Islet transplantation is becoming a potential cure for type 1 diabetes (T1D). However, the limited supply and significant islet loss in the peritransplant period are cast as the major limitations of this treatment strategy. This project is aimed to improve the therapeutic outcome of islet transplantation by introducing constitutively active Akt1 (CA-Akt1) into the insulin producing 2-cells ex vivo. The serine/threonine protein kinase Akt/PKB is the direct downstream target of PI3 Kinase pathway, and has been found to have dual functions of anti-apoptosis and induction of cell proliferation. Relevance of Akt on 2-cell survival and proliferation has been demonstrated in studies of transgenic and knockout mouse models, as well as using pharmacological methods. Nonetheless, in order to realize the therapeutic potential of CA-Akt1, a safe, efficient and specific vector is needed to deliver Akt1 into islet 2-cells ex vivo. In this regard, adenovirus serotype 5 (Ad5)-based vector is of great interest. Our previous studies have demonstrated the modified Ad5 vector, AdRGDpK7, exhibited significantly higher gene transfer efficiency for the human islet cells. We thus propose to employ Ad5RGDpK7 to deliver Akt1 into islet cells ex vivo. To further diminish the potential adverse effect of CA-Akt1, we will restrict exogenous Akt1 expression in 2-cells by employment of 2-cell specific promoter-rat insulin promoter (RIP) to drive Akt1 expression. In addition, we propose to co-express a dual functional modality, HSV-TK, with CA-Akt1 so that it can be used as both a non-invasive imaging modality to follow the transplanted islets and a suicide gene should malignancy occur.
Our specific aims are thus: 1) To develop a 2-cell specific, infectivity-enhanced Ad5 vector that allows efficient and specific CA-Akt1 and HSV-TK gene delivery into 2-cells ex vivo;2) To examine the capacity of the Ad5 vector developed above to promote islet survival and proliferation while minimizing transformation, thus enhancing the efficacy of islet transplantation;and 3) To evaluate the safety of the Ad5 vector developed above in the context of islet transplantation.
It is clear that islet transplantation holds great potential for the cure of Type 1 Diabetes. This study seeks to improve the therapeutic outcome of islet transplantation by modifying the islets with protective genes using a highly efficient, specific and safe gene delivery vector. Success of this study is expected to have significant impact in the field of islet transplantation treatment for type 1 diabetes.
|Dong, Shengli; Wu, Hongju (2018) Regenerating ? cells of the pancreas - potential developments in diabetes treatment. Expert Opin Biol Ther 18:175-185|
|Dong, H; Zhang, Y; Wang, J et al. (2017) Regulator of G protein signaling 2 is a key regulator of pancreatic ?-cell mass and function. Cell Death Dis 8:e2821|
|Zhang, Yanqing; Wu, Meifen; Htun, Wynn et al. (2017) Differential Effects of Linagliptin on the Function of Human Islets Isolated from Non-diabetic and Diabetic Donors. Sci Rep 7:7964|
|Fava, Genevieve E; Dong, Emily W; Wu, Hongju (2016) Intra-islet glucagon-like peptide 1. J Diabetes Complications 30:1651-1658|
|Zhang, Yanqing; Fava, Genevieve E; Wang, Hongjun et al. (2016) PAX4 Gene Transfer Induces ?-to-? Cell Phenotypic Conversion and Confers Therapeutic Benefits for Diabetes Treatment. Mol Ther 24:251-260|
|O'Malley, Thomas J; Fava, Genevieve E; Zhang, Yanqing et al. (2014) Progressive change of intra-islet GLP-1 production during diabetes development. Diabetes Metab Res Rev 30:661-8|
|Zhang, Yanqing; Zhang, Yuan; Bone, Robert N et al. (2012) Regeneration of pancreatic non-? endocrine cells in adult mice following a single diabetes-inducing dose of streptozotocin. PLoS One 7:e36675|
|Bone, Robert N; Icyuz, Mert; Zhang, Yanqing et al. (2012) Gene transfer of active Akt1 by an infectivity-enhanced adenovirus impacts ?-cell survival and proliferation differentially in vitro and in vivo. Islets 4:366-78|
|Wu, Guojin; Zhang, Wei; Na, Tao et al. (2012) Suppression of intestinal calcium entry channel TRPV6 by OCRL, a lipid phosphatase associated with Lowe syndrome and Dent disease. Am J Physiol Cell Physiol 302:C1479-91|