Liver transduction with a simian virus 40 vector encoding insulin-like growth factor I reduces hepatic damage and the development of liver cirrhosis

Vera, María; Sobrevals, Luciano; Zaratiegui, Mikel; Martínez, Luis; Palencia, Belén; Rodrı́guez, Carlos; Prieto, Jesús; Fortes, Puri

doi:10.1038/sj.gt.3302858

Cited by 23 publications

(30 citation statements)

References 41 publications

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“…52 Therapy allowing sustained hepatic expression of IGF-I is being considered as a strategy to halt the progression of liver cirrhosis. 53 In several reports using rat models of liver injury or aging, exogenous IGF-I rescued liver cells from apoptosis. [52][53][54][55][56] In LIGFREKO mice, in contrast, endogenous IGF-I signaling was suppressed before hepatic lesions were induced by BDL.…”

Section: Discussionmentioning

confidence: 99%

“…53 In several reports using rat models of liver injury or aging, exogenous IGF-I rescued liver cells from apoptosis. [52][53][54][55][56] In LIGFREKO mice, in contrast, endogenous IGF-I signaling was suppressed before hepatic lesions were induced by BDL. Constitutively reduced IGF signaling can increase cellular stress resistance through adaptive changes in gene expression and cellular physiology 2,3,57,58 In addition, when administered intravenously or by gene therapy, IGF-I reaches all cell types in the liver and may also act on extra-hepatic tissues, which likely generates indirect effects that cannot be distinguished from direct effects on hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

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IGF-1R Contributes to Stress-Induced Hepatocellular Damage in Experimental Cholestasis

Cadoret

Rey

Wendum

et al. 2009

The American Journal of Pathology

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The insulin-like growth factor type 1 receptor (IGF-1R) controls aging and cellular stress, both of which play major roles in liver disease. Stimulation of insulin-like growth factor signaling can generate cell death in vitro. Here, we tested whether IGF-1R contributes to stress insult in the liver. Cholestatic liver injury was induced by bile duct ligation in control and liver-specific IGF-1R knockout (LIGFREKO) mice. LIGFREKO mice displayed less bile duct ligation-induced hepatocyte damage than controls, while no differences in bile acid serum levels or better adaptation to cholestasis by efflux transporters were found. We therefore tested whether stress pathways contributed to this phenomenon; oxidative stress, ascertained by both malondialdehyde content and heme oxygenase-1 expression, was similar in knockout and control animals. However, together with a lower level of eukaryotic initiation factor-2 ␣ phosphorylation, the endoplasmic reticulum stress protein CHOP and its downstream pro-apoptotic target Bax were induced to lesser extents in LIGFREKO mice than in controls. Expression levels of cytokeratin 19, transforming growth factor-␤1, ␣-smooth muscle actin, and collagen ␣1(I) in LIGFREKO mice were all lower than in controls, indicating reduced ductular and fibrogenic responses and increased cholestasis tolerance in these mutants. This stress resistance phenotype was also evidenced by longer post-bile duct ligation survival in mutants than controls. These results indicate that IGF-1R contributes to cholestatic liver injury , and suggests the involvement of both CHOP and

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

IGF-1R Contributes to Stress-Induced Hepatocellular Damage in Experimental Cholestasis

Cadoret

Rey

Wendum

et al. 2009

The American Journal of Pathology

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“…Luciferase activity was measured at the indicated time points in living mice with a CCD Camera (Xenogen, Alameda, CA) 5 min after intraperitoneal injection of 3 mg of D-luciferin (Promega) and anesthetics (14). Bioluminescence was measured for 5 min until the luciferase signal started to decrease and light intensity was quantified as photons/s with Living Image software.…”

Section: Methodsmentioning

confidence: 99%

Increased in vivo inhibition of gene expression by combining RNA interference and U1 inhibition

Blázquez

Gonzalez-Rojas

Abad

et al. 2011

Nucleic Acids Research

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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.

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“…9 Luciferase was quantified from images obtained using the Living Image 2.20 software (Xenogen). Firefly luciferase activity was quantified in liver extracts by using the Luciferase System (Promega), as described previously, 35 in a Berthold Luminometer (Lumat LB 9507).…”

Section: Analysis Of Luciferase Expressionmentioning

confidence: 99%

“…Several authors have shown that these therapeutic effects can be achieved by inducing the expression of specific genes, such as interferon, bone morphogenetic proteins, superoxide dismutase, SPARC, HNF4a, methaloproteinases, urokinase plasminogen activator or insulin-like growth factor I among others, within the liver. [2][3][4][5][6][7][8][9][10] In most cases, the liver expression of the therapeutic transgene is obtained by using adenoviral vectors, which have a natural tropism for the liver. However, adenoviral vectors do not transduce cirrhotic livers as efficiently as healthy livers.…”

Section: Introductionmentioning

confidence: 99%

AAV vectors transduce hepatocytes in vivo as efficiently in cirrhotic as in healthy rat livers

et al. 2011

Self Cite

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In liver cirrhosis, abnormal liver architecture impairs efficient transduction of hepatocytes with large viral vectors such as adenoviruses. Here we evaluated the ability of adeno-associated virus (AAV) vectors, small viral vectors, to transduce normal and cirrhotic rat livers. Using AAV serotype-1 (AAV1) encoding luciferase (AAV1Luc) we analyzed luciferase expression with a CCD camera. AAV1Luc was injected through the hepatic artery (intra-arterial (IA)), the portal vein (intra-portal (IP)), directly into the liver (intra-hepatic (IH)) or infused into the biliary tree (intra-biliar). We found that AAV1Luc allows long-term and constant luciferase expression in rat livers. Interestingly, IP administration leads to higher expression levels in healthy than in cirrhotic livers, whereas the opposite occurs when using IA injection. IH administration leads to similar transgene expression in cirrhotic and healthy rats, whereas intra-biliar infusion is the least effective route. After 70% partial hepatectomy, luciferase expression decreased in the regenerating liver, suggesting lack of efficient integration of AAV1 DNA into the host genome. AAV1Luc transduced mainly the liver but also the testes and spleen. Within the liver, transgene expression was found mainly in hepatocytes. Using a liver-specific promoter, transgene expression was detected in hepatocytes but not in other organs. Our results indicate that AAVs are convenient vectors for the treatment of liver cirrhosis.

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Liver transduction with a simian virus 40 vector encoding insulin-like growth factor I reduces hepatic damage and the development of liver cirrhosis

Cited by 23 publications

References 41 publications

IGF-1R Contributes to Stress-Induced Hepatocellular Damage in Experimental Cholestasis

IGF-1R Contributes to Stress-Induced Hepatocellular Damage in Experimental Cholestasis

Increased in vivo inhibition of gene expression by combining RNA interference and U1 inhibition

AAV vectors transduce hepatocytes in vivo as efficiently in cirrhotic as in healthy rat livers

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