Enhanced plasma cholesterol lowering effect of retrovirus-mediated LDL receptor gene transfer to WHHL rabbit liver after improved surgical technique and stimulation of hepatocyte proliferation by combined partial liver resection and thymidine kinase– ganciclovir treatment

Abstract

In this study we report an improved method for in vivo gene A 50% decrease was also observed in plasma triglycertransfer to liver. Repeated injections of Moloney murine ides. Liver function tests indicated a transient increase in leukemia virus-derived retroviruses containing LDL recepplasma alkaline phosphatase level up to 12 weeks after tor cDNA were given to the portal vein in combination with the gene transfer. In situ PCR and RT-PCR analyses india 10% partial liver resection and stimulation of hepatocyte cated that the transgene was present in periportal areas proliferation by plasmid/liposome-mediated thymidine kinand was transcribed to mRNA 1 week after the gene transase gene transfer and ganciclovir treatment. The method fer. Because of the relatively simple and controllable techwas used for the treatment of LDL receptor deficiency in nique we suggest that repeated retrovirus injections via a Watanabe heritable hyperlipidemic rabbits. We demonportal vein catheter together with the limited partial liver strate an increase in hepatocyte proliferation index by thyresection and plasmid/liposome-mediated thymidine kinmidine kinase and ganciclovir treatment from 0.9 to 1.35% ase gene transfer-ganciclovir treatment may be used and a maximum of 35% decrease in total plasma cholesto improve the results of retrovirus-mediated liver gene terol level 2-3 months after the gene transfer. A 20% therapy. decline was still present after a 52-week follow-up period.

Regional and transient ischemia/reperfusion injury in the liver improves therapeutic efficacy of allogeneic intraportal hepatocyte transplantation in low-density lipoprotein receptor deficient Watanabe rabbits

“…A clinically applicable repopulation method to induce cell damage is surgical manipulation of liver tissue [10][11][12]. Removal or permanent blood vessel ligation of one or more liver lobes induces cell proliferation and restoration of the original cell mass from the remaining liver [13,14].…”

Clinical applications of vascular gene therapy

“…Patients with homozygous familial hypercholesterolemia lack functional LDL receptors and develop high plasma cholesterol levels leading to severe atherosclerosis and coronary heart disease during the first or second decade of life. One strategy besides the conventional therapy would be to restore the LDL receptor activity by transferring the functional LDL receptors into hepatocytes and thus lower the plasma cholesterol level [20,21]. The feasibility of this approach has been demonstrated in animal models with in vivo and ex vivo methods [20] and the results of the first clinical trial have also been reported.…”

“…One strategy besides the conventional therapy would be to restore the LDL receptor activity by transferring the functional LDL receptors into hepatocytes and thus lower the plasma cholesterol level [20,21]. The feasibility of this approach has been demonstrated in animal models with in vivo and ex vivo methods [20] and the results of the first clinical trial have also been reported. With retrovirus-mediated, LDL receptor ex vivo gene therapy a 6% to 23% reduction in plasma LDL levels was achieved in three of the five treated patients [21].…”

“…Retroviruses have also been used in preclinical and clinical studies for cardiovascular diseases [11,20,21]. They enter the cells via specific receptors after which genomic RNA is reverse transcribed to DNA that integrates into the host genome.…”

Gene therapy for atherosclerosis and atherosclerosis-related diseases

“…In a retrovirus-mediated in vivo study with Watannabe heritable hyperlipidemic (WHHL) rabbits, HSV thymidine kinase was used to induce hepatocyte proliferation with a minimal liver resection. A 20% decline of total cholesterol was present one year later [6].…”