Gene Therapy of Acquired Diseases and Cancer
Genetic diseases affecting the central nervous system often lack specific treatments and cause a progressive deterioration in the quality of life of patients. They are usually caused by mutations in genes essential for the function of neurons. However, in some cases these diseases develop as a consequence of enzymatic defects in hepatic metabolism, which trigger the accumulation of neurotoxic substances. The development of new vehicles (vectors) for the safe and efficient delivery of genes in these organs offers new therapeutic opportunities. In collaboration with groups from the Gene Therapy and Neuroscience programs at CIMA, we aim to design specific vectors for these diseases, taking into account the characteristics of the affected genes and the organs in which they exert their main functions.
Our laboratory has specialized in a type of vector called High-Capacity Adenovirus (HC-Ad). In contrast with earlier versions of adenoviral vectors, HC-Ads are devoid of all viral genes. This feature increases the safety of these vectors and provides two important properties: the possibility of harboring long sequences of DNA, and the stability of function during long periods of time in vivo. We have optimized the protocols for HC-Ad production to increase their yield and purity, and have used them extensively for the controlled expression of genes with antitumor effect.
We believe that the properties of HC-Ads allow us to take the challenge of transferring complex and large genes into the brain. Therefore, we have initiated a line of research on Dravet Syndrome (DS), an inborn encephalopathy characterized by severe seizures and progressive neurological deterioration. In most cases, DS is caused by mutations in the SCN1A gene, which encodes a Sodium channel essential for the function of inhibitory neurons. We are developing HC-Ads carrying the SCN1A gene under the control of promoters that will ensure physiological production of the protein in the target cells. These vectors will be evaluated in a mouse model designed by the Dravet Syndrome Foundation.
Cerebrotendinous Xanthomatosis (CTX) exemplifies a group of neurodegenerative diseases which, in principle, could be treated by liver-directed gene therapy. In this case a defect in the metabolism of bile acids causes the accumulation of neurotoxic intermediates. The affected gene (CYP27A1) is relatively small and is expressed mainly in the liver. Therefore, we propose the use of small vectors, derived from adeno-associated viruses (AAV), which have demonstrated remarkable safety and efficacy in several clinical trials. For the functional evaluation of these vectors we will employ a mouse strain with defects in the homologous gene, subjected to pharmacological treatments to mimic the neurological manifestations found in CTX patients.
Fecha de actualización: Noviembre 2018