Long‐term reversal of diabetes in non‐obese diabetic mice by liver‐directed gene therapy

Ren, Bin; O’Brien, Bronwyn A.; Byrne, M; Ch'ng, Edwin; Gatt, Prudence N.; Swan, M. A.; Nassif, Najah T.; Wei, Ming Q.; Gijsbers, Rik; Debyser, Zeger; Simpson, Ann M.

doi:10.1002/jgm.2692

Cited by 30 publications

(76 citation statements)

References 54 publications

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“…Az így kezelt állatok májsejtjeiben számos, a β-sejtekre jellemző transzkripciós faktor génje is expresszálódott. 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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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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“…63 Within our laboratory, LV is currently the gene transfer vector of choice for corrective gene therapy. We have successfully used a LV, HMD, which has a murine stem cell virus promoter to deliver furin-cleavable insulin (INS-FUR) to the livers of STZ-diabetic rats, 18 NOD mice, 19 and pancreatectomized Westran pigs. 20 In these animal models, we observed spontaneous expression of β-cell transcription factors, formation of storage granules, and permanent reversal of diabetes.…”

Section: Selecting a Suitable Vector For Gene Transfermentioning

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%

“…We permanently reversed diabetes in STZ-diabetic rats 18 and spontaneously diabetic NOD mice. 19 In both studies, we reported spontaneous expression of key β-cell transcription factors (Pdx-1, Neurog3, and NeuroD1), which are important in the development of insulin storage and regulated insulin expression in pancreatic β-cells.…”

mentioning

confidence: 93%

“…13,14 In addition, gene transfer of pancreatic transcription factors and insulin for the production of "artificial" β-cells that are capable of synthesizing and secreting insulin in response to metabolic signals is a promising alternative. Two common methods of generating surrogate β-cells are the dedifferentiation and directed transdifferentiation of autologous or allogeneic cells ex vivo [15][16][17] followed by transplantation, and the in vivo [18][19][20] transdifferentiation of target tissue via gene transfer of transcription factors or insulin within viral vectors. Animal models have been used in T1D research since the discovery of insulin by Banting and Best in 1922 21 for studying the pathogenesis of the disease and its complications and for the discovery of new treatments.…”

mentioning

confidence: 99%

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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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Response to the letter to the editor by M. Elsner et al: “Comment on Binhai Ren et al (2013;15:28–41). Long term reversal of diabetes in non‐obese diabetic mice by liver‐directed gene therapy”

Simpson

Ren

O’Brien

et al. 2013

The Journal of Gene Medicine

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Long‐term reversal of diabetes in non‐obese diabetic mice by liver‐directed gene therapy

Abstract: This gene therapy protocol has, for the first time, permanently reversed T1D with normal glucose tolerance in NOD mice and, as such, represents a novel therapeutic strategy for the treatment of T1D.

Cited by 30 publications

References 54 publications

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

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

Response to the letter to the editor by M. Elsner et al: “Comment on Binhai Ren et al (2013;15:28–41). Long term reversal of diabetes in non‐obese diabetic mice by liver‐directed gene therapy”

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