Transplantation of Gunn rats with autologous fibroblasts expressing bilirubin UDP-glucuronosyltransferase

Correction of genetic deficiency and tumor formation

Jurgen Seppen, Kouji Tada, Roelof Ottenhoff, Krishna Sengupta, Namita Roy Chowdhury, Jayanta Roy-Chowdhury, Piter J. Bosma, Ronald P J Oude Elferink

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

The end product of the breakdown of the heme group of hemoglobin and other heme-containing proteins is bilirubin. Bilirubin is hydrophobic and cannot be excreted as such. Therefore, mammals have a liver enzyme bilirubin UDP-glucuronosyltransferase (B-UGT), which conjugates bilirubin with glucuronic acid, thereby making the molecule much more water soluble. Bilirubin glucuronides are secreted into bile. Patients with Crigler-Najjar (CN) disease have a deficiency in bilirubin UDP-glucuronosyltransferase and acummulate high serum levels of bilirubin. An animal model for CN disease is the Gunn rat. The obvious target for gene therapy for CN disease is the liver, but because liver cells do only divide infrequently, they are difficult to transduce. To investigate whether cells that are easily transduced can be used to develop gene therapy for CN disease, we have transduced Gunn rat fibroblasts with B-UGT, using a recombinant retrovirus. Gunn rat fibroblasts expressing B-UGT were able to glucuronidate bilirubin present in cell culture media. In this study, we describe the intraperitoneal transplantation of Gunn rats with Gunn rat fibroblasts expressing B-UGT. Transplantation of the fibroblasts corrected the genetic deficiency of the Gunn rats, serum bilirubin concentrations of the transplanted Gunn rats were reduced to normal, and bilirubin glucuronides appeared in bile. However, due to the prolonged period of cell culture, the transplanted fibroblasts were transformed, and the experimental animals developed tumors after transplantation.

Original languageEnglish (US)
Pages (from-to)27-36
Number of pages10
JournalHuman Gene Therapy
Volume8
Issue number1
StatePublished - Jan 1 1997

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bilirubin glucuronoside glucuronosyltransferase
Gunn Rats
Fibroblasts
Transplantation
Bilirubin
Neoplasms
Heme
Bile
Genetic Therapy
Cell Culture Techniques
Liver
Retroviridae
Serum
Culture Media
Liver Diseases
Mammals
Hemoglobins

ASJC Scopus subject areas

  • Genetics

Cite this

Transplantation of Gunn rats with autologous fibroblasts expressing bilirubin UDP-glucuronosyltransferase : Correction of genetic deficiency and tumor formation. / Seppen, Jurgen; Tada, Kouji; Ottenhoff, Roelof; Sengupta, Krishna; Chowdhury, Namita Roy; Roy-Chowdhury, Jayanta; Bosma, Piter J.; Oude Elferink, Ronald P J.

In: Human Gene Therapy, Vol. 8, No. 1, 01.01.1997, p. 27-36.

Research output: Contribution to journalArticle

Seppen, J, Tada, K, Ottenhoff, R, Sengupta, K, Chowdhury, NR, Roy-Chowdhury, J, Bosma, PJ & Oude Elferink, RPJ 1997, 'Transplantation of Gunn rats with autologous fibroblasts expressing bilirubin UDP-glucuronosyltransferase: Correction of genetic deficiency and tumor formation', Human Gene Therapy, vol. 8, no. 1, pp. 27-36.
Seppen, Jurgen ; Tada, Kouji ; Ottenhoff, Roelof ; Sengupta, Krishna ; Chowdhury, Namita Roy ; Roy-Chowdhury, Jayanta ; Bosma, Piter J. ; Oude Elferink, Ronald P J. / Transplantation of Gunn rats with autologous fibroblasts expressing bilirubin UDP-glucuronosyltransferase : Correction of genetic deficiency and tumor formation. In: Human Gene Therapy. 1997 ; Vol. 8, No. 1. pp. 27-36.
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