Abstract
Objective. Wilson disease is a copper storage disorder caused by mutations in the ATP7B gene leading to liver cirrhosis. It has previously been shown that lentiviral vectors can govern an efficient delivery and stable expression of a transgene. The aim of this pilot study was to prove the principle of a lentiviral gene transfer in the Long-Evans cinnamon (LEC) rat, an animal model of Wilson disease. Material and methods. LEC rats were treated either by systemic application of lentiviral vectors or by intrasplenic transplantation of LEC-rat hepatocytes lentivirally transduced with ATP7B. The ATP7B gene expression was analyzed by RT-PCR and immunofluorescence analysis. The therapeutic effect was assessed by analysis of liver histology, serum ceruloplasmin oxidase activity, and liver copper content. Results. Hepatic expression of the transgene was detected at different time-points post-treatment and lasted for up to 24 weeks (end of experiment). Liver copper levels were lowered in all treatment groups compared to untreated LEC rats. Twenty-four weeks after treatment, the area of the examined liver-tissue sections occupied by fibrosis was 48.3-57.9% in untreated LEC rats and 10.7-19.8% in rats treated with cell therapy. In systemically treated rats, only small fibrous septa could be observed. Conclusions. These data prove for the first time that lentiviral ATP7B gene transfer is feasible in Wilson disease. In our pilot study the systemic approach was more promising in ameliorating disease progression than the transplantation of lentivirally transduced hepatocytes.
| Original language | English |
|---|---|
| Pages (from-to) | 974-982 |
| Number of pages | 9 |
| Journal | Scandinavian Journal of Gastroenterology |
| Volume | 41 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - Aug 1 2006 |
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Keywords
- Copper
- LEC rat
- Lentiviral gene therapy
- Wilson disease
ASJC Scopus subject areas
- Gastroenterology
Cite this
Lentiviral gene transfer ameliorates disease progression in Long-Evans cinnamon rats : An animal model for Wilson disease. / Merle, Uta; Enckea, Jens; Tuma, Sabine; Volkmann, Martin; Naldini, Luigi; Stremmel, Wolfgang.
In: Scandinavian Journal of Gastroenterology, Vol. 41, No. 8, 01.08.2006, p. 974-982.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Lentiviral gene transfer ameliorates disease progression in Long-Evans cinnamon rats
T2 - An animal model for Wilson disease
AU - Merle, Uta
AU - Enckea, Jens
AU - Tuma, Sabine
AU - Volkmann, Martin
AU - Naldini, Luigi
AU - Stremmel, Wolfgang
PY - 2006/8/1
Y1 - 2006/8/1
N2 - Objective. Wilson disease is a copper storage disorder caused by mutations in the ATP7B gene leading to liver cirrhosis. It has previously been shown that lentiviral vectors can govern an efficient delivery and stable expression of a transgene. The aim of this pilot study was to prove the principle of a lentiviral gene transfer in the Long-Evans cinnamon (LEC) rat, an animal model of Wilson disease. Material and methods. LEC rats were treated either by systemic application of lentiviral vectors or by intrasplenic transplantation of LEC-rat hepatocytes lentivirally transduced with ATP7B. The ATP7B gene expression was analyzed by RT-PCR and immunofluorescence analysis. The therapeutic effect was assessed by analysis of liver histology, serum ceruloplasmin oxidase activity, and liver copper content. Results. Hepatic expression of the transgene was detected at different time-points post-treatment and lasted for up to 24 weeks (end of experiment). Liver copper levels were lowered in all treatment groups compared to untreated LEC rats. Twenty-four weeks after treatment, the area of the examined liver-tissue sections occupied by fibrosis was 48.3-57.9% in untreated LEC rats and 10.7-19.8% in rats treated with cell therapy. In systemically treated rats, only small fibrous septa could be observed. Conclusions. These data prove for the first time that lentiviral ATP7B gene transfer is feasible in Wilson disease. In our pilot study the systemic approach was more promising in ameliorating disease progression than the transplantation of lentivirally transduced hepatocytes.
AB - Objective. Wilson disease is a copper storage disorder caused by mutations in the ATP7B gene leading to liver cirrhosis. It has previously been shown that lentiviral vectors can govern an efficient delivery and stable expression of a transgene. The aim of this pilot study was to prove the principle of a lentiviral gene transfer in the Long-Evans cinnamon (LEC) rat, an animal model of Wilson disease. Material and methods. LEC rats were treated either by systemic application of lentiviral vectors or by intrasplenic transplantation of LEC-rat hepatocytes lentivirally transduced with ATP7B. The ATP7B gene expression was analyzed by RT-PCR and immunofluorescence analysis. The therapeutic effect was assessed by analysis of liver histology, serum ceruloplasmin oxidase activity, and liver copper content. Results. Hepatic expression of the transgene was detected at different time-points post-treatment and lasted for up to 24 weeks (end of experiment). Liver copper levels were lowered in all treatment groups compared to untreated LEC rats. Twenty-four weeks after treatment, the area of the examined liver-tissue sections occupied by fibrosis was 48.3-57.9% in untreated LEC rats and 10.7-19.8% in rats treated with cell therapy. In systemically treated rats, only small fibrous septa could be observed. Conclusions. These data prove for the first time that lentiviral ATP7B gene transfer is feasible in Wilson disease. In our pilot study the systemic approach was more promising in ameliorating disease progression than the transplantation of lentivirally transduced hepatocytes.
KW - Copper
KW - LEC rat
KW - Lentiviral gene therapy
KW - Wilson disease
UR - http://www.scopus.com/inward/record.url?scp=33745712832&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33745712832&partnerID=8YFLogxK
U2 - 10.1080/00365520600554790
DO - 10.1080/00365520600554790
M3 - Article
VL - 41
SP - 974
EP - 982
JO - Scandinavian Journal of Gastroenterology
JF - Scandinavian Journal of Gastroenterology
SN - 0036-5521
IS - 8
ER -