Normal perinatal rise in serum cholesterol is inhibited by hepatic delivery of adenoviral vector expressing apolipoprotein B mRNA editing enzyme (Apobec1) in rabbits.

Abstract

BACKGROUND:

Prenatal or neonatal hepatic gene delivery may result in more effective therapy for inborn errors of metabolism due to the immature immune system of the perinatal animal, and the ability to intervene prior to any significant cellular damage. Newborn New Zealand White rabbits have low serum levels of cholesterol at birth, with a significant and sustained rise of cholesterol while they are nursing. We used this physiologic hypercholesterolemia model to study the effect of adenovirus-mediated hepatic gene transfer of rat apolipoprotein B mRNA editing enzyme (Apobec1) on modulation of plasma cholesterol levels.

METHODS AND RESULTS:

Transcutaneous injection of recombinant adenovirus expressing Apobec1 (AvApobec1) into the liver of newborn rabbits in vivo resulted in efficient Apobec1 expression until Day 50, as detected by PCR-Southern blot analysis. By in vitro editing assay, liver extracts of AvApobec1-treated rabbits were found to have apoB mRNA editing activities of approximately 12, 15, and 15%, on Days 2, 10, and 20 after AvApobec1 administration, compared with 0% editing activity in AvLacZ control vector-injected animals. This physiological level of Apobec1 expression was associated with the production of apoB-48-containing lipoprotein particles from rabbit liver, with a concomitant 30% reduction in total plasma cholesterol compared to AvLacZ-treated or untreated control animals.

CONCLUSION:

Neonatal intrahepatic delivery of a first-generation adenoviral vector results in efficient gene transfer with little immune response, suggesting that repeated administration may be possible in the neonatal period.

• Authors: Y Wu, B B Teng, M L Brandt, P A Piedra, J Liu, L Chan
• Journal: The Journal of surgical research (J Surg Res) Vol. 85 Issue 1 Pg. 148-57 (Jul 1999) ISSN: 0022-4804 [Print] United States
• PMID: 10383852 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
• Copyright: Copyright 1999 Academic Press.

Chemical References

• Anticholesteremic Agents
• Recombinant Proteins
• Cholesterol
• AICDA (activation-induced cytidine deaminase)
• APOBEC-1 Deaminase
• Apobec1 protein, rat
• Cytidine Deaminase

Topics

• APOBEC-1 Deaminase
• Adenoviridae (genetics, immunology)
• Aging (immunology)
• Animals
• Animals, Newborn (blood)
• Antibody Formation (physiology)
• Anticholesteremic Agents (metabolism)
• Cholesterol (blood)
• Cytidine Deaminase (genetics, immunology, physiology)
• Gene Transfer Techniques
• Genetic Vectors (immunology)
• Liver (physiology)
• Rabbits
• Rats
• Recombinant Proteins