Adeno-associated virus vector mediated gene transfer to pancreatic beta cells

Prasad, Konkal-Matt R; Yang, Zhaopeng; Bleich, David; Nadler, Jerry L.

doi:10.1038/sj.gt.3301279

Cited by 33 publications

(26 citation statements)

References 50 publications

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“…In addition to primary disease prevention, we and others have demonstrated the ability of rAAV to transduce islet cells (29,30). The delivery to islets of anti-inflammatory cytokines, cytoprotective antioxidant, and anti-inflammatory enzymes, and͞or anti-apoptotic molecules by rAAV may delay͞ prevent the recurrence of type 1 diabetes in islet transplantation and may offer a promising form of immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Adeno-associated virus vector-mediated IL-10 gene delivery prevents type 1 diabetes in NOD mice

Goudy

Song

Wasserfall

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

131

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The development of spontaneous autoimmune diabetes in nonobese diabetic (NOD) mice provides for their use as a model of human type 1 diabetes. To test the feasibility of muscle-directed gene therapy to prevent type 1 diabetes, we developed recombinant adeno-associated virus (rAAV) vectors containing murine cDNAs for immunomodulatory cytokines IL-4 or IL-10. Skeletal muscle transduction of female NOD mice with IL-10, but not IL-4, completely abrogated diabetes. rAAV-IL-10 transduction attenuated the production of insulin autoantibodies, quantitatively reduced pancreatic insulitis, maintained islet insulin content, and altered splenocyte cytokine responses to mitogenic stimulation. The beneficial effects were host specific, as adoptive transfer of splenocytes from rAAV IL-10-treated animals rapidly imparted diabetes in naive hosts, and the cells contained no protective immunomodulatory capacity, as defined through adoptive cotransfer analyses. These results indicate the utility for rAAV, a vector with advantages for therapeutic gene delivery, to transfer immunoregulatory cytokines capable of preventing type 1 diabetes. In addition, these studies provide foundational support for the concept of using immunoregulatory agents delivered by rAAV to modulate a variety of disorders associated with deleterious immune responses, including allergic reactions, transplantation rejection, immunodeficiencies, and autoimmune disorders.

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Section: Discussionmentioning

confidence: 99%

Adeno-associated virus vector-mediated IL-10 gene delivery prevents type 1 diabetes in NOD mice

Goudy

Song

Wasserfall

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

131

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“…Therefore, it is crucial if this function is altered by AAV transfection. We had previously shown no dysfunction of insulin secretion in isolated islets after culture with rAAV vectors (13). In this study, we cultured freshly isolated NOD islets with an AAV vector at a 1:1000 (islet:viral particle) ratio for 4 days, then tested their insulin-secretory function upon glucose stimulation.…”

Section: Preservation Of Insulin-secretory Function After Aav Viral Tmentioning

confidence: 99%

Suppression of Autoimmune Diabetes by Viral IL-10 Gene Transfer

Yang¹,

Chen²,

Wu³

et al. 2002

The Journal of Immunology

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Th1 cell activation and cytokine production shift the balance between Th1 and Th2, favoring the up-regulation of proinflammatory activity that leads to destruction of insulin-producing pancreatic β cells in type 1 diabetes. Th2-type cytokines, such as IL-10, have immune regulatory function. Administration of IL-10, or IL-10 gene transfer, prevents autoimmune diabetes in nonobese diabetic (NOD) mice. However, constant administration of purified rIL-10 is not practical for long-term therapy to prevent diabetes. In this study, we transferred the BCRF-1 gene, an open reading frame in the Epstein-Barr viral genome with remarkable homology to mouse IL-10 (viral IL-10 or vIL-10), by an adeno-associated viral (AAV) vector to NOD mice to attain sustained vIL-10 gene expression. Like endogenous mouse IL-10, vIL-10 has potent immunoregulatory and immunosuppressive functions, but can be specifically distinguished from endogenous mouse IL-10 for monitoring of the transgene expression. A single systemic administration of AAV vIL-10 significantly reduced insulitis and prevented diabetes development in NOD mice. This protective effect correlated with sustained transgene expression and protein production. Moreover, splenocytes from the treated mice blocked diabetes transfer to NOD recipients, suggesting that vIL-10 induces an active suppression of autoimmunity. This study provides evidence to support the possibility of using vIL-10 gene therapy to prevent type 1 diabetes.

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“…Ex vivo, the pancreatic islets of Langerhans have been successfully transduced by AAV (Prasad et al, 2000), but there has been no demonstration thus far of successful islet transduction by AAV in vivo. AdVLacZ was able to transduce both pancreatic acinar and endocrine cell types, but transduction of the endocrine islet cells was primarily limited to the periphery of the cell clusters.…”

mentioning

confidence: 99%

Comparison of Adenoviral and Adeno-Associated Viral Vectors for Pancreatic Gene DeliveryIn Vivo

et al. 2004

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Although effective gene therapy vectors have been developed for organ systems such as the liver, an effective delivery vector to the pancreas in vivo has remained elusive. Of the currently available viral vectors, adenovirus and adeno-associated virus (AAV) are two of the most efficient at transducing nondividing cells. We have constructed recombinant adenovirus (AdVLacZ), adeno-associated virus serotype 2 (AAV2LacZ), and pseudotyped adeno-associated virus serotype 5 and 8 (AAV5LacZ, AAV8LacZ) carrying the LacZ reporter, and compared the transduction efficiency of these four vectors in the pancreas of mice in vivo. We showed that adenovirus, AAV2, and AAV8 are capable of transducing the pancreas in vivo, but with different expression kinetics, efficiencies of transduction, and persistence. AdVLacZ-transduced pancreas exhibited maximum LacZ expression at 1 week postdelivery, with greater than 90% of expression lost at 4 weeks. AAV2LacZ-transduced pancreas displayed peak LacZ levels at 4 weeks postdelivery, with no significant decrease in expression for up to 8 weeks. AAV8LacZ was at least 10-fold more efficient than AAV2LacZ in transducing the pancreas in vivo, with significant levels of expression detectable at 1 week, whereas AAV5LacZ did not result in any detectable transgene expression at all tested time points. All three vectors primarily transduced pancreatic acinar cell types, with limited transduction of pancreatic endocrine cells. AdVLacZ elicited a significant leukocyte infiltration early after delivery into the pancreas, whereas none of the AAV vectors elicited a significant leukocyte response. None of the tested vectors caused significant changes in serum amylase or blood glucose levels, suggesting that they do not significantly alter pancreatic function. These vectors will be useful for studying novel gene delivery based treatments in animal models for diabetes and other pancreatic disorders. 405

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Adeno-associated virus vector mediated gene transfer to pancreatic beta cells

Cited by 33 publications

References 50 publications

Adeno-associated virus vector-mediated IL-10 gene delivery prevents type 1 diabetes in NOD mice

Adeno-associated virus vector-mediated IL-10 gene delivery prevents type 1 diabetes in NOD mice

Suppression of Autoimmune Diabetes by Viral IL-10 Gene Transfer

Comparison of Adenoviral and Adeno-Associated Viral Vectors for Pancreatic Gene DeliveryIn Vivo

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