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J Virol, February 1998, p. 926-933, Vol. 72, No. 2
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Production and Characterization of Improved Adenovirus Vectors with the E1, E2b, and E3 Genes Deleted

Andrea Amalfitano,1,2,* Michael A. Hauser,3 Huimin Hu,1 Delila Serra,1 Catherine R. Begy,3 and Jeffrey S. Chamberlain3

Department of Pediatrics, Division of Medical Genetics,1 and Department of Genetics,2 Duke University Medical Center, Durham, North Carolina 27710, and Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 481093

Received 2 July 1997/Accepted 27 October 1997

Adenovirus (Ad)-based vectors have great potential for use in the gene therapy of multiple diseases, both genetic and nongenetic. While capable of transducing both dividing and quiescent cells efficiently, Ad vectors have been limited by a number of problems. Most Ad vectors are engineered such that a transgene replaces the Ad E1a, E1b, and E3 genes; subsequently the replication-defective vector can be propagated only in human 293 cells that supply the deleted E1 gene functions in trans. Unfortunately, the use of high titers of E1-deleted vectors has been repeatedly demonstrated to result in low-level expression of viral genes still resident in the vector. In addition, the generation of replication-competent Ad (RCA) by recombination events with the E1 sequences residing in 293 cells further limits the usefulness of E1-deleted Ad vectors. We addressed these problems by isolating new Ad vectors deleted for the E1, E3, and the E2b gene functions. The new vectors can be readily grown to high titers and have several improvements, including an increased carrying capacity and a theoretically decreased risk for generating RCA. We have also demonstrated that the further block to Ad vector replication afforded by the deletion of both the E1 and E2b genes significantly diminished Ad late gene expression in comparison to a conventional E1-deleted vector, without destabilization of the modified vector genome. The results suggested that these modified vectors may be very useful both for in vitro and in vivo gene therapy applications.

* Corresponding author. Mailing address: Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Box 2618 Medical Sciences Research Building, Rm. 101B, Durham, NC 27710. Phone: (919) 681-6356. Fax: (919) 684-2362. E-mail: amalf001{at}mc.duke.edu.




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