/fisiologia , Receptores de GABA-A/metabolismo , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Radioisótopos de Carbono , Doenças do Sistema Nervoso Central/diagnóstico por imagem , Doenças do Sistema Nervoso Central/terapia , Doenças Desmielinizantes/fisiopatologia , Modelos Animais de Doenças , Imunofluorescência , Gliose/fisiopatologia , Ligantes , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/diagnóstico por imagem , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/terapia , Camundongos , Camundongos Transgênicos , Microscopia Confocal , Tomografia por Emissão de PósitronsRESUMO
The trigeminal sensory system was evaluated for the retrograde transfer of gene therapy vectors into the CNS. The feline immunodeficiency viral vector, FIV(HEXB), encoding for the human HEXB gene, was injected intra-articularly in the temporomandibular joint of 12 week-old HexB(-/-) mice displaying clinical and histopathological signs of Sandhoff disease. This treatment regiment reduced GM(2) storage and ameliorated neuroinflammation in the brain of HexB(-/-) mice, as well as attenuated behavioral deficits. In conclusion, retrograde transfer along trigeminal sensory nerves may prove to be a valuable route of gene therapy administration for the treatment of lysosomal storage disorders and other neurodegenerative diseases.
Assuntos
Terapia Genética/métodos , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/terapia , Doenças Neurodegenerativas/terapia , Nervo Trigêmeo/metabolismo , Cadeia beta da beta-Hexosaminidase/genética , Animais , Transporte Axonal/genética , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Encefalite/genética , Encefalite/terapia , Gangliosídeo G(M2)/genética , Gangliosídeo G(M2)/metabolismo , Vetores Genéticos/genética , Humanos , Vírus da Imunodeficiência Felina/genética , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/genética , Camundongos , Camundongos Knockout , Doenças Neurodegenerativas/genética , Doença de Sandhoff/genética , Doença de Sandhoff/terapia , Resultado do Tratamento , Nervo Trigêmeo/citologiaRESUMO
Glycosphingolipids, comprising a ceramide lipid backbone linked to one/more saccharides, are particularly abundant on the outer leaflet of the eukaryotic plasma membrane and play a role in a wide variety of essential cellular processes. Biosynthesis and subsequently degradation of these lipids is tightly regulated via the involvement of numerous enzymes, and failure of an enzyme to participate in the metabolism results in storage of the enzyme's substrate, giving rise to a lysosomal storage disease. The characteristics, severity and onset of the disease are dependent on the enzyme deficient and the residual activity. Most lysosomal storage disorders found thus far are caused by a defect in the catabolic activity of a hydrolase, causing progressive accumulation of its substrate, predominantly in the lysosome. Storage of gangliosides, sialic acid containing glycosphingolipids, mostly found in the central nervous system, is a hallmark of neuronopathic forms of the disease, that include GM1 and GM2 gangliosidoses, Gaucher type II and III and Niemann-Pick C. Models for these diseases have provided valuable insight into the disease pathology and potential treatment methods.Treatment of these rare but severe disorders proves challenging due to restricted access of therapeutics through the blood-brain barrier. However, recent advances in enzyme replacement, bone marrow transplantation, gene transfer, substrate reduction and chaperon-mediated therapy provide great potential in treating these devastating disorders.
Assuntos
Glicoesfingolipídeos/metabolismo , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/metabolismo , Animais , Transplante de Medula Óssea , Gangliosidoses GM2/metabolismo , Gangliosidose GM1/metabolismo , Doença de Gaucher/metabolismo , Terapia Genética , Humanos , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/terapia , Modelos Animais , Chaperonas Moleculares/uso terapêutico , Doenças de Niemann-Pick/metabolismo , Sialiltransferases/deficiênciaRESUMO
Most lysosomal storage disorders are characterized by progressive central nervous system impairment, with or without systemic involvement. Affected individuals have an array of symptoms related to brain dysfunction, the most devastating of which is neurodegeneration following a period of normal development. The blood-brain barrier has represented a significant impediment to developing therapeutic approaches to treat brain disease, but novel approaches-including enzyme replacement, small-molecule, gene, and cell-based therapies-have given children afflicted by these conditions and those who care for them hope for the future.
Assuntos
Sistema Nervoso Central/fisiopatologia , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/patologia , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/terapia , Animais , Terapia Baseada em Transplante de Células e Tecidos/métodos , Sistema Nervoso Central/enzimologia , Sistema Nervoso Central/patologia , Sistema Nervoso Central/cirurgia , Terapia Genética/métodos , Humanos , Hidrolases/uso terapêutico , Lisossomos/enzimologia , Lisossomos/genética , Lisossomos/patologiaAssuntos
Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/genética , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/terapia , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Aspirina/uso terapêutico , Transplante de Medula Óssea , Modelos Animais de Doenças , Proteína Ativadora de G(M2)/genética , Terapia Genética , Humanos , Mutação , beta-N-Acetil-Hexosaminidases/genéticaRESUMO
Lysosomal diseases comprise a group of inherited disorders resulting from defects of lysosomal enzymes and their cofactors, and in many of them the nervous system is affected. Recently, enzyme replacement therapy with recombinant lysosomal enzymes has been clinically available for several lysosomal diseases. Such enzyme replacement therapies can improve non-neurological disorders but is not effective for neurological ones. In this review, we discuss the molecular pathologies of lysosomal diseases from the protein structural aspect, current enzyme replacement therapies, and attempts to develop enzyme replacement therapies effective for lysosomal diseases associated with neurological disorders, i.e., production of enzymes, brain-specific delivery and incorporation of lysosomal enzymes into cells.
Assuntos
Terapia Enzimática , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/enzimologia , Lisossomos/enzimologia , Proteínas Recombinantes de Fusão/uso terapêutico , Animais , Meios de Cultivo Condicionados/farmacologia , Enzimas/química , Enzimas/genética , Gangliosídeo G(M2)/metabolismo , Humanos , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/genética , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/terapia , Lisossomos/genética , Lisossomos/patologia , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Doença de Sandhoff/enzimologia , Doença de Sandhoff/genética , Doença de Sandhoff/fisiopatologia , Doença de Tay-Sachs/enzimologia , Doença de Tay-Sachs/genética , Doença de Tay-Sachs/fisiopatologia , beta-N-Acetil-Hexosaminidases/química , beta-N-Acetil-Hexosaminidases/genéticaAssuntos
Aspartilglucosilaminase/urina , Transplante de Medula Óssea , Encéfalo/metabolismo , Heterozigoto , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/terapia , Lisossomos/metabolismo , Animais , Encéfalo/patologia , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/patologia , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/urina , Lisossomos/patologia , CamundongosRESUMO
There are more than 40 different forms of inherited lysosomal storage diseases (LSDs) known to occur in humans and the aggregate incidence has been estimated to approach 1 in 7000 live births. Most LSDs are associated with high morbidity and mortality and represent a significant burden on patients, their families, and health care providers. Except for symptomatic therapies, many LSDs remain untreatable, and gene therapy is among the only viable treatment options potentially available. Therapies for some LSDs do exist, or are under evaluation, including heterologous bone marrow transplantation (BMT), enzyme replacement therapy (ERT), and substrate reduction therapy (SRT), but these treatment options are associated with significant concerns, including high morbidity and mortality (BMT), limited positive outcomes (BMT), incomplete response to therapy (BMT, ERT, and SRT), life-long therapy (ERT, SRT), and cost (BMT, ERT, SRT). Gene therapy represents a potential alternative therapy, albeit a therapy with its own attendant concerns. Animal models of LSDs play a critical role in evaluating the efficacy and safety of therapy for many of these conditions. Naturally occurring animal homologs of LSDs have been described in the mouse, rat, dog, cat, guinea pig, emu, quail, goat, cattle, sheep, and pig. In this review we discuss those animal models that have been used in gene therapy experiments and those with promise for future evaluations.
Assuntos
Terapia Genética , Doenças por Armazenamento dos Lisossomos/terapia , Animais , Modelos Animais de Doenças , Doença de Depósito de Glicogênio Tipo II/genética , Doença de Depósito de Glicogênio Tipo II/terapia , Humanos , Doenças por Armazenamento dos Lisossomos/genética , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/genética , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/terapia , Mucopolissacaridoses/genética , Mucopolissacaridoses/terapiaRESUMO
Despite disappointments with early clinical studies, there is continued interest in the development of gene therapy for the group of metabolic diseases referred to as lysosomal storage disorders (LSDs). The LSDs are monogenic and several small and large, representative animal models of the human diseases are available. Further, the successful reconstitution of only low and unregulated tissue levels of the affected lysosomal enzymes are expected to be sufficient to correct the disease at least in the case of some of the LSDs. For these reasons, they are perceived as good models for the evaluation of different gene delivery vectors and of different strategies for treating chronic genetic diseases by gene transfer. In this review, we will highlight the progress that has been made over the past 2 years in preclinical research for this group of disorders and speculate on future prospects.