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Mol Metab. 2017 May 17;6(7):664-680. doi: 10.1016/j.molmet.2017.05.007. eCollection 2017 Jul.

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

Mallol C1,2,3, Casana E1,2, Jimenez V1,2,3, Casellas A1,2,3, Haurigot V1,2,3, Jambrina C1,2, Sacristan V1,2, Morró M1,2,3, Agudo J1,2,3, Vilà L1,2,3, Bosch F1,2,3.

Author information

1
Center of Animal Biotechnology and Gene Therapy (CBATEG), Spain.
2
Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
3
CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08017 Madrid, Spain.

Abstract

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.

KEYWORDS:

AAV; Autoimmune diabetes; IGF1; NOD; Pancreas

PMID:
28702323
PMCID:
PMC5485311
DOI:
10.1016/j.molmet.2017.05.007
[Indexed for MEDLINE]
Free PMC Article

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