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Líneas de Investigación
- Terapia génica enfermedades hereditarias hepáticas
- Terapia génica enfermedades hereditarias neurodegenerativas
- Terapia génica enfermedades renales
Palabras Clave
- AAV
- Adenovirus
- Enfermedades raras
- Terapia génica
Publicaciones Científicas desde 2018
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Autores: Fernández Montero, Alejandro; Zuaznabar Martinez, Jon; Pina Sanchez, Manuel; et al.Revista: FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGYISSN: 2235-2988 Vol.13 2023 págs. 1110467ResumenBackground: The main objective was to evaluate the efficacy of intranasal photodynamic therapy (PDT) in SARS-CoV-2 mildly symptomatic carriers on decreasing the infectivity period. SARS-CoV-2-specific immune-stimulating effects and safety were also analysed. Methods: We performed a randomized, placebo-controlled, clinical trial in a tertiary hospital (NCT05184205). Patients with a positive SARS-CoV-2 PCR in the last 48 hours were recruited and aleatorily assigned to PDT or placebo. Patients with pneumonia were excluded. Participants and investigators were masked to group assignment. The primary outcome was the reduction in in vitro infectivity of nasopharyngeal samples at days 3 and 7. Additional outcomes included safety assessment and quantification of humoral and T-cell immune-responses. Findings: Patients were recruited between December 2021 and February 2022. Most were previously healthy adults vaccinated against COVID-19 and most carried Omicron variant. 38 patients were assigned to placebo and 37 to PDT. Intranasal PDT reduced infectivity at day 3 post-treatment when compared to placebo with a ß-coefficient of -812.2 (CI95%= -478660 ¿ -1.3, p<0.05) infectivity arbitrary units. The probability of becoming PCR negative (ct>34) at day 7 was higher on the PDT-group, with an OR of 0.15 (CI95%=0.04-0.58). There was a decay in anti-Spike titre and specific SARS-CoV-2 T cell immunity in the placebo group 10 and 20 weeks after infection, but not in the PDT-group. No serious adverse events were reported. Interpretation: Intranasal-PDT is safe in pauci-symptomatic COVID-19 patients, it reduces SARS-CoV-2 infectivity and decelerates the decline SARS-CoV-2 specific immune-responses.
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Autores: Zabaleta, N.; Torella, Laura; Weber, N. D.; et al.Revista: HEPATOLOGYISSN: 0270-9139 Vol.76 N° 3 2022 págs. 869 - 887ResumenThe efficient delivery of RNA molecules to restore the expression of a missing or inadequately functioning protein in a target cell and the intentional specific modification of the host genome using engineered nucleases represent therapeutic concepts that are revolutionizing modern medicine. The initiation of several clinical trials using these approaches to treat metabolic liver disorders as well as the recently reported remarkable results obtained by patients with transthyretin amyloidosis highlight the advances in this field and show the potential of these therapies to treat these diseases safely and efficaciously. These advances have been possible due, firstly, to significant improvements made in RNA chemistry that increase its stability and prevent activation of the innate immune response and, secondly, to the development of very efficient liver-targeted RNA delivery systems. In parallel, the breakout of CRISPR/CRISPR-associated 9-based technology in the gene editing field has marked a turning point in in vivo modification of the cellular genome with therapeutic purposes, which can be based on gene supplementation, correction, or silencing. In the coming years we are likely to witness the therapeutic potential of these two strategies both separately and in combination. In this review we summarize the preclinical data obtained in animal models treated with mRNA as a therapeutic agent and discuss the different gene editing strategies applied to the treatment of liver diseases, highlighting both their therapeutic efficacy as well as safety concerns.
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Autores: Martinez Garcia, Javier; Molina Delgado, Angie; González Aseguinolaza, Gloria; et al.Revista: BIOMEDICINESISSN: 2227-9059 Vol.10 N° 6 2022 págs. 1238ResumenCholestatic diseases can be caused by the dysfunction of transporters involved in hepatobiliary circulation. Although pharmacological treatments constitute the current standard of care for these diseases, none are curative, with liver transplantation being the only long-term solution for severe cholestasis, albeit with many disadvantages. Liver-directed gene therapy has shown promising results in clinical trials for genetic diseases, and it could constitute a potential new therapeutic approach for cholestatic diseases. Many preclinical gene therapy studies have shown positive results in animal models of both acquired and genetic cholestasis. The delivery of genes that reduce apoptosis or fibrosis or improve bile flow has shown therapeutic effects in rodents in which cholestasis was induced by drugs or bile duct ligation. Most studies targeting inherited cholestasis, such as progressive familial intrahepatic cholestasis (PFIC), have focused on supplementing a correct version of a mutated gene to the liver using viral or non-viral vectors in order to achieve expression of the therapeutic protein. These strategies have generated promising results in treating PFIC3 in mouse models of the disease. However, important challenges remain in translating this therapy to the clinic, as well as in developing gene therapy strategies for other types of acquired and genetic cholestasis.
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Autores: Weber, N. D. (Autor de correspondencia); Martinez Garcia, Javier; González Aseguinolaza, GloriaRevista: JOURNAL OF HEPATOLOGY (ONLINE)ISSN: 0168-8278 Vol.76 N° 3 2022 págs. 749 - 751
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Autores: Bazo Ochoa, Andrea; Lantero, A.; Mauleón Mayora, Itsaso; et al.Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCESISSN: 1422-0067 Vol.23 N° 23 2022 págs. 14940ResumenCitrullinemia type I (CTLN1) is a rare autosomal recessive disorder caused by mutations in the gene encoding argininosuccinate synthetase 1 (ASS1) that catalyzes the third step of the urea cycle. CTLN1 patients suffer from impaired elimination of nitrogen, which leads to neurotoxic levels of circulating ammonia and urea cycle byproducts that may cause severe metabolic encephalopathy, death or irreversible brain damage. Standard of care (SOC) of CTLN1 consists of daily nitrogen-scavenger administration, but patients remain at risk of life-threatening decompensations. We evaluated the therapeutic efficacy of a recombinant adeno-associated viral vector carrying the ASS1 gene under the control of a liver-specific promoter (VTX-804). When administered to three-week-old CTLN1 mice, all the animals receiving VTX-804 in combination with SOC gained body weight normally, presented with a normalization of ammonia and reduction of citrulline levels in circulation, and 100% survived for 7 months. Similar to what has been observed in CTLN1 patients, CTLN1 mice showed several behavioral abnormalities such as anxiety, reduced welfare and impairment of innate behavior. Importantly, all clinical alterations were notably improved after treatment with VTX-804. This study demonstrates the potential of VTX-804 gene therapy for future clinical translation to CTLN1 patients.
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Autores: Mitxelena Iribarren, Oihane (Autor de correspondencia); Mondragón, B.; Pérez Lorenzo, Eva; et al.Revista: MATERIALS TODAY COMMUNICATIONSISSN: 2352-4928 Vol.31 2022 págs. 103690ResumenDue to the COVID19 pandemic, solutions to automate disinfection using UV-C combined with mobile robots are beginning to be explored. It has been proved that the use of these systems highly reduces the risk of contagion. However, its use in real applications is not being as rapid as it needs to be. One of the main market input barriers is the fear of degrading facilities. For this reason, it is crucial to perform a detailed study on the degradation effect of UV-C light on inert materials. This experimental study proves that, considering exposition times equivalent to several work years in hospital rooms, only the appearance of the material is affected, but not their mechanical functionalities. This relevant result could contribute to accelerate the deployment of these beneficial disinfection technologies. For that purpose, a colorimetry test, tensile strength test, and analysis of the surface microstructure were carried out. The results showed that polymers tend to turn yellow, while fabrics lose intensity depending on the color. Red is hardly affected by UV-C, but blue and green are. Thus, this study contributes to the identification of the best materials and colors to be used in rooms subjected to disinfection processes. In addition, it is shown how the surface microstructure of the materials is altered in most of the materials, but not the tensile strength of the fabrics.
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Autores: Ros-Ganan, I.; Hommel, Mirja; Trigueros-Motos, L.; et al.Revista: CLINICAL & TRANSLATIONAL IMMUNOLOGYISSN: 2050-0068 Vol.11 N° 2 2022 págs. e1375ResumenObjective. Pre-existing neutralising antibodies (NAbs) to adeno-associated viruses (AAVs) remain an impediment for systemically administered AAV-mediated gene therapy treatment in many patients, and various strategies are under investigation to overcome this limitation. Here, IgG-degrading enzymes (Ides) derived from bacteria of the genus Streptococcus were tested for their ability to cleave human IgG and allow AAV-mediated transduction in individuals with pre-existing NAbs. Methods. Cleavage activity of three different Ides was evaluated in vitro in serum from different species. Passively immunised mice or non-human primates (NHP) with naturally occurring anti-AAV NAbs were used to define the optimal IdeS dose and administration window for AAVAnc80 and AAV8 vectors in mice and AAV3B in NHPs. Results. The selected candidate, IdeS, was found to be highly efficient at cleaving human IgG, less efficient against NHP IgG and inefficient against mouse IgG. In vivo, we observed differences in how IdeS affected liver transduction in the presence of NAbs depending on the AAV serotype. For AAVAnc80 and AAV3B, the best transduction levels were achieved when the vector was administered after IgG digestion products were cleared from circulation. However, for AAV8 we only observed a modest and transient inhibition of transduction by IdeS cleavage products. Conclusion. Preconditioning with IdeS represents a unique treatment opportunity for patients primarily excluded from participation in gene therapy clinical trials because of elevated circulating anti-AAV NAb levels. However, careful determination of the optimal IdeS dose and timing for the administration of each AAV serotype is essential for optimal transduction.
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Autores: Martinez Garcia, Javier; Molina González, Manuela; Odriozola Moncayola, Leticia; et al.Revista: CELL & BIOSCIENCEISSN: 2045-3701 Vol.12 N° 1 2022 págs. 79ResumenBackground Bile acid (BA) homeostasis is mainly regulated by bile salt excretory pump (BSEP), a hepatocyte transporter that transfers BAs to the bile. BSEP expression is regulated by BA levels through activation of farnesoid X receptor transcription factor, which binds to the inverted repeat (IR-1) element in the BSEP promoter. Gene therapy of cholestatic diseases could benefit from using vectors carrying endogenous promoters physiologically regulated by BAs, however their large size limits this approach, especially when using adeno-associated viral vector (AAV) vectors. Results We evaluated the functionality and BA-mediated regulation of minimal versions of human and mouse BSEP promoters containing IR-1 using AAV vectors expressing luciferase. Unexpectedly, a minimal mouse BSEP promoter (imPr) showed higher BA-mediated expression and inducibility than a minimal human promoter (ihPr) or than full-length BSEP promoters in human hepatic cells. In addition, in mice receiving an AAV8 vector carrying imPr promoter-driven luciferase expression was efficiently regulated by administration of a BA-enriched diet. Interestingly, this vector also expressed significantly higher luciferase levels in Abcb4(-/-) mice, which have high levels of BAs, compared to wild type mice, or to mice receiving a vector containing the luciferase gene downstream of the constitutive alpha-1 antitrypsin promoter. In contrast, the AAV vector containing ihPr showed very low luciferase expression with no inducibility. Finally, we optimized imPr by adding three IR-1 repeats at its 5 ' end. This new promoter provided higher levels of luciferase than imPr both in vitro and in vivo. Conclusions The imPr could represent a useful tool for gene therapy approaches in which physiological BA regulation is desired.
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Autores: Olague Micheltorena, María Cristina; Mitxelena Iribarren, Oihane; Sierra-García, J.E.; et al.Revista: JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGYISSN: 2666-4690 Vol.11 2022 págs. 100138 - *ResumenSARS-CoV-2 is responsible for the COVID-19 pandemic, which has caused almost 570 million infections and over six million deaths worldwide. To help curb its spread, solutions using ultraviolet light (UV) for quick virus inactivation inside buildings without human intervention could be very useful to reduce chances of contagion. The UV dose must be sufficient to inactivate the virus considering the different materials in the room, but it should not be too high, not to degrade the environment. In the present study, we have analyzed the ability of a 254nm wavelength UV-C lamp to inactivate dried samples of SARS-CoV-2 exposed at a distance of two meters, simulating a full-scale scenario. Our results showed that virus inactivation was extremely efficient in most tested materials, which included plastic, metal, wood, and textile, with a UV-C exposure of only 42s (equivalent to 10mJ/cm2). However, porous materials like medium density fibreboard, were hard to decontaminate, indicating that they should be avoided in hospital rooms and public places.
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Autores: Pacin-Ruiz, B.; Cortese, M. F. (Autor de correspondencia); Tabernero, D. (Autor de correspondencia); et al.Título: Inspecting the ribozyme region of hepatitis delta virus genotype 1: conservation and variabilityRevista: VIRUSES-BASELISSN: 1999-4915 Vol.14 N° 2 2022 págs. 215ResumenThe hepatitis delta virus (HDV) genome has an autocatalytic region called the ribozyme, which is essential for viral replication. The aim of this study was to use next-generation sequencing (NGS) to analyze the ribozyme quasispecies (QS) in order to study its evolution and identify highly conserved regions potentially suitable for a gene-silencing strategy. HDV RNA was extracted from 2 longitudinal samples of chronic HDV patients and the ribozyme (nucleotide, nt 688-771) was analyzed using NGS. QS conservation, variability and genetic distance were analyzed. Mutations were identified by aligning sequences with their specific genotype consensus. The main relevant mutations were tested in vitro. The ribozyme was conserved overall, with a hyper-conserved region between nt 715-745. No difference in QS was observed over time. The most variable region was between nt 739-769. Thirteen mutations were observed, with three showing a higher frequency: T23C, T69C and C64 deletion. This last strongly reduced HDV replication by more than 1 log in vitro. HDV Ribozyme QS was generally highly conserved and was maintained during follow-up. The most conserved portion may be a valuable target for a gene-silencing strategy. The presence of the C64 deletion may strongly impair viral replication, as it is a potential mechanism of viral persistence.
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Autores: Murillo Sauca, Oihana; Collantes Martínez, María; Gazquez López, Cristina; et al.Revista: MOLECULAR THERAPY. METHODS & CLINICAL DEVELOPMENTISSN: 2329-0501 Vol.9 N° 26 2022 págs. 98 - 106ResumenWilson's disease (WD) is an inherited disorder of copper metabolism associated with mutations in ATP7B gene. We have shown that the administration of an adeno-associated vector (AAV) encoding a mini version of human ATP7B (VTX-801) provides long-term correction of copper metabolism in a murine WD model. In preparation of a future clinical trial, we have evaluated by positron emission tomography (PET) the value of 64Cu biodistribution, excretion pattern, and blood kinetics as pharmacodynamic biomarkers of VTX-801 effects. Six-week-old WD mice were injected intravenously with increasing doses of VTX-801 and 3 weeks or 3 months later with [64Cu]CuCl2. Untreated WD and wild-type (WT) mice were included as controls. Control WD mice showed increased hepatic 64Cu retention, reduced fecal excretion of the radiotracer, and altered 64Cu blood kinetics (BK) compared with WT mice. VTX-801 treatment in WD mice resulted in a significant reduction of hepatic 64Cu accumulation, the restoration of fecal 64Cu excretion, and the correction of 64Cu BK. This study showed that VTX-801 restores physiological copper metabolism in WD mice, confirming the mechanism of action of VTX-801, and demonstrated the translational potential of [64Cu]CuCl2-PET to explore VTX-801 pharmacodynamics in a minimally invasive and sensitive manner in WD patients.
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Autores: Kronborg Hansen, A. K.; Dubik, M.; Marczynska, J.; et al.Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCESISSN: 1422-0067 Vol.23 N° 19 2022 págs. 11292ResumenType I interferons (IFN), including IFN beta, play a protective role in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Type I IFNs are induced by the stimulation of innate signaling, including via cytoplasmic RIG-I-like receptors. In the present study, we investigated the potential effect of a chimeric protein containing the key domain of RIG-I signaling in the production of CNS endogenous IFN beta and asked whether this would exert a therapeutic effect against EAE. We intrathecally administered an adeno-associated virus vector (AAV) encoding a fusion protein comprising RIG-I 2CARD domains (C) and the first 200 amino acids of mitochondrial antiviral-signaling protein (MAVS) (M) (AAV-CM). In vivo imaging in IFN beta/luciferase reporter mice revealed that a single intrathecal injection of AAV-CM resulted in dose-dependent and sustained IFN beta expression within the CNS. IFN beta expression was significantly increased for 7 days. Immunofluorescent staining in IFN beta-YFP reporter mice revealed extraparenchymal CD45+ cells, choroid plexus, and astrocytes as sources of IFN beta. Moreover, intrathecal administration of AAV-CM at the onset of EAE induced the suppression of EAE, which was IFN-I-dependent. These findings suggest that accessing the signaling pathway downstream of RIG-I represents a promising therapeutic strategy for inflammatory CNS diseases, such as MS.
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Autores: Silva Pilipich, Noelia Romina; Lasarte-Cía, A.; Lozano Moreda, Teresa; et al.Revista: MOLECULAR THERAPY - NUCLEIC ACIDSISSN: 2162-2531 Vol.29 2022 págs. 387 - 399ResumenAlphavirus vectors based on self-amplifying RNA (saRNA) generate high and transient levels of transgene expression and induce innate immune responses, making them an interesting tool for antitumor therapy. These vectors are usually delivered as viral particles, but it is also possible to administer them as RNA. We evaluated this possibility by invivo electroporation of Semliki Forest virus (SFV) saRNA for local treatment of murine colorectal MC38 subcutaneous tumors. Optimization of saRNA electroporation conditions in tumors was performed using an SFV vector coding for luciferase. Then we evaluated the therapeutic potential of this approach using an SFV saRNA coding for interleukin-12 (SFV-IL-12), a proinflammatory cytokine with potent antitumor effects. Delivery of SFV-IL-12 saRNA by electroporation led to improvement in tumor control and higher survival compared with mice treated with electroporation or with SFV-IL-12 saRNA alone. The antitumor efficacy of SFV-IL-12 saRNA electroporation increased by combination with systemic PD-1 blockade. This therapy, which was also validated in a hepatocellular carcinoma tumor model, suggests that local delivery of saRNA by electroporation could be an attractive strategy for cancer immunotherapy. This approach could have easy translation to the clinical practice, especially for percutaneously accessible tumors.
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Autores: Milagros, S.; Uribarri, A.; Castro, C.; et al.Revista: HUMAN GENE THERAPYISSN: 1043-0342 Vol.33 N° 23-24 2022 págs. A48 - A48
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Autores: Motos, L. T.; Ros-Ganan, I.; Hommel, Mirja; et al.Revista: MOLECULAR THERAPYISSN: 1525-0016 Vol.30 N° 4 2022 págs. 528 - 528ResumenObjective: Pre-existing neutralising antibodies (NAbs) to adeno-associated viruses (AAVs) remain an impediment for systemically administered AAV-mediated gene therapy treatment in many patients, and various strategies are under investigation to overcome this limitation. Here, IgG-degrading enzymes (Ides) derived from bacteria of the genus Streptococcus were tested for their ability to cleave human IgG and allow AAV-mediated transduction in individuals with pre-existing NAbs. Methods: Cleavage activity of three different Ides was evaluated in vitro in serum from different species. Passively immunised mice or non-human primates (NHP) with naturally occurring anti-AAV NAbs were used to define the optimal IdeS dose and administration window for AAVAnc80 and AAV8 vectors in mice and AAV3B in NHPs. Results: The selected candidate, IdeS, was found to be highly efficient at cleaving human IgG, less efficient against NHP IgG and inefficient against mouse IgG. In vivo, we observed differences in how IdeS affected liver transduction in the presence of NAbs depending on the AAV serotype. For AAVAnc80 and AAV3B, the best transduction levels were achieved when the vector was administered after IgG digestion products were cleared from circulation. However, for AAV8 we only observed a modest and transient inhibition of transduction by IdeS cleavage products. Conclusion: Preconditioning with IdeS represents a unique treatment opportunity for patients primarily excluded from participation in gene therapy clinical trials because of elevated circulating anti-AAV NAb levels. However, careful determination of the optimal IdeS dose and timing for the administration of each AAV serotype is essential for optimal transduction.
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Autores: Klermund, J.; Loiacono, L.; Torella, Laura; et al.Revista: HUMAN GENE THERAPYISSN: 1043-0342 Vol.33 N° 23-24 2022 págs. A6 - A7
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Autores: Saande, Cassondra Jeanette; Bazo Ochoa, Andrea; Fernández-Huarte, L.; et al.Revista: HUMAN GENE THERAPYISSN: 1043-0342 Vol.33 N° 23-24 2022 págs. A179 - A179
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Autores: Pacin-Ruiz, B.; Camps Ramón, Gracián; Cortese, M. F.; et al.Revista: JOURNAL OF HEPATOLOGY (ONLINE)ISSN: 0168-8278 Vol.77 N° S1 2022 págs. S257 - S258
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Autores: Camps Ramón, Gracián; Maestro Galilea, Sheila; Usai, C.; et al.Revista: JOURNAL OF HEPATOLOGY (ONLINE)ISSN: 0168-8278 Vol.77 N° Suppl. 1 2022 págs. S248 - S248
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Autores: Torella, Laura; Tamayo Uria, Ibon; Vales, A.; et al.Revista: MOLECULAR THERAPYISSN: 1525-0016 Vol.30 N° 4 2022 págs. 211 - 211
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Autores: Molina Delgado, Angie; Odriozola Moncayola, Leticia; Trigueros-Motos, L.; et al.Revista: MOLECULAR THERAPYISSN: 1525-0016 Vol.30 N° 4 2022 págs. 524 - 525
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Autores: Weber, N. D.; Odriozola Moncayola, Leticia; Gazquez López, Cristina; et al.Revista: HUMAN GENE THERAPYISSN: 1043-0342 Vol.33 N° 23-24 2022 págs. A54 - A55
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Autores: González-de Zarate, A.; Covo-Vergara, A.; Igea-Sucunza, A.; et al.Revista: HUMAN GENE THERAPYISSN: 1043-0342 Vol.33 N° 23-24 2022 págs. A185 - A186
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Autores: Tamarit, B.; González Aseguinolaza, Gloria; Brossel, A.; et al.Título: Safety and biodistribution of VTX-801, an AAV3B gene therapy vector, in healthy cynomolgus monkeysRevista: MOLECULAR THERAPYISSN: 1525-0016 Vol.30 N° 4 2022 págs. 592 - 592
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Autores: Maestro Galilea, Sheila; Weber, N. D.; Zabaleta, N.; et al.Revista: JHEP REPORTSISSN: 2589-5559 Vol.3 N° 4 2021 págs. 100300ResumenGene therapy is becoming an increasingly valuable tool to treat many genetic diseases with no or limited treatment options. This is the case for hundreds of monogenic metabolic disorders of hepatic origin, for which liver transplantation remains the only cure. Furthermore, the liver contains 10-15% of the body's total blood volume, making it ideal for use as a factory to secrete proteins into the circulation. In recent decades, an expanding toolbox has become available for liver-directed gene delivery. Although viral vectors have long been the preferred approach to target hepatocytes, an increasing number of non-viral vectors are emerging as highly efficient vehicles for the delivery of genetic material. Herein, we review advances in gene delivery vectors targeting the liver and more specifically hepatocytes, covering strategies based on gene addition and gene editing, as well as the exciting results obtained with the use of RNA as a therapeutic molecule. Moreover, we will briefly summarise some of the limitations of current liver-directed gene therapy approaches and potential ways of overcoming them.
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Autores: Cartón García, Fernando; Saande, Cassondra Jeanette; Meraviglia-Crivelli, D.; et al.Revista: BIOMEDICINESISSN: 2227-9059 Vol.9 N° 3 2021 págs. 303ResumenThe global burden of chronic kidney disease (CKD) is increasing every year and represents a great cost for public healthcare systems, as the majority of these diseases are progressive. Therefore, there is an urgent need to develop new therapies. Oligonucleotide-based drugs are emerging as novel and promising alternatives to traditional drugs. Their expansion corresponds with new knowledge regarding the molecular basis underlying CKD, and they are already showing encouraging preclinical results, with two candidates being evaluated in clinical trials. However, despite recent technological advances, efficient kidney delivery remains challenging, and the presence of off-targets and side-effects precludes development and translation to the clinic. In this review, we provide an overview of the various oligotherapeutic strategies used preclinically, emphasizing the most recent findings in the field, together with the different strategies employed to achieve proper kidney delivery. The use of different nanotechnological platforms, including nanocarriers, nanoparticles, viral vectors or aptamers, and their potential for the development of more specific and effective treatments is also outlined.
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Autores: Silva Pilipich, Noelia Romina; Smerdou Picazo, Cristian (Autor de correspondencia); Vanrell, L. (Autor de correspondencia)Revista: MICROORGANISMSISSN: 2076-2607 Vol.9 N° 9 2021 págs. 1956ResumenNanobodies are camelid-derived single-domain antibodies that present some advantages versus conventional antibodies, such as a smaller size, and higher tissue penetrability, stability, and hydrophilicity. Although nanobodies can be delivered as proteins, in vivo expression from adeno-associated viral (AAV) vectors represents an attractive strategy. This is due to the fact that AAV vectors, that can provide long-term expression of recombinant genes, have shown an excellent safety profile, and can accommodate genes for one or several nanobodies. In fact, several studies showed that AAV vectors can provide sustained nanobody expression both locally or systemically in preclinical models of human diseases. Some of the pathologies addressed with this technology include cancer, neurological, cardiovascular, infectious, and genetic diseases. Depending on the indication, AAV-delivered nanobodies can be expressed extracellularly or inside cells. Intracellular nanobodies or "intrabodies" carry out their function by interacting with cell proteins involved in disease and have also been designed to help elucidate cellular mechanisms by interfering with normal cell processes. Finally, nanobodies can also be used to retarget AAV vectors, when tethered to viral capsid proteins. This review covers applications in which AAV vectors have been used to deliver nanobodies, with a focus on their therapeutic use.
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Autores: González Aseguinolaza, Gloria (Autor de correspondencia); Izeta, A.; Martín Molina, F.Revista: HUMAN GENE THERAPYISSN: 1043-0342 Vol.32 N° 23-24 2021 págs. 1425 - 1426
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Autores: Pérez Iturralde, Andrea; Carte Abad, Beatriz; Aldabe Arregui, Rafael (Autor de correspondencia)Revista: HUMAN GENE THERAPYISSN: 1043-0342 Vol.32 N° 19 - 20 2021 págs. 1242 - 1250ResumenThe efficiency of recombinant adeno-associated virus (AAV) vectors transducing host cells is very low, limiting their therapeutic potential in patients. There are several cellular pathways interacting and interfering with the journey of the AAV from the cell surface to the nucleus, opening the possibility to enhance AAV transduction by modifying these interactions. In this study, we explored the results of AAV hepatic transduction when different mammalian target of rapamycin (mTOR) inhibitors, rapamycin, MLN0128, RapaLink-1, were used in preconditioned juvenile and adult mice. We confirmed rapamycin as an AAV hepatic transduction enhancer in juvenile and adult mice; however, RapaLink-1, a stronger mTOR inhibitor and a clear hepatic autophagy inducer, had no positive effect. Moreover, MLN0128 reduced AAV hepatic transduction. Therefore, our results show a complex interaction between the mTOR pathway and AAV-mediated hepatic transduction and indicate that mTOR inhibition is not a straightforward strategy for improving AAV transduction. More studies are necessary to elucidate the molecular mechanisms involved in the positive and negative effects of mTOR inhibitors on AAV transduction efficiency.</p>
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Autores: Casales Zoco, Erkuden; Martisová, Eva; Villanueva, H.; et al.Revista: SCIENTIFIC REPORTSISSN: 2045-2322 Vol.11 N° 1 2021 págs. 21427ResumenA promising therapy for patients with B-cell lymphoma is based on vaccination with idiotype monoclonal antibodies (mAbs). Since idiotypes are different in each tumor, a personalized vaccine has to be produced for each patient. Expression of immunoglobulins with appropriate post-translational modifications for human use often requires the use of stable mammalian cells that can be scaled-up to reach the desired level of production. We have used a noncytopathic self-amplifying RNA vector derived from Semliki Forest virus (ncSFV) to generate BHK cell lines expressing murine follicular lymphoma-derived idiotype A20 mAb. ncSFV/BHK cell lines expressed approximately 2 mg/L/24 h of A20 mAb with proper quaternary structure and a glycosylation pattern similar to that of A20 mAb produced by hybridoma cells. A20 mAb purified from the supernatant of a ncSFV cell line, or from the hybridoma, was conjugated to keyhole limpet hemocyanin and used to immunize Balb/c mice by administration of four weekly doses of 25 mu g of mAb. Both idiotype mAbs were able to induce a similar antitumor protection and longer survival compared to non-immunized mice. These results indicate that the ncSFV RNA vector could represent a quick and efficient system to produce patient-specific idiotypes with potential application as lymphoma vaccines.
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Autores: Rodríguez García, Estefanía; Zabaleta Lasarte, Nerea; Gil Fariña, Irene; et al.Revista: JOURNAL OF IMMUNOLOGYISSN: 0022-1767 Vol.206 N° 2 2021 págs. 376 - 385ResumenSeveral dinucleotide cyclases, including cyclic GMP-AMP synthase, and their involvement in STING-mediated immunity have been extensively studied. In this study, we tested five bacterial diguanylate cyclases from the Gram-negative bacterium Salmonella Enteritidis, identifying AdrA as the most potent inducer of a STING-mediated IFN response. AdrA wild-type (wt) or its inactive version AdrA mutant (mut) were delivered by an adenovirus (Ad) vector. Dendritic cells obtained from wt mice and infected in vitro with Ad vector containing AdrA wt, but not mut, had increased activation markers and produced large amounts of several immunostimulatory cytokines. For dendritic cells derived from STING-deficient mice, no activation was detected. The potential antiviral activity of AdrAwas addressed in hepatitis B virus (HBV)-transgenic and adenovirus-associated virus (AAV)-HBV mouse models. Viremia in serum of Ad AdrAwt-treatedmice was reduced significantly compared with that in Ad AdrA mut-injected mice. The viral load in the liver at sacrifice was in line with this finding. To further elucidate the molecular mechanism(s) by which AdrA confers its antiviral function, the response in mice deficient in STING or its downstream effector molecules was analyzed. wt and IFN-alpha R (IFNAR)(-/-) animals were additionally treated with anti- TNF-alpha (Enbrel). Interestingly, albeit less pronounced than in wt mice, in IFNAR(-/-) and Enbrel-treated wt mice, a reduction of serum viremia was achieved-an observation that was lost in anti-TNF-alpha-treated IFNAR(-/-) animals. No effect of AdrA wt was seen in STING- deficient animals. Thus, although STING is indispensable for the antiviral activity of AdrA, type I IFN and TNF-alpha are both required and act synergistically.
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Autores: Nistal-Villán, E. (Autor de correspondencia); Argemí Ballbé, José María; de Jaime Soguero, A.; et al.Revista: HUMAN GENE THERAPYISSN: 1043-0342 Vol.32 N° 7-8 2021 págs. 341 - 348ResumenTight control of transgene expression is key to ensure the efficacy of a wide range of gene therapy interventions, in which the magnitude and duration of gene expression have to be adjusted to therapeutic needs, thereby limiting secondary effects. The development of upgraded strategies to link transgene expression to pathological stress episodes is an unmet need in gene therapy. Here, we propose an expression strategy that associates transgene expression to an intracellular stress coping mechanism, the unfolded protein response. Specifically, we harnessed the cis elements required to sustain the noncanonical splicing of X-box binding protein 1 (XBP1) messenger RNA (mRNA) in response to the dysfunction of the endoplasmic reticulum (ER), a situation commonly known as ER stress, to drive the expression of heterologous genes. Since ER stress features a wide variety of pathological conditions, including viral infections, cancer, or metabolic disorders, this new expression module stimulates the synthesis of therapeutic genes as a response to cellular damage, and ensures their expression only when necessary. Validation of this inducible expression system was performed in vitro and in vivo, and its potential to limit/inhibit viral infections has been shown in proof-of principle experiments.
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Autores: Kaiser, R. A.; Weber, N. D.; Trigueros-Motos, L.; et al.Revista: JOURNAL OF INHERITED METABOLIC DISEASEISSN: 0141-8955 Vol.44 N° 6 2021 págs. 1369 - 1381ResumenPhenylketonuria (PKU) is the most common inborn error of metabolism of the liver, and results from mutations of both alleles of the phenylalanine hydroxylase gene (PAH). As such, it is a suitable target for gene therapy via gene delivery with a recombinant adeno-associated virus (AAV) vector. Here we use the synthetic AAV vector Anc80 via systemic administration to deliver a functional copy of a codon-optimized human PAH gene, with or without an intron spacer, to the Pah(enu2) mouse model of PKU. Dose-dependent transduction of the liver and expression of PAH mRNA were present with both vectors, resulting in significant and durable reduction of circulating phenylalanine, reaching near control levels in males. Coat color of treated Pah(enu2) mice reflected an increase in pigmentation from brown to the black color of control animals, further indicating functional restoration of phenylalanine metabolism and its byproduct melanin. There were no adverse effects associated with administration of AAV up to 5 x 10(12) VG/kg, the highest dose tested. Only minor and/or transient variations in some liver enzymes were observed in some of the AAV-dosed animals which were not associated with pathology findings in the liver. Finally, there was no impact on cell turnover or apoptosis as evaluated by Ki-67 and TUNEL staining, further supporting the safety of this approach. This study demonstrates the therapeutic potential of AAV Anc80 to safely and durably cure PKU in a mouse model, supporting development for clinical consideration.
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Autores: Weber, N. D.; Odriozola Moncayola, Leticia; Bouquet, C.; et al.Revista: MOLECULAR THERAPYISSN: 1525-0016 Vol.29 N° 4 2021 págs. 245 - 245
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Autores: Bazo Ochoa, Andrea; Lantero, A.; Mauleón Mayora, Itsaso; et al.Revista: MOLECULAR THERAPYISSN: 1525-0016 Vol.29 N° 4 Supl. 1 2021 págs. 254 - 255
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Autores: Bazo Ochoa, Andrea; Lantero, A.; Neri, L.; et al.Revista: HUMAN GENE THERAPYISSN: 1043-0342 Vol.32 N° 19-20 2021 págs. A105 - A105
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Autores: Weber, N. D.; Salas Gómez, David; Odriozola Moncayola, Leticia; et al.Revista: MOLECULAR THERAPYISSN: 1525-0016 Vol.29 N° 4 2021 págs. 14 - 15
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Autores: Martinez Garcia, Javier; Molina González, Manuela; Odriozola Moncayola, Leticia; et al.Revista: HUMAN GENE THERAPYISSN: 1043-0342 Vol.32 N° 19-20 2021 págs. A105
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Autores: Palmeiro, E. B.; Ibáñez, M.; Hernández Sáez, Carlos; et al.Revista: ANNALS OF ONCOLOGYISSN: 0923-7534 Vol.32 N° Supl. 5 2021 págs. S368 - S368
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Autores: Lumbreras Roche, Sara; Ricobaraza Abarquero, Ana; Baila-Rueda, L.; et al.Revista: HUMAN GENE THERAPYISSN: 1043-0342 Vol.32 N° 19-20 2021 págs. A105 - A106
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Autores: Torella, Laura; Tamayo Uria, Ibon; Vales Aranguren, África; et al.Revista: HUMAN GENE THERAPYISSN: 1043-0342 Vol.32 N° 19-20 2021 págs. A16
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Autores: Ballesteros Briones, M. C. ; Silva Pilipich, Noelia Romina; Herrador Cañete, Guillermo; et al.Revista: CURRENT OPINION IN VIROLOGYISSN: 1879-6257 Vol.44 2020 págs. 145 - 153ResumenDNA or mRNA vaccines have potential advantages over conventional vaccines since they are easier to manufacture and have higher safety profiles. In particular, self-amplifying RNA (saRNA) derived from alphavirus expression vectors has shown to be very efficient to induce humoral and cellular responses against many antigens in preclinical models, being superior to non-replicating mRNA and DNA. This is mainly due to the fact that saRNA can provide very high expression levels and simultaneously induces strong innate responses, potentiating immunity. saRNA can be administered as viral particles or DNA, but direct delivery as RNA represents a safer and more simple approach. Although saRNA can be delivered as naked RNA, in vivo transfection can be enhanced by electroporation or by complexing it with cationic lipids or polymers. Alphavirus saRNA could have broad application to vaccinate against human pathogens, including emerging ones like SARS-CoV-2, for which clinical trials have been recently initiated.
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Autores: González Aseguinolaza, Gloria (Autor de correspondencia)Revista: NEW ENGLAND JOURNAL OF MEDICINEISSN: 0028-4793 Vol.382 N° 24 2020 págs. 2366 - 2367ResumenThe porphyrias are a group of rare and ultra-rare devastating disorders of heme biosynthesis. The majority of these disorders are inherited, and patients present with disabling symptoms that have a profound effect on their quality of life. The subtypes of acute hepatic porphyria - including acute intermittent porphyria (the most common subtype), hereditary coproporphyria, variegate porphyria, and delta-aminolevulinic acid (ALA) dehydratase-deficiency porphyria - are characterized by the occurrence of severe neurovisceral attacks. The genetic deficit that causes acute hepatic porphyria reduces heme availability under conditions of increased heme demands, which leads to activation of the heme-synthesis pathway and up-regulation of . . .
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Autores: Zalba Oteiza, Sara; Contreras Sandoval, Ana Margarita; Martisová, Eva; et al.Revista: PHARMACEUTICSISSN: 1999-4923 Vol.12 N° 6 2020 págs. 595ResumenImmunotherapy has changed the paradigm of cancer treatments. In this way, several combinatorial strategies based on monoclonal antibodies (mAb) such as anti (a)-PD-1 or anti (a)-PD-L1 are often reported to yield promising clinical benefits. However, the pharmacokinetic (PK) behavior of these mAbs is a critical issue that requires selective analytical techniques. Indeed, few publications report data on a-PD1/a-PD-L1 exposure and its relationship with therapeutic or toxic effects. In this regard, preclinical assays allow the time profiles of antibody plasma concentrations to be characterized rapidly and easily, which may help to increase PK knowledge. In this study, we have developed and validated two in-house ELISAs to quantify a-PD-1 and a-PD-L1 in plasma collected from tumor-bearing mice. The linear range for the a-PD-1 assay was 2.5-125 ng/mL and 0.11-3.125 ng/mL for the a-PD-L1 assay, whereas the intra-and inter-day precision was lower than 20% for both analytes. The PK characterization revealed a significant decrease in drug exposure after administration of multiple doses. Plasma half-life for a-PD-1 was slightly shorter (22.3 h) than for a-PD-L1 (46.7 h). To our knowledge, this is the first reported preclinical ELISA for these immune checkpoint inhibitors, which is sufficiently robust to be used in different preclinical models. These methods can help to understand the PK behavior of these antibodies under different scenarios and the relationship with response, thus guiding the choice of optimal doses in clinical settings.
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Autores: Vinueza Gavilanes, Rodrigo; Íñigo Marco, Ignacio; Larrea, L. ; et al.Revista: NEUROBIOLOGY OF DISEASEISSN: 0969-9961 Vol.137 2020 págs. 104781ResumenAlpha-synuclein (aSyn) protein levels are sufficient to drive Parkinson's disease (PD) and other synucleinopathies. Despite the biomedical/therapeutic potential of aSyn protein regulation, little is known about mechanisms that limit/control aSyn levels. Here, we investigate the role of a post-translational modification, N-terminal acetylation, in aSyn neurotoxicity. N-terminal acetylation occurs in all aSyn molecules and has been proposed to determine its lipid binding and aggregation capacities; however, its effect in aSyn stability/neurotoxicity has not been evaluated. We generated N-terminal mutants that alter or block physiological aSyn N-terminal acetylation in wild-type or pathological mutant E46K aSyn versions and confirmed N-terminal acetylation status by mass spectrometry. By optical pulse-labeling in living primary neurons we documented a reduced half-life and accumulation of aSyn N-terminal mutants. To analyze the effect of N-terminal acetylation mutants in neuronal toxicity we took advantage of a neuronal model where aSyn toxicity was scored by longitudinal survival analysis. Salient features of aSyn neurotoxicity were previously investigated with this approach. aSyn-dependent neuronal death was recapitulated either by higher aSyn protein levels in the case of WT aSyn, or by the combined effect of protein levels and enhanced neurotoxicity conveyed by the E46K mutation. aSyn N-terminal mutations decreased E46K aSyn-dependent neuronal death both by reducing protein levels and, importantly, by reducing the intrinsic E46K aSyn toxicity, being the D2P mutant the least toxic. Together, our results illustrate that the N-terminus determines, most likely through its acetylation, aSyn protein levels and toxicity, identifying this modification as a potential therapeutic target.
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Autores: Anasagasti, A. ; Lara-Lopez, A.; Milla-Navarro, S. ; et al.Revista: PHARMACEUTICSISSN: 1999-4923 Vol.12 N° 10 2020 págs. 913ResumenInherited retinal dystrophies (IRDs) are a group of rare retinal conditions, including retinitis pigmentosa (RP), caused by monogenic mutations in 1 out of more than 250 genes. Despite recent advancements in gene therapy, there is still a lack of an effective treatment for this group of retinal conditions. MicroRNAs (miRNAs) are a class of highly conserved small non-coding RNAs that inhibit gene expression. Control of miRNAs-mediated protein expression has been described as a widely used mechanism for post-transcriptional regulation in many physiological and pathological processes in different organs, including the retina. Our main purpose was to test the hypothesis that modulation of a group of miRNAs can protect photoreceptor cells from death in the rd10 mouse model of retinitis pigmentosa. For this, we incorporated modulators of three miRNAs in adeno-associated viruses (AAVs), which were administered through sub-retinal injections. The results obtained indicate that inhibition of the miR-6937-5p slows down the visual deterioration of rd10 mice, reflected by an increased electroretinogram (ERG) wave response under scotopic conditions and significant preservation of the outer nuclear layer thickness. This work contributes to broadening our knowledge on the molecular mechanisms underlying retinitis pigmentosa and supports the development of novel therapeutic approaches for RP based on miRNA modulation.
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Autores: Silva-Pilipich, N.; Martisová, Eva; Ballesteros-Briones, M. C.; et al.Revista: BIOMEDICINESISSN: 2227-9059 Vol.8 N° 12 2020 págs. 562ResumenImmune checkpoint blockade using monoclonal antibodies (mAbs) able to block programmed death-1 (PD-1)/PD-L1 axis represents a promising treatment for cancer. However, it requires repetitive systemic administration of high mAbs doses, often leading to adverse effects. We generated a novel nanobody against PD-1 (Nb11) able to block PD-1/PD-L1 interaction for both mouse and human molecules. Nb11 was cloned into an adeno-associated virus (AAV) vector downstream of four different promoters (CMV, CAG, EF1 alpha, and SFFV) and its expression was analyzed in cells from rodent (BHK) and human origin (Huh-7). Nb11 was expressed at high levels in vitro reaching 2-20 micrograms/mL with all promoters, except SFFV, which showed lower levels. Nb11 in vivo expression was evaluated in C57BL/6 mice after intravenous administration of AAV8 vectors. Nb11 serum levels increased steadily along time, reaching 1-3 microgram/mL two months post-treatment with the vector having the CAG promoter (AAV-CAG-Nb11), without evidence of toxicity. To test the antitumor potential of this vector, mice that received AAV-CAG-Nb11, or saline as control, were challenged with colon adenocarcinoma cells (MC38). AAV-CAG-Nb11 treatment prevented tumor formation in 30% of mice, significantly increasing survival. These data suggest that continuous expression of immunomodulatory nanobodies from long-term expression vectors could have antitumor effects with low toxicity.
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Autores: Simoes, I. T.; Aranda, F. (Autor de correspondencia); Casado-Llombart, S. ; et al.Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCERISSN: 2051-1426 Vol.8 N° 1 2020 págs. e000172ResumenBackground CD6 is a lymphocyte surface co-receptor physically associated with the T-cell receptor (TCR)/CD3 complex at the center of the immunological synapse. There, CD6 assists in cell-to-cell contact stabilization and modulation of activation/differentiation events through interaction with CD166/ALCAM (activated leukocyte cell adhesion molecule), its main reported ligand. While accumulating evidence is attracting new interest on targeting CD6 for therapeutic purposes in autoimmune disorders, little is known on its potential in cancer. In an attempt to elucidate the in vivo relevance of blocking CD6-mediated interactions in health and disease, we explored the consequences of expressing high circulating levels of a soluble form CD6 (sCD6) as a decoy receptor. Methods High sCD6 serum levels were achieved by using transgenic C57BL/6 mice expressing human sCD6 under the control of lymphoid-specific transcriptional elements (shCD6LckE mu Tg) or wild type either transduced with hepatotropic adeno-associated virus coding for mouse sCD6 or undergoing repeated infusions of recombinant human sCD6 protein. Characterization of sCD6-induced changes was performed by ex vivo flow cytometry and functional analyses of mouse lymphoid organ cells. The in vivo relevance of those changes was explored by challenging mice with subcutaneous or metastatic tumors induced by syngeneic cancer cells of different lineage origins. Results Through a combination of in vitro and in vivo studies, we show that circulating sCD6 expression induces defective regulatory T cell (Treg) generation and function, decreased CD166/ALCAM-mediated tumor cell proliferation/migration and impaired galectin-induced T-cell apoptosis, supporting the fact that sCD6 modulates antitumor lymphocyte effector function and tumorigenesis. Accordingly, sCD6 expression in vivo resulted in delayed subcutaneous tumor growth and/or reduced metastasis on challenge of mice with syngeneic cancer cells. Conclusions Evidence is provided for the disruption of CD6 receptor-ligand interactions as a feasible immunomodulatory approach in cancer.
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Autores: Lasa Ventura, Marta; Neri, L.; Carte Abad, Beatriz; et al.Revista: JOURNAL OF MOLECULAR BIOLOGYISSN: 0022-2836 Vol.432 N° 22 2020 págs. 5889 - 5901ResumenProtein lifespan is regulated by co-translational modification by several enzymes, including methionine aminopeptidases and N-alpha-aminoterminal acetyltransferases. The NatB enzymatic complex is an N-terminal acetyltransferase constituted by two subunits, NAA20 and NAA25, whose interaction is necessary to avoid NAA20 catalytic subunit degradation. We found that deletion of the first five amino acids of hNAA20 or fusion of a peptide to its amino terminal end abolishes its interaction with hNAA25. Substitution of the second residue of hNAA20 with amino acids with small, uncharged side-chains allows NatB enzymatic complex formation. However, replacement by residues with large or charged side-chains interferes with its hNAA25 interaction, limiting functional NatB complex formation. Comparison of NAA20 eukaryotic sequences showed that the residue following the initial methionine, an amino acid with a small uncharged side-chain, has been evolutionarily conserved. We have confirmed the relevance of second amino acid characteristics of NAA20 in NatB enzymatic complex formation in Drosophila melanogaster. Moreover, we have evidenced the significance of NAA20 second residue in Saccharomyces cerevisiae using different NAA20 versions to reconstitute NatB formation in a yNAA20-KO yeast strain. The requirement in humans and in fruit flies of an amino acid with a small uncharged side-chain following the initial methionine of NAA20 suggests that methionine aminopeptidase action may be necessary for the NAA20 and NAA25 interaction. We showed that inhibition of MetAP2 expression blocked hNatB enzymatic complex formation by retaining the initial methionine of NAA20. Therefore, NatB-mediated protein N-terminal acetylation is dependent on methionine aminopeptidase, providing a regulatory mechanism for protein N-terminal maturation. (C) 2020 Elsevier Ltd. All rights reserved.
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Autores: Mevel, M. (Autor de correspondencia); Bouzelha, M. ; Leray, A.; et al.Revista: CHEMICAL SCIENCEISSN: 2041-6520 Vol.11 N° 4 2020 págs. 1122 - 1131ResumenGene delivery vectors based on adeno-associated virus (AAV) are highly promising due to several desirable features of this parent virus, including a lack of pathogenicity, efficient infection of dividing and non-dividing cells and sustained maintenance of the viral genome. However, the conclusion from clinical data using these vectors is that there is a need to develop new AAVs with a higher transduction efficiency and specificity for relevant target tissues. To overcome these limitations, we chemically modified the surface of the capsid of AAV vectors. These modifications were achieved by chemical coupling of a ligand by the formation of a thiourea functionality between the amino group of the capsid proteins and the reactive isothiocyanate motif incorporated into the ligand. This strategy does not require genetic engineering of the capsid sequence. The proof of concept was first evidenced using a fluorophore (FITC). Next, we coupled the N-acetylgalactosamine ligand onto the surface of the AAV capsid for asialoglycoprotein receptor-mediated hepatocyte-targeted delivery. Chemically-modified capsids also showed reduced interactions with neutralizing antibodies. Taken together, our findings reveal the possibility of creating a specific engineered platform for targeting AAVs via chemical coupling.
Proyectos desde 2018
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Título: Generación de vectores de terapia génica quiméricos para tratar la poliquistosis renal autosómica dominante tipo IICódigo de expediente: 0011-1408-2020-000028Investigador principal: SERGIO MILAGROS SOLCHAGA.Financiador: GOBIERNO DE NAVARRAConvocatoria: FIMA 2020 -GN DOCTORANDOS INDUSTRIALES 2020- 2021Fecha de inicio: 29-09-2020Fecha fin: 28-09-2023Importe concedido: 78.897,12€Otros fondos: -
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Título: Gene therapy of colorectal cancer using a self-replicating RNA vector expressing inhibitors of tumor cell adhesion in combination with immunostimulatory antibodiesCódigo de expediente: 0011-0537-2019-000006Investigador principal: GUILLERMO HERRADOR CAÑETE.Financiador: GOBIERNO DE NAVARRA / DPTO. EDUCACIÓN CULTURA Y TURISMOConvocatoria: FIMA GNE 2019 BECAS PREDOCTORALES FIMA GNE 2019 BECAS PREDOCTORALESFecha de inicio: 01-06-2020Fecha fin: 31-10-2022Importe concedido: 68.743,32€Otros fondos: -
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Título: Creación de una plataforma para el desarrollo de vectores de terápia génica con tropismo renal.(Drones Génicos)Código de expediente: 0011-1411-2019-000074Investigador principal: RAFAEL ALDABE ARREGUI.Financiador: GOBIERNO DE NAVARRAConvocatoria: FIMA 2019 GN PROYECTOS ESTRATEGICOS DE I+D 2019-2021Fecha de inicio: 01-04-2019Fecha fin: 30-11-2021Importe concedido: 631.682,12€Otros fondos: -
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Título: Análisis de la interación del virus de la hepatitis delta (HDV) con el hospedador y con el virus de la hepatitis B (HBV) (INTERDELTACódigo de expediente: RTI2018-101936-B-I00Investigador principal: GLORIA GONZALEZ ASEGUINOLAZA.Financiador: MINISTERIO DE CIENCIA E INNOVACIÓNConvocatoria: 2018 - PROYECTOS DE I+D RETOS INVESTIGACIONFecha de inicio: 01-01-2019Fecha fin: 30-09-2022Importe concedido: 338.800,00€Otros fondos: Fondos FEDER
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Título: RNA autorreplicativo armado con nanobodies inmunoestimuladores para terapia del cáncer colorectalCódigo de expediente: 64/2018Investigador principal: CRISTIAN SMERDOU PICAZO.Financiador: GOBIERNO DE NAVARRA. DEPARTAMENTO DE SALUDConvocatoria: 2018 PROYECTOS DE I+D EN SALUDFecha de inicio: 31-12-2018Fecha fin: 30-12-2021Importe concedido: 78.775,00€Otros fondos: Fondos FEDER
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Título: Terapia génica con glucocerebrosidasa para el tratamiento de la enfermedad de Parkinson.Código de expediente: 0011-1383-2019-000006Investigador principal: JOSE LUIS LANCIEGO PEREZ.Financiador: GOBIERNO DE NAVARRAConvocatoria: 2019 - GN INDUSTRIA PROYECTOS CENTROS TECNOLOGICOS Y ORGANISMOS DE INVESTIGACIONFecha de inicio: 01-12-2018Fecha fin: 30-11-2019Importe concedido: 132.648,00€Otros fondos: -
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Título: Desarrollo de una plataforma de terapia génica para enfermedades genéticas renalesCódigo de expediente: RTC-2017-6600-1Investigador principal: RAFAEL ALDABE ARREGUI.Financiador: MINISTERIO DE CIENCIA E INNOVACIÓNConvocatoria: 2017 - PROYECTOS RETOS-COLABORACIONFecha de inicio: 01-04-2018Fecha fin: 30-04-2022Importe concedido: 150.913,59€Otros fondos: Fondos FEDER
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Título: Selección y optimización de nuevas moléculas antitumorales. Validación de la acetilación aminoterminal de proteínas como diana terapéutica antitumoral.Código de expediente: 0011-1383-2018-000011Investigador principal: RAFAEL ALDABE ARREGUI.Financiador: GOBIERNO DE NAVARRAConvocatoria: 2018 - GN INDUSTRIA PROYECTOS CENTROS TECNOLOGICOS Y ORGANISMOS DE INVESTIGACIONFecha de inicio: 01-02-2018Fecha fin: 30-11-2018Importe concedido: 175.851,50€Otros fondos: -
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Título: CREACION DE UNA PLATAFORMA EUROPEA INNOVADORA DE TERAPIA GENICA PARA ENFERMEDADES HEREDITARIAS POCO FRECUENTES.Código de expediente: EUIN2017-89279Investigador principal: GLORIA GONZALEZ ASEGUINOLAZA.Financiador: MINISTERIO DE CIENCIA E INNOVACIÓNConvocatoria: 2017 MINECO Europa InvestigaciónFecha de inicio: 01-10-2017Fecha fin: 30-09-2019Importe concedido: 20.700,00€Otros fondos: Fondos FEDER
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Título: PREPARACION DE LA PROPUESTA ITN-NMATTERSCódigo de expediente: EUIN2017-89194Investigador principal: RAFAEL ALDABE ARREGUI.Financiador: MINISTERIO DE CIENCIA E INNOVACIÓNConvocatoria: 2017 MINECO Europa InvestigaciónFecha de inicio: 01-07-2017Fecha fin: 31-12-2018Importe concedido: 18.130,00€Otros fondos: Fondos FEDER
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Título: Desarrollo y caracterización de un modelo de infeccíón crónica por el virus de la Hepatitis Delta en ratón y desarrollo de nuevos tratamientosCódigo de expediente: SAF2015-70028-RInvestigador principal: GLORIA GONZALEZ ASEGUINOLAZA.Financiador: MINISTERIO DE CIENCIA E INNOVACIÓNConvocatoria: 2015 - PROYECTOS DE I+D RETOSFecha de inicio: 01-01-2016Fecha fin: 31-12-2018Importe concedido: 210.240,00€Otros fondos: Fondos FEDER
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Título: Curing Dravet Syndrome by Gene TherapyCódigo de expediente: AC17/00029Investigador principal: ROCIO SANCHEZ-CARPINTERO ABADFinanciador: INSTITUTO DE SALUD CARLOS IIIConvocatoria: E-RAREFecha de inicio: 01-01-2018Fecha fin: 31-05-2021Importe concedido: 59.290,00€Otros fondos: Fondos FEDER
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Título: Optimización de vectores de terapia génica para el tratamiento del síndrome de DravetInvestigador principal: RUBEN HERNANDEZ ALCOCEBAFinanciador: GOBIERNO DE NAVARRAConvocatoria: FIMA 2020 -GN DOCTORANDOS INDUSTRIALES 2020- 2021Fecha de inicio: 24-09-2020Fecha fin: 30-09-2021Importe concedido: 14.000,00€
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Título: Desarrollo de nuevas estrategias de inmunoterapia para el tratamiento del cáncer colorectal usando vectores basados en RNA autorreplicativoInvestigador principal: CRISTIAN SMERDOU PICAZOFinanciador: INSTITUTO DE SALUD CARLOS IIIConvocatoria: 2017 - PROYECTOS DE I+D EN SALUDFecha de inicio: 01-01-2018Fecha fin: 31-12-2021Importe concedido: 141.570,00€
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Título: Terapia Génica para el Síndrome de DravetInvestigador principal: MIGUEL VALENCIA USTARROZFinanciador: FUNDACION INOCENTE INOCENTEConvocatoria: FUNDACION INOCENTE INOCENTE 2017Fecha de inicio: 19-10-2017Fecha fin: 31-01-2019Importe concedido: 29.755,00€