Center for Applied Medical Research

Pamplona, Spain

Center for Applied Medical Research

Pamplona, Spain
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News Article | May 16, 2017

Spanish scientists at the University of Navarra and Vivet Therapeutics expect to begin the first clinical trials on patients in 2018 with the new VTX801 treatment which corrects an advanced stage of this rare disease in animals Pamplona (Spain), May 16. Scientists at the Center for Applied Medical Research (CIMA) at the University of Navarra (Spain) have designed a promising gene therapy method to treat Wilson's disease, a rare pathology caused by the lack of or malfunction of a gene. The gene therapy consists in introducing the correct version of the gene into the damaged cells by means of vehicles or vectors, generally viruses which have been modified in the laboratory to eliminate their capacity to cause disease but maintain their ability to penetrate the cells. With this promising method Dr. Gloria González Aseguinolaza, director of the Gene Therapy Program at CIMA, and her team have designed VTX801, a viral vector that corrects an advanced stage of Wilson's disease in animals. The Massachusetts Eye and Ear (MEE), a hospital associated with Harvard University, has participated in the development process of her innovative therapeutic strategy by contributing an advanced viral capsid (Anc80), the coating of the genetic material of the modified virus. This advance has been possible thanks to the CIMA agreement and exclusive license, through its foundation for applied medical research (FIMA) with the emerging French bio-technical company Vivet Therapeutics (Vivet). This company, which develops new treatments based on gene therapy for hereditary metabolic rare diseases, has raised €37.5 million in its Series A financing round from a consortium of investors led by Novartis Venture Fund and Columbus Venture Partners and including Roche Venture Fund, HealthCap, Kurma Partners and Ysios Capital. Outstanding is the fact that a project from a Spanish academic institution research center should attract so many international investors in the biotechnology sector. An injection with beneficial effects that continue for years Wilson's disease is caused by a mutation of the ATP7B gene, which is responsible for metabolizing copper. It causes this metal to accumulate in the liver and other tissues and produces hepatic and neurologic damage and potentially death. It affects one in 30,000 people worldwide. The current treatment attempts to mitigate the progress of the disease and consists of taking several pills daily for life, with great discomfort for the patient and a chronicity which implies high health care costs at a global level. "Our strategy goes to the root of the disease and tries to correct it", stated Dr. Gloria González Aseguinozala. And, "it consists in applying a single injection whose effects may last up to seven years, which is, up to now, the follow-up time of a patient treated with gene therapy". According to the researcher, the successful results in mice at an advanced stage of the disease together with the agreement with Vivet "have allowed us to optimize the VTX801 vector and its production system in order to obtain large clinical grade quantities". Once the CIMA researchers have tested the safety and effectiveness of the new drug, Vivet expects to begin the first clinical trials with VTX801 towards the end of 2018. González Aseguinozala points out that her research "has focused on Wilson's disease because it is the first for which we have satisfactory data and the possibilities of being of benefit to patients are more immediate. However, the potential of this therapeutic strategy opens the doors to other treatments with gene therapy, as, by changing the defective gene, we may be able to address diseases with a similar cause". Caption: CIMA researchers on the Vivet project. In the center, Gloria González Aseguinolaza and on the far right Jesús Hernández, a representative of FIMA and previous director general of CIMA.

Lopez B.,Center for Applied Medical Research | Querejeta R.,San Sebastián University | Gonzalez A.,Center for Applied Medical Research | Larman M.,San Sebastián University | And 2 more authors.
Hypertension | Year: 2012

We investigated whether the quality of myocardial collagen associates with elevated left-sided filling pressures in 38 hypertensive patients with stage C chronic heart failure. Filling pressures were assessed invasively measuring pulmonary capillary wedge pressure. Left ventricular chamber stiffness constant was calculated from the deceleration time of the early mitral filling wave. The fraction of myocardial volume occupied by total collagen tissue and collagen type I fibers was assessed histomorphologically. The degree of collagen cross-linking (CCL), which determines the formation of insoluble stiff collagen, was assessed by colorimetric and enzymatic procedures. The expression of lysyl oxidase (LOX), which regulates CCL, was assessed by Western blot. Compared with patients with normal pulmonary capillary wedge pressure (≤12 mm Hg; n=16), patients with elevated pulmonary capillary wedge pressure (>12 mm Hg; n=22) exhibited increases of left ventricular chamber stiffness constant, fraction of myocardial volume occupied by total collagen tissue, fraction of myocardial volume occupied by collagen type I fibers, CCL, insoluble stiff collagen, and LOX. Pulmonary capillary wedge pressure was correlated with left ventricular chamber stiffness constant (r=0.639; P<0.001), insoluble stiff collagen (r=0.474; P<0.005), CCL (r=0.625; P<0.001), and LOX (r=0.410; P<0.05) in all of the patients but not with fraction of myocardial volume occupied by total collagen tissue or fraction of myocardial volume occupied by collagen type I fibers. In addition, CCL was correlated with insoluble stiff collagen (r=0.612; P<0.005), LOX (r=0.538; P<0.01), left ventricular chamber stiffness constant (r=0.535; P<0.005), peak filling rate (r=-0.343; P<0.05), ejection fraction (r=-0.430; P<0.01), and amino-terminal propeptide of brain natriuretic peptide (r=0.421; P<0.05) in all of the patients. These associations were independent of confounding factors. These findings indicate that, in hypertensive patients with stage C heart failure, it is only the quality of collagen (ie, degree of cross-linking) that associates with elevated filling pressures. It is suggested that LOX-mediated excessive CCL facilitates the increase in left ventricular stiffness with the resulting elevation of filling pressures in these patients. © 2012 American Heart Association, Inc.

Arganda-Carreras I.,Autonomous University of Madrid | Fernandez-Gonzalez R.,Sloan Kettering Institute | Munoz-Barrutia A.,Center for Applied Medical Research | Ortiz-De-Solorzano C.,Center for Applied Medical Research
Microscopy Research and Technique | Year: 2010

In this article, we present a novel method for the automatic 3D reconstruction of thick tissue blocks from 2D histological sections. The algorithm completes a high-content (multiscale, multifeature) imaging system for simultaneous morphological and molecular analysis of thick tissue samples. This computer-based system integrates image acquisition, annotation, registration, and three-dimensional reconstruction. We present an experimental validation of this tool using both synthetic and real data. In particular, we present the 3D reconstruction of an entire mouse mammary gland and demonstrate the integration of high-resolution molecular data. © 2010 Wiley-Liss, Inc.

Larrea E.,University of Navarra | Riezu-Boj J.-I.,University of Navarra | Aldabe R.,University of Navarra | Guembe L.,Center for Applied Medical Research | And 6 more authors.
Gut | Year: 2014

Background: IL-7 and IL-15 are produced by hepatocytes and are critical for the expansion and function of CD8 T cells. IL-15 needs to be presented by IL-15Rα for efficient stimulation of CD8 T cells. Methods We analysed the hepatic levels of IL-7, IL-15, IL-15Rα and interferon regulatory factors (IRF) in patients with chronic hepatitis C (CHC) (78% genotype 1) and the role of IRF1 and IRF2 on IL-7 and IL-15Rá expression in Huh7 cells with or without hepatitis C virus (HCV) replicon. Results: Hepatic expression of both IL-7 and IL-15Rα, but not of IL-15, was reduced in CHC. These patients exhibited decreased hepatic IRF2 messenger RNA levels and diminished IRF2 staining in hepatocyte nuclei. We found that IRF2 controls basal expression of both IL-7 and IL-15Rα in Huh7 cells. IRF2, but not IRF1, is downregulated in cells with HCV genotype 1b replicon and this was accompanied by decreased expression of IL-7 and IL-15Rα, a defect reversed by overexpressing IRF2. Treating Huh7 cells with IFNα plus oncostatin M increased IL-7 and IL-15Rα mRNA more intensely than either cytokine alone. This effect was mediated by strong upregulation of IRF1 triggered by the combined treatment. Induction of IRF1, IL-7 and IL-15Rá by IFNá plus oncostatin M was dampened in replicon cells but the combination was more effective than either cytokine alone. Conclusions: HCV genotype 1 infection downregulates IRF2 in hepatocytes attenuating hepatocellular expression of IL-7 and IL-15Rα. Our data reveal a new mechanism by which HCV abrogates specific T-cell responses and point to a novel therapeutic approach to stimulate anti-HCV immunity.

News Article | February 21, 2017

Researchers at CIMA of the University of Navarra prove that the inhibition of this gene provokes a drastic reduction in the size of these tumors in different experimental models Pamplona, February 21. Researchers at the Center for Applied Medical Research (CIMA) of the University of Navarra (Spain) have identified a critical gene, FOSL1, in the development of lung and pancreatic cancer. The results of the work, a collaboration with researchers in the USA, UK, Germany and Denmark, have been published in the latest issue of the scientific journal Nature Communications. Approximately 25% of patients with lung cancer and 90% of those with pancreatic cancer show mutations in the KRAS gene, the most commonly mutated oncogene in cancer, and, at present, there are no effective therapies for these patients. Using an innovative bioinformatic application (which analyzes many series of samples from patients with different types of cancer) the CIMA researchers have identified a core of 8 genes regulated by the KRAS oncogene. From these genes, the researchers focused on FOSL1 because they found that in lung and pancreatic cancer, "patients with high-level mutations of the gene we have identified had the worst survival prognosis", explained Dr. Silve Vicent, a researcher on the CIMA Solid Tumors and Biomarkers Program and head of this research. "What is most important is that inhibition of FOSL1 brings about a great reduction in the size of the tumors in the lungs and pancreas. Thus, the results present this gene as a new molecular target to which new drugs should be directed", the researcher added. The work, which begun three years ago, has used a total of 2000 samples from patients with lung cancer, pancreatic cancer, cholangiocarcinoma, colorectal cancer and multiple myeloma, together with cell lines from human and mouse tumors and genetically- modified models. The CIMA researchers have also shown that FOSL1 affects another gene, AURKA, which, to date, had been thought to be regulated independently of the KRAS oncogene; currently clinical trials with a drug inhibiting it are currently on going. For the first time, the CIMA researchers have tested the combination of drugs against AURKA with drugs against another important gene for tumors with KRAS mutation, MEK, and have observed greater elimination of tumor cells. "This combined strategy promotes reduction of the size of tumors with mutated KRAS", Dr. Vicent stressed. "The fact that both drugs are already being used clinically is heartening as the benefits of this new treatment may reach patients within a relatively short time". "The next step will be the identification of biomarkers which respond to the combined treatment we have described. This step is critical, as not all patients with mutated KRAS are identical; therefore the type of molecular changes which characterize patients who may finally benefit from this treatment must be better defined", concluded the CIMA researcher. Caption: Dr. Vicent (center) with his team of CIMA researchers Audio: Explanation of the finding and its potential clinical application, declarations by Dr. Vicent (1'49") Images: Human lung cancer cells WITH & WITHOUT FOSL1. An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer

Pio R.,Center for Applied Medical Research | Pio R.,University of Navarra | Ajona D.,Center for Applied Medical Research | Lambris J.D.,University of Pennsylvania
Seminars in Immunology | Year: 2013

For decades, complement has been recognized as an effector arm of the immune system that contributes to the destruction of tumor cells. In fact, many therapeutic strategies have been proposed that are based on the intensification of complement-mediated responses against tumors. However, recent studies have challenged this paradigm by demonstrating a tumor-promoting role for complement. Cancer cells seem to be able to establish a convenient balance between complement activation and inhibition, taking advantage of complement initiation without suffering its deleterious effects. Complement activation may support chronic inflammation, promote an immunosuppressive microenvironment, induce angiogenesis, and activate cancer-related signaling pathways. In this context, inhibition of complement activation would be a therapeutic option for treating cancer. This concept is relatively new and deserves closer attention. In this article, we summarize the mechanisms of complement activation on cancer cells, the cancer-promoting effect of complement initiation, and the rationale behind the use of complement inhibition as a therapeutic strategy against cancer. © 2013 Elsevier Ltd.

Melero I.,Center for Applied Medical Research | Melero I.,University of Navarra | Rouzaut A.,Center for Applied Medical Research | Motz G.T.,University of Pennsylvania | And 2 more authors.
Cancer Discovery | Year: 2014

Cancer immunotherapy has great promise, but is limited by diverse mechanisms used by tumors to prevent sustained antitumor immune responses. Tumors disrupt antigen presentation, T/NK-cell activation, and T/NK-cell homing through soluble and cell-surface mediators, the vasculature, and immunosuppressive cells such as myeloid-derived suppressor cells and regulatory T cells. However, many molecular mechanisms preventing the efficacy of antitumor immunity have been identified and can be disrupted by combination immunotherapy. Here, we examine immunosuppressive mechanisms exploited by tumors and provide insights into the therapies under development to overcome them, focusing on lymphocyte traffic. © 2014 American Association for Cancer Research.

Blazquez L.,Center for Applied Medical Research | Gonzalez-Rojas S.J.,Center for Applied Medical Research | Abad A.,Center for Applied Medical Research | Abad A.,Digna Biotech | And 4 more authors.
Nucleic Acids Research | Year: 2012

Inhibition of gene expression can be achieved with RNA interference (RNAi) or U1 small nuclear RNA -snRNA -interference (U1i). U1i is based on U1 inhibitors (U1in), U1 snRNA molecules modified to inhibit polyadenylation of a target pre-mRNA. In culture, we have shown that the combination of RNAi and U1i results in stronger inhibition of reporter or endogenous genes than that obtained using either of the techniques alone. We have now used these techniques to inhibit gene expression in mice. We show that U1ins can induce strong inhibition of the expression of target genes in vivo. Furthermore, combining U1i and RNAi results in synergistic inhibitions also in mice. This is shown for the inhibition of hepatitis B virus (HBV) sequences or endogenous Notch1. Surprisingly, inhibition obtained by combining a U1in and a RNAi mediator is higher than that obtained by combining two U1ins or two RNAi mediators. Our results suggest that RNAi and U1i cooperate by unknown mechanisms to result in synergistic inhibitions. Analysis of toxicity and specificity indicates that expression of U1i inhibitors is safe. Therefore, we believe that the combination of RNAi and U1i will be a good option to block damaging endogenous genes, HBV and other infectious agents in vivo. © 2011 The Author(s).

Enguita-German M.,Center for Applied Medical Research | Fortes P.,Center for Applied Medical Research
World Journal of Hepatology | Year: 2014

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Only 30%-40% of the patients with HCC are eligible for curative treatments, which include surgical resection as the first option, liver transplantation and percutaneous ablation. Unfortunately, there is a high frequency of tumor recurrence after surgical resection and most HCC seem resistant to conventional chemotherapy and radiotherapy. Sorafenib, a multi-tyrosine kinase inhibitor, is the only chemotherapeutic option for patients with advanced hepatocellular carcinoma. Patients treated with Sorafenib have a significant increase in overall survival of about three months. Therefore, there is an urgent need to develop alternative treatments. Due to its role in cell growth and development, the insulin-like growth factor system is commonly deregulated in many cancers. Indeed, the insulin-like growth factor (IGF) axis has recently emerged as a potential target for hepatocellular carcinoma treatment. To this aim, several inhibitors of the pathway have been developed such as monoclonal antibodies, small molecules, antisense oligonucleotides or small interfering RNAs. However recent studies suggest that, unlike most tumors, HCC development requires increased signaling through insulin growth factor II rather than insulin growth factor I. This may have great implications in the future treatment of HCC. This review summarizes the role of the IGF axis in liver carcinogenesis and the current status of the strategies designed to target the IGF-I signaling pathway for hepatocellular carcinoma treatment. © 2014 Baishideng Publishing Group Inc.

Malumbres R.,Center for Applied Medical Research
Methods in molecular biology (Clifton, N.J.) | Year: 2010

In this chapter, we provide a review on the functions of the most important miRNAs in lymphocytes. Most of them are involved in lymphopoiesis, immune response, and lymphoid malignancies, highlighting the importance of miRNAs in these cells.

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