RESUMEN

Huntington's disease (HD) is a lethal, neurodegenerative disorder caused by expansion of the polyglutamine repeat in the Huntingtin gene (HTT), leading to mutant protein misfolding, aggregation, and neuronal death. Feeding a Drosophila HD model cystamine, or expressing a transgene encoding the anti-htt intracellular antibody (intrabody) C4-scFv in the nervous system, demonstrated therapeutic potential, but suppression of pathology was incomplete. We hypothesized that a combinatorial approach entailing drug and intrabody administration could enhance rescue of HD pathology in flies and that timing of treatment would affect outcomes. Feeding cystamine to adult HD flies expressing the intrabody resulted in a significant, additional rescue of photoreceptor neurodegeneration, but no additional benefit in longevity. Feeding cystamine during both larval and adult stages produced the converse result: longevity was significantly improved, but increased photoreceptor survival was not. We conclude that cystamine-intrabody combination therapies can be effective, reducing neurodegeneration and prolonging survival, depending on administration protocols.

Asunto(s)

Anticuerpos/administración & dosificación , Anticuerpos/genética , Cistamina/administración & dosificación , Drosophila melanogaster/genética , Enfermedad de Huntington/tratamiento farmacológico , Modelos Genéticos , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/inmunología , Proteínas Nucleares/genética , Proteínas Nucleares/inmunología , Animales , Animales Modificados Genéticamente , Anticuerpos/metabolismo , Cistamina/uso terapéutico , Modelos Animales de Enfermedad , Drosophila melanogaster/crecimiento & desarrollo , Quimioterapia Combinada , Femenino , Terapia Genética/métodos , Humanos , Proteína Huntingtina , Enfermedad de Huntington/dietoterapia , Enfermedad de Huntington/patología , Masculino , Degeneración Nerviosa/dietoterapia , Degeneración Nerviosa/patología , Degeneración Nerviosa/prevención & control , Proteínas del Tejido Nervioso/biosíntesis , Proteínas Nucleares/biosíntesis , Células Fotorreceptoras de Invertebrados/efectos de los fármacos , Células Fotorreceptoras de Invertebrados/patología , Análisis de Supervivencia , Resultado del Tratamiento