Mucopolissacaridoses : mecanismos patogênicos e abordagens terapêuticas baseadas em terapia gênica e reposição enzimática
AUTOR(ES)
Guilherme Baldo
FONTE
IBICT - Instituto Brasileiro de Informação em Ciência e Tecnologia
DATA DE PUBLICAÇÃO
2012
RESUMO
In this work we aimed to study the pathogenesis of mucopolysaccharidosis (MPS), especially organs that have been described as difficult-to-reach by current therapies. We also aimed to evaluate new therapies for these diseases. Our studies focused on MPS I and VII mice showed an increase in the activity of proteases, including cathepsins and metallopeptidases, that can contribute to the disease pathogenesis in the aorta, joints and brain. In the same organs, we observed activation of inflammatory pathways, including the complement system, the toll-like recetor pathway and a neuroinflammatory process, who can also contribute to the abnormalities observed. Two gene terapy protocols were tested and, while the cell encapsulation only achieved transient correction in vivo (possibly due to a pericapsular fibrosis), the use of a retroviral gene vector reached supernormal serum IDUA levels and correction of brain abnormalities. Finally the use of enzyme replacement therapy from birth showed improvements in visceral organs, specially the aorta and heart valves, and a reduction in the levels of serum anti-IDUA antibodies. Surprisingly, the enzyme could be detected in the brain, suggesting that a fraction crosses the blood-brain-barier. Our data altogether suggest the participation of inflammatory pathways and proteases in the pathogenesis of MPS, and although the treatment with microcapsules still presents limitations, retroviral gene therapy and enzyme replacement therapy started from birth are promising treatment alternatives.
ASSUNTO(S)
erros inatos do metabolismo mucopolissacaridoses terapia gênica terapia de reposição de enzimas
ACESSO AO ARTIGO
http://hdl.handle.net/10183/55087Documentos Relacionados
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