Gene therapy for hepatic diseases
The investigation performed in our laboratory is divided in two main lines of research:
1. Gene therapy for hepatic rare disorders of genetic origin
What are rare diseases?
A disease is considered rare when it has a prevalence of 5 inhabitants per 10,000. Most have a genetic origin and more than 50% of them affect children. At present it is estimated that there are between 5,000 and 8,000 rare diseases in the EU that affect between 6% and 8% of the population, that is, between 27 and 36 million people. Specifically in Spain there are more than 3 million people affected.
What do we investigate?
Our laboratory focuses on the study of diseases whose origin is found in the liver and in particular those inherited diseases that can be cured by a liver transplant. We work on the understanding of the pathophysiology of some of these rare diseases and in developing new therapies. The therapeutic strategies we use are based on gene transfer and gene editing technique that can offer solutions to these pathologies.
In addition, our group is making a great effort in the improvement of the gene transfer vehicles, thanks to a better knowledge of the vector at the molecular level, and of different aspects that affect its efficacy, such as the immune response.
· Development of a gene therapy treatment for Wilson's disease (vector design and analysis of efficacy and toxicity)
· Development of gene editing strategies for the primary Hyperoxaluria type I.
Study of chronic viral hepatitis infection and development of new treatments
The main objective of our laboratory is to achieve a better understanding of the pathology associated with the hepatitis B virus (HBV) and the hepatitis Delta virus (HDV) coinfection and the development of new treatments.
Viral hepatitis B and D
In spite of the existence of a vaccine capable of effectively preventing HBV infection, currently more than 350 million people worldwide are chronic carriers of HBV of which 15 million are infected by HDV. These patients present a high risk of developing diseases that in many cases will cause death, such as cirrhosis and hepatocarcinoma. The current treatment for this disease, based on prolonged administration of IFN-α and antivirals, is far from adequate. Many of the patients do not respond to treatment, they may experience significant side effects and in many treatment-resistant viruses develop. For these reasons the need to develop new therapies for this disease is evident.
The work we develop in the laboratory has two main objectives:
· Development of new animal models of infection by both viruses that allow us to achieve a better knowledge of the pathogens and their interaction with the host cell
· Development of new antiviral treatments.
Thanks to the use of adenoassociated viruses as vehicles for the transfer of genes to the liver we have developed a mouse model that replicates some of the most important characteristics of the HDV infection in humans. The use of this model has allowed us to identify the elements involved in the innate response to the virus and to identify MAVS as the main mediator. In this model we observe, as occurs in patients that replication the virus is associated with significant hepatic damage. Now our goal is to try to elucidate the mechanism of damage and develop strategies to stop or ameliorate them.
Finally our model represents a tool of great value the development of new antivirals.
Research group leader: Dr. Rubén Hernández.
What it is: Dravet Syndrome is a rare genetic disease with one case occurring per 20,000 people. It is one of the most severe congenital epilepsies. It causes very frequent convulsions, occasionally long-lasting, which do not respond well to conventional pharmacological treatment. These symptoms usually begin at around four months of age. Later, it causes neurological disorders and intellectual disability. In over 80% of cases the cause is a mutation in the SCN1A gene, which results in a reduction of a sodium channel in the neurons responsible for controlling the propagation of nerve stimuli in the brain. In most cases these are new mutations in the individual, with no previous family history...
Objective: This disease offers a major challenge due to the size and relative instability of the SCN1A gene, and the complexity of its functions in the brain. For this reason, the Gene Therapy and Neurosciences programs at CIMA, in close collaboration with the Pediatric Department of the Clínica Universidad de Navarra, have initiated a project to transfer the corrected gene to the neurons by using high-capacity adenoviral vectors and to control its expression as physiologically as possible. Currently we are in the development phase of these vectors and assessing the most suitable regulatory sequences. For testing in animal models we are implementing an advanced model of the disease in mice, developed by the Fundación Síndrome de Dravet.
Research group leader: Dr. Gloria González Aseguinolaza.
What it is: Type I primary hyperoxaluria (PH1) is a rare metabolic disease caused by mutations in the AGXT, which encodes AGT. The absence of AGT leads to the blockage of the glyoxylate detoxification route and, consequently, to the accumulation of oxalate crystals in the kidney. The patients present with serious renal damage and the only remedial treatment is a liver transplant, in addition to a kidney transplant in most cases.
Objective: In collaboration with the Dutch company uniQure and European clinical groups we are working on the optimization of a therapeutic vector for this disease with funding from the American Oxalosis and Hyperoxaluria Foundation (OHF). Additionally, in collaboration with the Cell Therapy groups at CIMA, the Universidad de La Laguna and CIEMAT, we are working on the development of gene correction strategies to treat the disease.
"Para desarrollar nuevos tratamientos mediante terapia génica, utilizamos como vehículo uno de los vectores virales más seguros y eficaces que existen actualmente: el virus adenoasociado. Esperamos obtener en los próximos años un claro beneficio clínico en pacientes con enfermedades raras como la hiperoxaluria", Dra. Gloria González, directora del programa.
Síndrome de Dravet