Development of New Gene-Therapy Vectors

Gene therapy has recently been shown to be a potential therapeutic alternative for many types of cancer, as well as for the treatment of rare genetic diseases.

Cancer gene therapy

Our research focuses on the development of vectors based on self-replicating RNA derived from alphaviruses to express immunostimulatory molecules locally in tumors. These vectors present several advantages, such as high expression levels, induction of interferon (IFN) type I responses and apoptosis, as well as a high degree of biosafety, since they cannot propagate. In numerous studies we have shown that vectors derived from the alphavirus SFV (Semliki Forest virus) expressing immunostimulatory cytokines, such as interleukin-12 (IL-12), IFNα, or Flt3L (a dendritic cell growth factor) are capable of inducing potent antitumor responses in models of colorectal cancer and hepatocarcinoma, including spontaneous tumors of clinical relevance. We have also shown that the activity of these vectors can be enhanced by combining them with immunomodulatory monoclonal antibodies (MAbs), such as an agonist MAb for CD137, a molecule expressed on the surface of activated T cells, or with MAbs able to block immune checkpoints, such as PD-L1 or PD-1. We are currently evaluating the use of SFV RNA vectors to express these MAbs locally in tumors, which would allow to diminish the toxicity produced by said MAbs when they are administered systemically.

On the other hand, in order to improve SFV vectors, we have developed non-cytopathic variants of them that allow generation of stable cell lines to express therapeutic proteins with potential application in cancer, like immunomodulatory MAbs. We have also recently described that alphaviruses can propagate in the complete absence of their capsid, which has allowed us to develop a new generation of propagative RNA vectors with potential application as oncolytic vectors.

Gene therapy of rare genetic diseases

In a second line of work our goal is the development of gene therapy treatments for two monogenic diseases called "progressive familial intrahepatic cholestasis" (PFIC) type 2 and 3. PFIC2 and PFIC3 are diseases that manifest at a young age, being the consequence of mutations in two genes involved in the transport of metabolites to bile (ABCB11 and ABCB4) which express BSEP and MDR3 proteins, respectively. These diseases have devastating consequences for children who suffer them, being liver transplant the only effective therapy in most cases. Our goal is to introduce a correct version of the affected gene in the hepatic cells of these patients by using a vector derived from adeno-associated virus (AAV). This type of treatment would allow to permanently restore normal production of bile in patients, avoiding liver damage. This research is financed by Vivet Therapeutics (Paris, France).

Fecha de actualización: Noviembre 2018

"We are evaluating the use of monoclonal antibodies (mAbs) with immunomodulatory properties for the treatment of cancer", Dr. Cristian Smerdou, Principal Investigator.


Cibeles Pinto
Avda. Pío XII, 55
31008 Pamplona

+34 948 194 700 Ext. 4012