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AAV-mediated pancreatic overexpression of Igf1 counteracts progression to autoimmune diabetes in mice

OBJECTIVE: Type 1 diabetes is characterized by autoimmune destruction of β-cells leading to severe insulin deficiency. Although many improvements have been made in recent years, exogenous insulin therapy is still imperfect; new therapeutic approaches, focusing on preserving/expanding β-cell mass and...

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Autores principales: Mallol, Cristina, Casana, Estefania, Jimenez, Veronica, Casellas, Alba, Haurigot, Virginia, Jambrina, Claudia, Sacristan, Victor, Morró, Meritxell, Agudo, Judith, Vilà, Laia, Bosch, Fatima
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2017
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5485311/
https://www.ncbi.nlm.nih.gov/pubmed/28702323
http://dx.doi.org/10.1016/j.molmet.2017.05.007
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author Mallol, Cristina
Casana, Estefania
Jimenez, Veronica
Casellas, Alba
Haurigot, Virginia
Jambrina, Claudia
Sacristan, Victor
Morró, Meritxell
Agudo, Judith
Vilà, Laia
Bosch, Fatima
author_facet Mallol, Cristina
Casana, Estefania
Jimenez, Veronica
Casellas, Alba
Haurigot, Virginia
Jambrina, Claudia
Sacristan, Victor
Morró, Meritxell
Agudo, Judith
Vilà, Laia
Bosch, Fatima
author_sort Mallol, Cristina
collection PubMed
description OBJECTIVE: Type 1 diabetes is characterized by autoimmune destruction of β-cells leading to severe insulin deficiency. Although many improvements have been made in recent years, exogenous insulin therapy is still imperfect; new therapeutic approaches, focusing on preserving/expanding β-cell mass and/or blocking the autoimmune process that destroys islets, should be developed. The main objective of this work was to test in non-obese diabetic (NOD) mice, which spontaneously develop autoimmune diabetes, the effects of local expression of Insulin-like growth factor 1 (IGF1), a potent mitogenic and pro-survival factor for β-cells with immunomodulatory properties. METHODS: Transgenic NOD mice overexpressing IGF1 specifically in β-cells (NOD-IGF1) were generated and phenotyped. In addition, miRT-containing, IGF1-encoding adeno-associated viruses (AAV) of serotype 8 (AAV8-IGF1-dmiRT) were produced and administered to 4- or 11-week-old non-transgenic NOD females through intraductal delivery. Several histological, immunological, and metabolic parameters were measured to monitor disease over a period of 28–30 weeks. RESULTS: In transgenic mice, local IGF1 expression led to long-term suppression of diabetes onset and robust protection of β-cell mass from the autoimmune insult. AAV-mediated pancreatic-specific overexpression of IGF1 in adult animals also dramatically reduced diabetes incidence, both when vectors were delivered before pathology onset or once insulitis was established. Transgenic NOD-IGF1 and AAV8-IGF1-dmiRT-treated NOD animals had much less islet infiltration than controls, preserved β-cell mass, and normal insulinemia. Transgenic and AAV-treated islets showed less expression of antigen-presenting molecules, inflammatory cytokines, and chemokines important for tissue-specific homing of effector T cells, suggesting IGF1 modulated islet autoimmunity in NOD mice. CONCLUSIONS: Local expression of Igf1 by AAV-mediated gene transfer counteracts progression to diabetes in NOD mice. This study suggests a therapeutic strategy for autoimmune diabetes in humans.
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spelling pubmed-54853112017-07-12 AAV-mediated pancreatic overexpression of Igf1 counteracts progression to autoimmune diabetes in mice Mallol, Cristina Casana, Estefania Jimenez, Veronica Casellas, Alba Haurigot, Virginia Jambrina, Claudia Sacristan, Victor Morró, Meritxell Agudo, Judith Vilà, Laia Bosch, Fatima Mol Metab Original Article OBJECTIVE: Type 1 diabetes is characterized by autoimmune destruction of β-cells leading to severe insulin deficiency. Although many improvements have been made in recent years, exogenous insulin therapy is still imperfect; new therapeutic approaches, focusing on preserving/expanding β-cell mass and/or blocking the autoimmune process that destroys islets, should be developed. The main objective of this work was to test in non-obese diabetic (NOD) mice, which spontaneously develop autoimmune diabetes, the effects of local expression of Insulin-like growth factor 1 (IGF1), a potent mitogenic and pro-survival factor for β-cells with immunomodulatory properties. METHODS: Transgenic NOD mice overexpressing IGF1 specifically in β-cells (NOD-IGF1) were generated and phenotyped. In addition, miRT-containing, IGF1-encoding adeno-associated viruses (AAV) of serotype 8 (AAV8-IGF1-dmiRT) were produced and administered to 4- or 11-week-old non-transgenic NOD females through intraductal delivery. Several histological, immunological, and metabolic parameters were measured to monitor disease over a period of 28–30 weeks. RESULTS: In transgenic mice, local IGF1 expression led to long-term suppression of diabetes onset and robust protection of β-cell mass from the autoimmune insult. AAV-mediated pancreatic-specific overexpression of IGF1 in adult animals also dramatically reduced diabetes incidence, both when vectors were delivered before pathology onset or once insulitis was established. Transgenic NOD-IGF1 and AAV8-IGF1-dmiRT-treated NOD animals had much less islet infiltration than controls, preserved β-cell mass, and normal insulinemia. Transgenic and AAV-treated islets showed less expression of antigen-presenting molecules, inflammatory cytokines, and chemokines important for tissue-specific homing of effector T cells, suggesting IGF1 modulated islet autoimmunity in NOD mice. CONCLUSIONS: Local expression of Igf1 by AAV-mediated gene transfer counteracts progression to diabetes in NOD mice. This study suggests a therapeutic strategy for autoimmune diabetes in humans. Elsevier 2017-05-17 /pmc/articles/PMC5485311/ /pubmed/28702323 http://dx.doi.org/10.1016/j.molmet.2017.05.007 Text en © 2017 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Mallol, Cristina
Casana, Estefania
Jimenez, Veronica
Casellas, Alba
Haurigot, Virginia
Jambrina, Claudia
Sacristan, Victor
Morró, Meritxell
Agudo, Judith
Vilà, Laia
Bosch, Fatima
AAV-mediated pancreatic overexpression of Igf1 counteracts progression to autoimmune diabetes in mice
title AAV-mediated pancreatic overexpression of Igf1 counteracts progression to autoimmune diabetes in mice
title_full AAV-mediated pancreatic overexpression of Igf1 counteracts progression to autoimmune diabetes in mice
title_fullStr AAV-mediated pancreatic overexpression of Igf1 counteracts progression to autoimmune diabetes in mice
title_full_unstemmed AAV-mediated pancreatic overexpression of Igf1 counteracts progression to autoimmune diabetes in mice
title_short AAV-mediated pancreatic overexpression of Igf1 counteracts progression to autoimmune diabetes in mice
title_sort aav-mediated pancreatic overexpression of igf1 counteracts progression to autoimmune diabetes in mice
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5485311/
https://www.ncbi.nlm.nih.gov/pubmed/28702323
http://dx.doi.org/10.1016/j.molmet.2017.05.007
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