Reversal of Diabetes Through Gene Therapy of Diabetic Rats by Hepatic Insulin Expression via Lentiviral Transduction

Terbish, Taivankhuu; Jörns, Anne; Naujok, Ortwin; Wedekind, Dirk; Hedrich, Hans-Jürgen; Lenzen, Sigurd

doi:10.1038/mt.2012.8

Cited by 49 publications

(54 citation statements)

References 36 publications

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“…AAV has limited cargo capacity and low transduction efficiency (Sanlioglu et al 2001). Compared with other gene therapy vectors, lentiviral vectors appear to be the vector of choice when considering long-term gene expression, transduction efficacy, and safety (Elsner et al 2012). As thirdgeneration lentiviral vectors can inactivate themselves following integration into the genome, they do not possess the insertional mutagenesis risk associated with retroviral vectors inducing oncogene activation.…”

Section: Vip-mediated Gene Transfer Studiesmentioning

confidence: 99%

Therapeutic potential of VIP vs PACAP in diabetes

Şanlioğlu

Karaçay²,

Balcı³

et al. 2012

Journal of Molecular Endocrinology

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Type 2 diabetes (T2D) is characterized by chronic insulin resistance and a progressive decline in beta-cell function. Although rigorous glucose control can reduce morbidity and mortality associated with diabetes, achieving optimal longterm glycemic control remains to be accomplished in many diabetic patients. As beta-cell mass and function inevitably decline in T2D, exogenous insulin administration is almost unavoidable as a final outcome despite the use of oral antihyperglycemic agents in many diabetic patients. Pancreatic islet cell death, but not the defect in new islet formation or beta-cell replication, has been blamed for the decrease in beta-cell mass observed in T2D patients. Thus, therapeutic approaches designed to protect islet cells from apoptosis could significantly improve the management of T2D, because of its potential to reverse diabetes not just ameliorate glycemia. Therefore, an ideal beta-cell-preserving agent is expected to protect beta cells from apoptosis and stimulate postprandial insulin secretion along with increasing beta-cell replication and/or islet neogenesis. One such potential agent, the islet endocrine neuropeptide vasoactive intestinal peptide (VIP) strongly stimulates postprandial insulin secretion. Because of its broad spectrum of biological functions such as acting as a potent anti-inflammatory factor through suppression of Th1 immune response, and induction of immune tolerance via regulatory T cells, VIP has emerged as a promising therapeutic agent for the treatment of many autoimmune diseases including diabetes.

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Section: Vip-mediated Gene Transfer Studiesmentioning

confidence: 99%

Therapeutic potential of VIP vs PACAP in diabetes

Şanlioğlu

Karaçay²,

Balcı³

et al. 2012

Journal of Molecular Endocrinology

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“…Mindez nem váltott ki gyulladásos vagy egyéb reakciót, a májenzimek szintje nem emelkedett [15,16]. Hasonló experimentális eredményeket közöltek Elsner és mtsai, valamint Gerace és mtsai is [17,18].…”

Section: Langerhans-sziget-neogenezis In Vivo Körülmények Közöttunclassified

Őssejtterápia, β-sejt- és Langerhans-sziget-neogenezis: a jövő lehetséges terápiái 1-es típusú diabetesben?

Gerö

2016

Orvosi Hetilap

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Tökéletes normoglykaemia az 1-es típusú diabeteses betegekben csak sikeres pancreas-vagy Langerhans-szigettranszplantációval érhető el. A teljes pancreas sebészi beültetése invazív, a beteget jelentősen terhelő beavatkozás. A Langerhans-szigetek átültetése nem jelent nagyobb terhelést, de a szigetgraft túlélése korlátozott. Mindkét beavatkozás közös hátránya a nagyfokú donorhiány. A nehézségek egy része áthidalható lenne olyan "mesterséges β-sejtek" alkalmazásával, amelyek ultrastruktúrája azonos a természetes ß-sejtekével, és glükózdependens módon termelnek és választanak el inzulint. Jelenleg három ilyen módszer is rendelkezésünkre áll: β-sejt-képzés az exokrin pancreas ductalis sejtjeiből, β-sejt-képzés őssejtekből, valamint a transzkripciós faktorok virális bevitelével előidézett Langerhanssziget-neogenezis. A szerző e három módszerrel szerzett tapasztalatokat, experimentális eredményeket foglalja össze. Orv. Hetil, 2016, 157(19), 740-745.Kulcsszavak: 1-es típusú diabetes, mesterséges β-sejt, pluripotens őssejt, β-sejt-és szigetneogenezis Stem-cell therapy, β-cell-and islet cell-neogenesis: possible treatments of type 1 diabetes in the future?In type 1 diabetic patients perfect normoglycaemia can only be achieved by successful transplantation of the pancreas or Langerhans' islets. Surgical transplantation of the whole pancreas is an invasive operation exerting great burden on the patients. Transplantation of the islets of Langerhans does not burden the patients but the survival of the islet grafts is limited. Both interventions are hampered by the lack of donor organs. However, much of these difficulties could be overcome by the use of "artificial β-cells" which ought to have an ultrastructure identical with that of natural β-cells and produce and secrete insulin in a glucose dependent manner. At present three such methods are at our disposal: transformation of the ductal cells of the exocrine pancreas into β-cells, development of β-cells from stem-cells, and neogenesis of Langerhans' islets induced by viral delivery of transcription factors. The author summarises the experience and experimental results obtained with the use of the three methods. Rövidítések ActA = ActivinA; Btc = betacellulin; GLP-1 = glükagonszerű peptid-1; HNF = hepaticus nukleáris faktor; Ngn3 = neurogenin-3; NOD-egér = (non-obese diabetic mous) nem elhízott diabeteses egér; PD-L1 = programmed-death ligand1; SC-β = (stem-cell-derived β-cell) őssejt eredetű β-sejt; SPK = (simultaneous pancreas-kidney [transplantation]) szimultán pancreasvese [átültetés] Az 1-es típusú diabetes kialakulásának oka a β-sejtek ellen irányuló autoimmun folyamat, amely e sejtek pusztulásához és így az endogén inzulintermelés teljes és végle-ges megszűnéséhez vezet. E betegeknek tehát az életben maradáshoz inzulinterápiára van szükségük. Amíg azonban az endogén inzulinelválasztás szinte másodpercnyi pontossággal követi a vércukorszint változásait (és ezzel

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“…16 Many studies that have attempted to reproduce this phenomenon by simply expressing either insulin or insulin analogs in liver without the expression of β-cell transcription factors have only reported constitutive release of insulin that is not stored or secreted in a regulated fashion. [71][72][73] More recently, mesenchymal stem cells (MSCs) have been targeted for gene transfer due to their extensive immunomodulatory capacity and reported ability to evade immune rejection. [74][75][76][77] Most use of MSCs in diabetes reversal in animal models has been in the form of native MSC transplantations aimed at modulating immune responses.…”

Section: Target Cells For T1d Gene Therapymentioning

confidence: 99%

“…By contrast, in our NOD mouse study and a similar study by Elsner et al, a simple injection of insulin into the portal circulation resulted in unregulated constitutive release of insulin, no pancreatic transdifferentiation, and an abnormal glucose response. 19,71 Pancreatic transdifferentiation of the liver has been seen in other situations: following a dose of the hepatotoxin carbon tetrachloride 102 and when oval cells were cultured in high glucose. 103,104 We are yet to define the mechanism that has resulted in pancreatic differentiation in our studies, which is being analyzed at the molecular level in our laboratory.…”

Section: -101mentioning

confidence: 99%

Diabetes reversal via gene transfer: building on successes in animal models

Gerace¹,

Martiniello‐Wilks²,

Simpson³

2015

RRED

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Type 1 diabetes (T1D) is caused by the autoimmune destruction of the insulinproducing pancreatic β-cells. People with T1D manage their hyperglycemia using daily insulin injections; however, this does not prevent the development of long-term diabetic complications such as retinopathy, nephropathy, neuropathy, and various macrovascular disorders. Currently, the only "cure" for T1D is pancreas transplantation or islet-cell transplantation; however, this is hampered by the limited number of donors and the requirement for life-long immunosuppression. As a result, the need for alternative therapies is vital. One of the strategies employed to correct T1D is the use of gene transfer to generate the production of an "artificial" β-cell that is capable of secreting insulin in response to fluctuating glucose concentrations that normally occurs in people without T1D. The treatment of many diseases using cell and gene therapy is generating significant attention in the T1D research community; however, for a cell therapy to enter clinical trials, success and safety must first be shown in an appropriate animal model. Animal models have been used in diabetes research for over a century, have improved our understanding of the pathophysiology of diabetes, and have led to the discovery of useful drugs for the treatment of the disease. Currently, the nonobese diabetic mouse is the animal model of choice for the study of T1D as it most closely reflects disease development in humans. The aim of this review is to evaluate the success of cell and gene therapy to reverse T1D in animal models for future clinical application.

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Reversal of Diabetes Through Gene Therapy of Diabetic Rats by Hepatic Insulin Expression via Lentiviral Transduction

Cited by 49 publications

References 36 publications

Therapeutic potential of VIP vs PACAP in diabetes

Therapeutic potential of VIP vs PACAP in diabetes

Őssejtterápia, β-sejt- és Langerhans-sziget-neogenezis: a jövő lehetséges terápiái 1-es típusú diabetesben?

Diabetes reversal via gene transfer: building on successes in animal models

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