Lentiviral vectors encoding rabbit low-density lipoprotein receptor (LDLR) or green fluorescent protein (GFP) under the control of a liver-specific promoter (LSP) were used for intraportal gene transfer into the liver of hypercholesterolemic LDLR-deficient Watanabe Heritable Hyperlipidemic rabbits. In vitro cell culture analysis demonstrated functionality of the LSP-LDLR vector in mediating increased degradation of LDL in transduced liver cells. Twenty-five rabbits were each injected with 1 x 10(9) infectious virus particles into the portal vein. Liver biopsy samples were collected 4 weeks after the gene transfer and the rabbits were followed up for 2 years. Histological and RT-PCR analyses showed the expression of GFP and LDLR transgenes in the biopsy samples. Clinical chemistry and histological analyses revealed normal liver function and morphology during the 2-year follow-up with no safety issues. LSP-LDLR-treated rabbits demonstrated an average of 14 +/- 7% decrease in serum cholesterol levels during the first 4 weeks, 44 +/- 8% decrease at 1 year, and 34 +/- 10% decrease at the 2-year time point compared to the control rabbits. This study demonstrates the safety and potential benefits of the third-generation liver-specific lentiviral vectors in the treatment of familial hypercholesterolemia using direct intraportal liver gene therapy without the need for liver resection.
We compared effects of antiangiogenic gene therapy with a combination of soluble sVEGFR‐1, sVEGFR‐2 and sVEGFR‐3 to chemotherapy with carboplatin and paclitaxel and to antiangiogenic monoclonal anti‐VEGF‐antibody bevacizumab in an intraperitoneal ovarian cancer xenograft model in mice (n = 80). Gene therapy was also combined with chemotherapy. Therapy was initiated when sizable tumors were confirmed in magnetic resonance imaging (MRI). Adenovirus‐mediated gene transfer was performed intravenously (2 × 109 pfu), while chemotherapy and monoclonal anti‐VEGF‐antibody were dosed intraperitoneally. The study groups were as follows: AdLacZ control (n = 21); combination of AdsVEGFR‐1, ‐2 and ‐3 (n = 21); combination of AdsVEGFR‐1, ‐2, ‐3 and paclitaxel (n = 9); bevacizumab (n = 14); paclitaxel (n = 9) and carboplatin (n = 5). Effectiveness was assessed by survival time and surrogate measures such as sequential MRI, immunohistochemistry, microvessel density and tumor growth. Antiangiogenic gene therapy combined with paclitaxel significantly prolonged the mean survival of mice (25 days) compared to the controls (15 days) and all other treatment groups (p = 0.001). Bevacizumab treatment did not have any significant effect on the survival. Tumors of the mice treated by gene therapy were significantly smaller than in the control group (p = 0.021). The mean vascular density and total vascular area were also significantly smaller in the tumors of the gene therapy group (p = 0.01). These results show potential of the antiangiogenic gene therapy to improve efficacy of chemotherapy with paclitaxel and support testing of this approach in a phase I clinical trial for the treatment of ovarian cancer.
There were no statistical differences between the three meshes in pain, a feeling of a foreign body or use of analgesics after 5 years of Lichtenstein hernioplasty, when the same surgeon operated all patients with exactly the same surgical technique. CLINICAL TRIAL REGISTER: NCT01295437.
It is concluded that the transduction pattern of uterine tissues varies significantly with the reproductive cycle. Secondly, although the transduction efficiency was relatively high in the endometrial epithelium, the effect of the AdvTK and ganciclovir treatment was poor and not sufficient for clinical applications.
Familial hypercholesterolemia (FH) is an inherited disease of lipoprotein metabolism caused by a defect in the LDL receptor (LDLR) leading to severe hypercholesterolemia, and associated with an increased risk of coronary heart disease and myocardial infarction. We have developed a gene therapy protocol for FH using AAV2, AAV9 and lentiviral vectors and tested safety and efficacy in LDL receptor deficient Watanabe Heritable Hyperlipidemic rabbits. We show that LV-LDLR produced a significant long-lasting decrease in total serum cholesterol whereas AAV9-LDLR resulted only in a transient decrease and AAV2-LDLR failed to reduce serum cholesterol levels. A significant pathological side effect, bile-duct proliferation, was seen in the liver of AAV2-LDLR rabbits associated with an increased expression of Cyr61 matricellular protein. Special attention should be given to liver changes in gene therapy applications when genes affecting cholesterol and lipoprotein metabolism are used for therapy.
Although AdvTK gene therapy may initially affect ovarian cells, the influence appears to be transient. However, after direct exposure of the ovarian cells in high concentration of adenoviruses, transmission of a transgene in the offspring cannot be excluded.
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