Long-Term Improvement of Hypercholesterolemia After Ex Vivo Gene Therapy in LDLR-Deficient Rabbits

Chowdhury, Jayanta Roy; Grossman, Mariann; Gupta, Sanjeev; Chowdhury, Namita Roy; Baker, James R.; Wilson, James M.

doi:10.1126/science.1722351

Cited by 356 publications

(132 citation statements)

References 11 publications

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“…[1][2][3][4][5] Efforts to solve this problem have generally used partial hepatectomy (PH) to remove a portion of the resident liver and thus provide a proliferative stimulus to transplanted cells. [3][4][5] Because host hepatocytes can also respond to this liver-regenerative stimulus, selective repopulation by transplanted cells does not occur under most circumstances.…”

mentioning

confidence: 99%

Role of thyroid hormone in stimulating liver repopulation in the rat by transplanted hepatocytes

et al. 1999

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Recently, we reported near-complete repopulation of the rat liver by transplanted hepatocytes using retrorsine (RS), a pyrrolizidine alkaloid that alkylates cellular DNA and blocks proliferation of resident hepatocytes, followed by transplantation of normal hepatocytes in conjunction with two-thirds partial hepatectomy (PH). Because two-thirds PH is not feasible for use in humans, in the present study, we evaluated the ability of thyroid hormone (triiodothyronine [T 3 ]), a known hepatic mitogen, to stimulate liver repopulation in the retrorsine model. Because T 3 initiates morphogenesis in amphibians through a process involving both cell proliferation and apoptosis, we also determined whether apoptosis might play a role in the mechanism of hepatocyte proliferation induced by T 3 . Following hepatocyte transplantation and repeated injections of T 3 , the number of transplanted hepatocytes in the liver of RSpretreated animals increased progressively to repopulate 60% to 80% of parenchymal cell mass in 60 days. We show further that T 3 treatment augments proliferation of normal hepatocytes, as evidenced by increased histone 3 mRNA and cyclin-dependent kinase 2 (cdk2) expression, and this is followed by apoptosis. These combined effects of T 3 lead to selective proliferation of transplanted hepatocytes in RS-pretreated rats, while endogenous hepatocytes, which are blocked in their proliferative capacity by RS, mainly undergo apoptosis. Thus, T 3 can replace PH in the RS-based rat liver repopulation model and therefore represents a significant advance in developing methods for hepatocyte transplantation. (HEPATOLOGY 1999;30:903-913.)A major problem in most hepatocyte transplantation studies to date has been the limited growth of transplanted cells in the recipient liver. [1][2][3][4][5] Efforts to solve this problem have generally used partial hepatectomy (PH) to remove a portion of the resident liver and thus provide a proliferative stimulus to transplanted cells. [3][4][5] Because host hepatocytes can also respond to this liver-regenerative stimulus, selective repopulation by transplanted cells does not occur under most circumstances. However, PH is not practical for routine use in human hepatocyte transplantation protocols, and thus, establishing alternative methods to stimulate hepatocyte proliferation in the context of cell transplantation is of great interest.Three experimental models of extensive liver repopulation have recently been described: the urokinase-type plasminogen activator (uPA) transgenic mouse, 6-8 the fumarylacetoacetate hydrolase (FAH) null mouse, 9,10 and the retrorsine (RS)/PH-treated rat. 11 In the uPA model, endogenous hepatocytes that have deleted the transgene, 6 or transplanted normal hepatocytes, 7,8 proliferate extensively because of continuous proteolytic destruction of resident hepatocytes expressing uPA. [6][7][8] Similarly, in FAH null mice, transplanted wild-type hepatocytes exhibit a growth advantage over enzymedeficient host cells, because the latter accumulate toxic intermedia...

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Role of thyroid hormone in stimulating liver repopulation in the rat by transplanted hepatocytes

et al. 1999

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“…In this study, transplantation of genetically modified autologous hepatocytes (200 millions, which corresponds to 2% of rabbit liver mass) resulted in a long-term and 25-45% reduction in serum cholesterol, and reconstitution of in vivo LDLR activity to 2-4% of normal value. 63 Nonetheless, prevention of atherosclerotic plaques formation was not shown. This preclinical study was followed by a clinical trial in five patients with FH.…”

Section: Mulv Retroviral Vectorsmentioning

confidence: 99%

Liver gene therapy: advances and hurdles

Nguyen

Ferry

2004

Gene Ther

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“…10,11 Since hepatocytes are long-lived cells, 12 the expression of the transgene is stable. [13][14][15] The integrated gene will persist for the life time of the transduced cell and will be present in cells that arise by subsequent cell division.…”

Section: Introductionmentioning

confidence: 99%

A preclinical model of hepatocyte gene transfer: the in vivo, in situ perfused rat liver

Godoy

Malafosse

Fabrè³

et al. 2000

Gene Ther

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Long-Term Improvement of Hypercholesterolemia After Ex Vivo Gene Therapy in LDLR-Deficient Rabbits

Cited by 356 publications

References 11 publications

Role of thyroid hormone in stimulating liver repopulation in the rat by transplanted hepatocytes

Role of thyroid hormone in stimulating liver repopulation in the rat by transplanted hepatocytes

Liver gene therapy: advances and hurdles

A preclinical model of hepatocyte gene transfer: the in vivo, in situ perfused rat liver

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