RESUMO
G(M2) gangliosidoses are severe neurodegenerative disorders resulting from a deficiency in ß-hexosaminidase A activity and lacking effective therapies. Using a Sandhoff disease (SD) mouse model (Hexb(-/-)) of the G(M2) gangliosidoses, we tested the potential of systemically delivered adeno-associated virus 9 (AAV9) expressing Hexb cDNA to correct the neurological phenotype. Neonatal or adult SD and normal mice were intravenously injected with AAV9-HexB or -LacZ and monitored for serum ß-hexosaminidase activity, motor function, and survival. Brain G(M2) ganglioside, ß-hexosaminidase activity, and inflammation were assessed at experimental week 43, or an earlier humane end point. SD mice injected with AAV9-LacZ died by 17 weeks of age, whereas all neonatal AAV9-HexB-treated SD mice survived until 43 weeks (P < 0.0001) with only three exhibiting neurological dysfunction. SD mice treated as adults with AAV9-HexB died between 17 and 35 weeks. Neonatal SD-HexB-treated mice had a significant increase in brain ß-hexosaminidase activity, and a reduction in G(M2) ganglioside storage and neuroinflammation compared to adult SD-HexB- and SD-LacZ-treated groups. However, at 43 weeks, 8 of 10 neonatal-HexB injected control and SD mice exhibited liver or lung tumors. This study demonstrates the potential for long-term correction of SD and other G(M2) gangliosidoses through early rAAV9 based systemic gene therapy.
Assuntos
Dependovirus/genética , Gangliosídeo G(M2)/metabolismo , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Doença de Sandhoff/terapia , Cadeia beta da beta-Hexosaminidase/genética , Fatores Etários , Animais , Animais Recém-Nascidos , Encéfalo/enzimologia , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Expressão Gênica , Vetores Genéticos/efeitos adversos , Inflamação/genética , Inflamação/mortalidade , Inflamação/patologia , Inflamação/terapia , Injeções Intravenosas , Óperon Lac , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/patologia , Lisossomos/enzimologia , Lisossomos/patologia , Masculino , Camundongos , Camundongos Knockout , Atividade Motora/genética , Doença de Sandhoff/genética , Doença de Sandhoff/mortalidade , Doença de Sandhoff/patologia , Análise de Sobrevida , Cadeia beta da beta-Hexosaminidase/metabolismoRESUMO
Mutations of the glycogen branching enzyme gene, GBE1, result in glycogen storage disease (GSD) type IV, an autosomal recessive disorder having multiple clinical forms. One mutant allele of this gene, GBE1 c.1076A>C, has been reported in Ashkenazi Jewish cases of an adult-onset form of GSD type IV, adult polyglucosan body disease (APBD), but no epidemiological analyses of this mutation have been performed. We report here the first epidemiological study of this mutation in persons of Ashkenazi Jewish background and find that this mutation has a gene frequency of 1 in 34.5 (95% CI: 0.0145-0.0512), similar to the frequency of the common mutation causing Tay-Sachs disease among Ashkenazi Jews. This finding reveals APBD to be another monogenic disorder that occurs with increased frequency in persons of Ashkenazi Jewish ancestry.