Tri-iodothyronine and a deleted form of hepatocyte growth factor act synergistically to enhance liver proliferation and enable in vivo retroviral gene transfer via the peripheral venous system

Forbes, Stuart J.; Themis, Michael; Alison, Malcolm R.; Shiota, Akira; Kobayashi, Toshiya; Coutelle, Charles; Hodgson, H. J. F.

doi:10.1038/sj.gt.3301143

Cited by 14 publications

(16 citation statements)

References 36 publications

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“…This is the first demonstration that injection of purified HGF protein prior to an RV can result in long-term expression of a therapeutic gene, although others have previously demonstrated that HGF potentiates RV transduction, [38][39][40][41] and we showed that intramuscular injection of an adenoviral vector expressing HGF increased RV transduction and improved clinical efficacy in MPS VII mice. 42 The level of cFIX achieved at late times after transfer into adult BALB/c mice (1.75 g/mL) was only 19% of the average value observed in 3 different stains after transfer into neonatal mice (9.3 g/mL) despite use of the same dose of RV per kg body weight.…”

Section: Hgf-potentiated Rv Transfer Into Adult Mice Achieves Therapementioning

confidence: 97%

“…57 However, most of the concerns noted above for neonatal gene transfer need to be addressed prior to implementing this approach in human adults. In addition, it would be necessary to demonstrate that transient administration of HGF is safe, although it has been efficacious and well tolerated in animal models of liver disease 58 and no overt adverse effects were noted in this or previous [38][39][40][41][42] studies. Finally, immune modulation may be necessary at the time of gene therapy, given that antibody responses occurred in all animals that were transduced as adults.…”

Section: Hgf-potentiated Rv Transfer Into Adult Mice Achieves Therapementioning

confidence: 99%

“…Although MLV-based RVs transduce only dividing cells, 34 it was recently shown that they transduce hepatocytes from newborn mice 35,36 and dogs 37 without a stimulus for replication, or hepatocytes from adults after the administration of hepatocyte growth factor (HGF) to induce replication. [38][39][40][41][42] In addition, use of the human ␣ 1 -antitrypsin (hAAT) promoter 43,44 and the woodchuck hepatitis virus posttranscriptional regulatory element (WPRE) 45 have improved the expression per copy of RV. These advances led us to investigate the ability of this vector to correct the bleeding diathesis in hemophilia B.…”

Section: Introductionmentioning

confidence: 99%

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Neonatal or hepatocyte growth factor–potentiated adult gene therapy with a retroviral vector results in therapeutic levels of canine factor IX for hemophilia B

Gao

Sands

et al. 2003

Blood

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Hemophilia B is a bleeding disorder resulting from factor IX (FIX) deficiency that might be treated with gene therapy. Neonatal delivery would correct the disease sooner than would transfer into adults, and could reduce immunological responses. Neonatal mice were injected intravenously with a Moloney murine leukemia virus-based retroviral vector (RV) expressing canine FIX (cFIX). They achieved 150% to 280% of normal cFIX antigen levels in plasma (100% is 5 g/ mL), which was functional in vitro and in vivo. Three newborn hemophilia B dogs that were injected intravenously with RV achieved 12% to 36% of normal cFIX antigen levels, which improved coagulation tests. Only one mild bleed has occurred during 14 total months of evaluation. This is the first demonstration of prolonged expression after neonatal gene therapy for hemophilia B in mice or dogs. Most animals failed to make antibodies to cFIX, demonstrating that neonatal gene transfer may induce tolerance. Although hepatocytes from newborns replicate, those from adults do not. Adult mice therefore received hepatocyte growth factor to induce hepatocyte replication prior to intravenous injection of RV. This resulted in expression of 35% of normal cFIX antigen levels for 11 months, although all mice produced anti-cFIX antibodies. This is the first demonstration that high levels of FIX activity can be achieved with an RV in adults without a partial hepatectomy to induce hepatocyte replication. We conclude that RV-mediated hepatic gene therapy is effective for treating hemophilia B in mice and dogs, although the immune system may complicate gene transfer in adults. IntroductionHemophilia B is a sex-linked disorder due to deficiency of factor IX (FIX) activity that affects 1 in 30 000 males. 1 Hepatic gene therapy could result in the continuous secretion of FIX into the blood and improve bleeding symptoms. Achieving more than 10% of normal activity should prevent most spontaneous bleeds, whereas 1% of normal activity should reduce, but not prevent, bleeding. There has been recent success in using hepatic gene therapy to express therapeutic levels of FIX in mice. 2 For example, lentiviral vectors resulted in FIX antigen levels that were 2% to 7% of normal 3,4 ; adeno-associated virus (AAV) vectors resulted in levels that were 10% to 40% of normal [5][6][7][8][9] or 400% of normal 10 ; adenoviral vectors resulted in levels that were 8% of normal 11 or 60% to 4100% of normal [12][13][14][15][16] ; and plasmids resulted in levels that were 7% to 80% of normal. [17][18][19] In addition, intramuscular injection of AAV vectors resulted in 3% to 7% of normal 5,20,21 or 1000% of normal levels, 22 whereas other nonhepatic approaches generally result in lower long-term expression. 2 Gene therapy appears to be less efficacious in large-animal models than in mice. In some cases, lower expression was obtained despite the use of a dose of vector per body weight similar to that used in mice, although in other cases lower expression could be attributed at least in part to the use of ...

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Section: Hgf-potentiated Rv Transfer Into Adult Mice Achieves Therapementioning

confidence: 97%

Section: Hgf-potentiated Rv Transfer Into Adult Mice Achieves Therapementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Neonatal or hepatocyte growth factor–potentiated adult gene therapy with a retroviral vector results in therapeutic levels of canine factor IX for hemophilia B

Gao

Sands

et al. 2003

Blood

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“…More recently, a number of studies have shown that pretreatment with growth factors can enable retroviral gene transfer to the liver to be achieved. HGF, KGF, T3 as well as a combination thereof resulted in successful transduction of up to 7% of hepatocytes (12)(13)(14)(15). However, the clinical safety of some of these polypeptidic growth factors has not been documented.…”

mentioning

confidence: 91%

Efficient Retroviral Gene Transfer to the Liver in Vivo Using Nonpolypeptidic Mitogens

Pichard

Aubert

Ferry

2001

Biochemical and Biophysical Research Communications

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“…At least in experimental animals, an opportunity is provided by tri-iodothyronine which has proved to be a modulator of liver cell mass, acting as a primary mitogen for the liver (ie able to initiate hepatocyte proliferation in the intact liver). This was initially explored as a means of initiating DNA synthesis and rendering cells susceptible to retroviral gene transfer 7,8 (as discussed below). However, it has the interesting potential of increasing total liver cell mass, total DNA and total protein by inducing proliferation of cells, acting predominantly on hepatocytes in the mid-zonal area of the liver lobule.…”

Section: Growth Factors In Therapy For Liver Diseasementioning

confidence: 99%

Liver cells: biology to therapeutics

Hodgson

2003

Clinical Medicine

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-The liver has a remarkable capacity to regenerate after injury. Recent work has demonstrated that repair may call upon either the division of pre-existing mature cells, or the expansion of intrahepatic progenitor cells. Furthermore, progenitors may migrate into the liver from the bone marrow. Understanding and exploiting the cell biology of the liver provides the basis for innovational treatment, including the use of growth factors, transplantation of isolated cells, genetic manipulation of hepatocytes and liver cell progenitors, and the development of artificial liver support systems.

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Tri-iodothyronine and a deleted form of hepatocyte growth factor act synergistically to enhance liver proliferation and enable in vivo retroviral gene transfer via the peripheral venous system

Cited by 14 publications

References 36 publications

Neonatal or hepatocyte growth factor–potentiated adult gene therapy with a retroviral vector results in therapeutic levels of canine factor IX for hemophilia B

Neonatal or hepatocyte growth factor–potentiated adult gene therapy with a retroviral vector results in therapeutic levels of canine factor IX for hemophilia B

Efficient Retroviral Gene Transfer to the Liver in Vivo Using Nonpolypeptidic Mitogens

Liver cells: biology to therapeutics

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