Lentiviral gene transfer ameliorates disease progression in Long-Evans cinnamon rats: an animal model for Wilson disease.
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.


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.
Merle
Uta
U
Department of Gastroenterology, University Hospital Heidelberg, Germany. Uta_Merle@med.uni-heidelberg.de
Encke
Jens
J
Tuma
Sabine
S
Volkmann
Martin
M
Naldini
Luigi
L
Stremmel
Wolfgang
W
D000251:Adenosine Triphosphatases / Q000235:genetics; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics; D002570:Ceruloplasmin / Q000032:analysis; D003300:Copper / Q000032:analysis; D000073840:Copper-Transporting ATPases; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D022781:Hepatocytes; D006527:Hepatolenticular Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D016086:Lentivirus; D008099:Liver / Q000737:chemistry / Q000473:pathology; D051381:Rats; D020332:Rats, Inbred LEC; D020318:Rats, Long-Evans; D014161:Transduction, Genetic
D027682:Cation Transport Proteins; D003300:Copper; D002570:Ceruloplasmin; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases