mRNA destabilization improves glycemic responsiveness of transcriptionally regulated hepatic insulin gene therapy <i>in vitro</i> and <i>in vivo</i>

Thulé, Peter M.; Lin, Yulin; Jia, Dingwu; Olson, Darin E.; Tang, Shiue–Cheng; Sambanis, Athanassios

doi:10.1002/jgm.2946

Cited by 2 publications

(2 citation statements)

References 36 publications

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“…Together, these observations strongly suggest a need for further improvements to 3xGIRE.ALB.Ins1-2xfur. Namely, it would be ideal to increase the degree of glucose-induced insulin transcription [23] while also incorporating mechanism(s) to more quickly reduce insulin levels upon restoration of normoglycemia [24]. Overall, such modifications would greatly enhance the dynamic insulin response to changes in glucose levels, leading to a more effective and safer strategy with greater latitude in dosing.…”

Section: Discussionmentioning

confidence: 99%

Long-term correction of diabetic hyperglycemia through glucose-responsive hepatic insulin production using lentivirus

Am¹,

Hw²,

T³

2017

J Diabetol Endocrinol.

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Type 1 diabetes mellitus (T1DM) is a chronic metabolic disorder resulting from the autoimmune destruction of the insulin-producing β cells of the pancreas. The predominant treatment option requires multiple daily insulin injections to control hyperglycemia, but normal glucose regulation remains elusive. As a result, exogenous insulin therapy delays, but does not prevent, the onset of secondary complications associated with T1DM. Whole pancreas and islet transplantation therapies result in better glucose regulation but are greatly limited by donor shortage and the need for lifelong immunosuppression. Hence, there is clearly a need for alternative, state-of-the-art treatment options.Several gene therapy-based strategies have emerged as promising alternatives to current treatments. One potential strategy is to prevent the autoimmune destruction of β cells by delivering genes capable of modifying the immune system or preventing the apoptosis of native β cells [1,2]. Unfortunately, this strategy relies on the early detection of diabetes, which is difficult given that greater than 80% of an individual's β cells have often already been destroyed Journal of Diabetology and EndocrinologyOriginal research Handorf AM et al., J Diabetol Endocrinol. 2017 AbstractType 1 diabetes mellitus (T1DM) is caused by the autoimmune destruction of the insulin-producing β cells of the pancreas. Insulin gene therapy is a promising strategy capable of overcoming the limitations of current treatments, but to become a viable option, it must provide long-term, glucose-responsive control of insulin production. We have previously achieved glucose-responsivity by incorporating glucose-inducible response elements (GIREs) upstream of a liver-specific insulin expression cassette (3xGIRE.ALB.Ins1-2xfur). In this study, 3xGIRE.ALB.Ins1-2xfur was delivered into streptozotocin-induced diabetic rats using lentivirus, resulting in remission of diabetic hyperglycemia for at least 482 days while restoring rate of weight gain in a dose-dependent fashion. Insulin immunostaining showed abundant insulin production in the liver, and qPCR showed 13-20 lentiviral integrations per cell in the liver of rats treated with high dose lentivirus. Negligible integration was found in the pancreas, kidney, spleen and muscle of LV-treated rats, confirming liver specificity. In vitro, LV.3xGIRE.ALB. Ins1-2xfur produced a 4.5-fold increase in insulin production in high glucose conditions, and in vivo, a 1.7-fold increase in insulin levels was found during an intraperitoneal glucose tolerance test. Unfortunately, limitations in large-scale lentivirus production and use of a tissue-specific promoter prevented treatment of more than one rat per batch of lentivirus. Thus, two of the LV-treated diabetic rats were undertreated, while another two rats were over treated, becoming hypoglycemic in the fed state. Nonetheless, we have established the framework for a long-term, glucose-responsive treatment for T1DM from which further improvements can be made. Keywords Open AccessAn Open...

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Section: Discussionmentioning

confidence: 99%

Long-term correction of diabetic hyperglycemia through glucose-responsive hepatic insulin production using lentivirus

Am¹,

Hw²,

T³

2017

J Diabetol Endocrinol.

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“…Because plasma insulin has a short half-life, it might be possible to mimic insulin secretion by controlling the half-life of transgenic insulin mRNA. Thulé PM, et al [48] tested this hypothesis by creating an insulin construct producing a destabilized proinsulin message and compared the results with their standard construct. They showed that the construct producing a destabilized pro-insulin has improved glycemic responsiveness both in vitro and in vivo.…”

Section: Journal Of Diabetes Research and Therapymentioning

confidence: 99%

Insulin Gene Therapy for Treating Type I Diabetes Mellitus: History, Progress and Future Challenges

Akcan¹,

Alam²,

Hw³

2020

J Diab Res Ther

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Type 1 Diabetes Mellitus (T1DM) results from the autoimmune destruction of insulin-producing pancreatic β cells. Despite advances in our understanding of both the pathogenesis and management of diabetes and treatment options, which mainly include injectable insulin and whole pancreas transplant, these advancements remain unsatisfactory and only a small portion of patients achieve their glycemic goals. Insulin gene therapy refers to the development of β cell substitutes by introducing an insulin producing gene into endogenous cell populations that do not normally produce insulin. This strategy has the promise to overcome the limitations of current treatments. Here, we present an overview of the history of insulin gene therapy and review current achievements. We also briefly discuss areas for improvement and potential future directions.

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mRNA destabilization improves glycemic responsiveness of transcriptionally regulated hepatic insulin gene therapy in vitro and in vivo

Abstract: The data obtained in the present study suggest that combining transcriptional and post-transcriptional regulatory strategies may reduce undesirable glycemic excursion in models of HIGT.

Cited by 2 publications

References 36 publications

Long-term correction of diabetic hyperglycemia through glucose-responsive hepatic insulin production using lentivirus

Long-term correction of diabetic hyperglycemia through glucose-responsive hepatic insulin production using lentivirus

Insulin Gene Therapy for Treating Type I Diabetes Mellitus: History, Progress and Future Challenges

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