Lentiviral gene therapy vectors encoding VIP suppressed diabetes-related inflammation and augmented pancreatic beta-cell proliferation

Abstract

Type 1 diabetes (T1DM) is an autoimmune condition in which the immune system attacks and destroys insulin-producing beta cells in the pancreas leading to hyperglycemia. Vasoactive intestinal peptide (VIP) manifests insulinotropic and anti-inflammatory properties, which are useful for the treatment of diabetes. Because of its limited half-life due to DPP-4-mediated degradation, constant infusions or multiple injections are needed to observe any therapeutic benefit. Since gene therapy has the potential to treat genetic diseases, an HIV-based lentiviral vector carrying VIP gene (LentiVIP) was generated to provide a stable VIP gene expression in vivo. The therapeutic efficacy of LentiVIP was tested in a multiple low-dose STZ-induced animal model of T1DM. LentiVIP delivery into diabetic animals reduced hyperglycemia, improved glucose tolerance, and prevented weight loss. Also, a decrease in serum CRP levels, and serum oxidant capacity, but an increase in antioxidant capacity were observed in LentiVIP-treated animals. Restoration of islet cell mass was correlated with an increase in pancreatic beta-cell proliferation. These beneficial results suggest the therapeutic effect of LentiVIP is due to the repression of diabetes-induced inflammation, its insulinotropic properties, and VIP-induced beta-cell proliferation.

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Fig. 1: Experimental animal model of Type 1 diabetes. STZ (30 mg/kg) was injected IP into Wistar or Sprague Dawley rats (n = 8) for 5 consecutive days.
Fig. 2: Construction of pLentiVIP transfer plasmid for lentivirus vector production using Gateway Technology.
Fig. 3: In vitro expression and functional analysis of the LentiVIP vector.
Fig. 4: Therapeutic efficacy of LentiVIP injection in STZ-induced rat model of diabetes.
Fig. 5: Improved glucose tolerance in LentiVIP-injected rats correlated with higher serum VIP levels.
Fig. 6: VIP restores beta-cell loss in STZ-induced diabetes.
Fig. 7: LentiVIP suppresses diabetes-induced inflammation.

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Acknowledgements

This work is supported by the Akdeniz University Scientific Research Administration Division and “the gene therapy for diabetes” project funded by The Scientific and Technological Research Council of Turkey (TUBITAK) under Grant No: 215S820.

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Erendor, F., Sahin, E.O., Sanlioglu, A.D. et al. Lentiviral gene therapy vectors encoding VIP suppressed diabetes-related inflammation and augmented pancreatic beta-cell proliferation. Gene Ther (2020). https://doi.org/10.1038/s41434-020-0183-3

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