Tesis doctorales: TESEO

Ayuda Salir

Ficha de Tesis

Imprimir

Ministerio de Universidades - Gobierno de España

Título: INTRATHECAL ADMINISTRATION OF AAVRH10 CODING FOR B-GLUCURONIDASE CORRECTS BIOCHEMICAL AND HISTOLOGICAL HALLMARKS OF MUCOPOLYSACCHARIDOSIS TYPE VII MICE AND IMPROVES BEHAVIOR AND SURVIVAL
Autor: Pagès Pi, Gemma
Universidad: Universidad Autónoma de Barcelona
Departamento: BIOQUIMICA Y BIOLOGIA MOLECULAR
Fecha de Lectura: 10/07/2015
Mención Europeo / Mención Internacional: Concedido
Programa de doctorado: Bioquímica, biologia molecular i biomedicina
Dirección:
- Bosch Merino, Assumpció (DIRECTOR)
Tribunal:
- Pineda, Mercè (PRESIDENTE)
- Consiglio, Antonella (SECRETARIO)
- Salinas, Sara (VOCAL)
Descriptores:
- BIOQUIMICA
Localización: BIBLIOTECA DE COMUNICACIÓN Y HEMEROTECA GENERAL UAB
Marcador: https://www.educacion.gob.es/teseo/mostrarRef.do?ref=1164945Añadir a favoritos.
Resumen:
Mucopolysaccharidosis type VII (MPS VII) is an ultrarare monogenic lysosomal storage disease. It is caused by the lack of ß-glucuronidase activity, a lysosomal enzyme involved in the degradation pathway of glycosaminoglycans. This inborn genetic alteration causes a dysfunction of the lysosomal system that entails abnormal lysosomal storage and disruption of cell homeostasis. The disease presents a range of clinical severity among patients, from death in utero to a life expectancy of up to 20 or 30 years for the milder forms. The severe form of MPS VII among cases with postnatal disease onset is characterized by hepatosplenomegaly, skeletal abnormalities, developmental delay and mental retardation, among other symptoms. Currently, the only treatments for MPS VII patients are interventions to alleviate the symptoms, but no curative treatment is available. Gene therapy is a promising therapeutic approach to find a cure for monogenic diseases. Among the available gene delivery vectors, adeno-associated viruses (AAVs) present several features that make them attractive for gene therapy strategies: they are able to transduce dividing and quiescent cells, they provide long term expression of the transgene, they are not able to autonomously replicate without a helper virus, and wild type AAV infections are not pathogenic. Different AAV serotypes have been used as gene therapy vectors in preclinical studies. Among them, AAV9 and AAVrh10 are the serotypes which show greater transduction capacity and a broader range of cell-type specific tropism, particularly in the central nervous system. The use of AAVrh10, a non-human serotype, may avoid the neutralization by anti-AAV immune factors present in human sera after natural AAV infections. However, cross-reactivity with antibodies raised against AAV2, the most common human AAV serotype, may still interfere in the therapeutic outcome. In this work, we propose a gene therapy strategy for MPS VII based on a single intrathecal injection of an AAVrh10 coding for the ß-glucuronidase gene, tested in young adult MPS VII mice. We show that vector delivery to the CSF by lumbar puncture, a poorly invasive technique, allows the transduction of CNS structures using a lower vector dose than by intravenous delivery. In addition, the drainage of the vector from the CSF to the bloodstream results in transduction of somatic organs such as liver, thus providing a systemic ß-glucuronidase source that achieves serum enzymatic activity comparable to wild type mice. The sustained recombinant enzyme expression by AAV-transduced cells, and the cross-correction provided by enzyme secretion, attains the correction of biochemical and histopathological hallmarks of the disease in CNS and somatic organs. This correction at the cellular level leads to a significant improvement of physical, cognitive and emotional characteristics of MPS VII mice and a doubling of the MPS VII mouse life span.

Imprimir

Modificar Consulta Nueva Consulta

Versión 4.4