Gene therapy for B-cell lymphoma in a SCID mouse model using an immunoglobulin-regulated diphtheria toxin gene delivered by a novel adenovirus-polylysine conjugate.
Despite advances in conventional therapy, many lives continue to be lost to common forms of B-cell cancers, including leukemias, lymphomas and multiple myeloma. We propose a novel approach to therapy of such cancers using controlled expression of a diphtheria toxin gene (DT-A) to kill malignant cells. We have previously demonstrated selective killing of various cell types, in vitro and in vivo, by cell-specific, transcriptionally controlled expression of this gene. Organ-specific ablation in otherwise healthy transgenic mice has convincingly demonstrated the exquisite specificity achievable by this technique. In the studies now described, DT-A was delivered in vitro and in vivo using a novel gene delivery system employing DNA physically attached to the exterior of adenovirus. After demonstrating the efficacy of gene delivery to Epstein-Barr virus transformed human B-cells in vitro, in vivo work was performed using a SCID mouse model for B-cell lymphoma, in which protection against tumor was observed. The concepts of tissue-regulated toxin gene therapy, and this novel adenovirus gene delivery system are discussed.
Cook
D R
DR
Division of Infectious Disease, University of Colorado Health Sciences Center, Denver 80262.
Maxwell
I H
IH
Glode
L M
LM
Maxwell
F
F
Stevens
J O
JO
Purner
M B
MB
Wagner
E
E
Curiel
D T
DT
Curiel
T J
TJ
D000256:Adenoviridae; D000818:Animals; D001710:Biotin; D002461:Cell Line, Transformed; D004274:DNA, Recombinant / Q000008:administration & dosage*; D004167:Diphtheria Toxin / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005803:Genes, Immunoglobulin; D017930:Genes, Reporter; D005813:Genes, Synthetic; D015316:Genetic Therapy; D004854:Herpesvirus 4, Human; D007145:Immunoglobulin kappa-Chains / Q000235:genetics*; D008024:Ligands; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use*; D011107:Polylysine; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use
D004274:DNA, Recombinant; D004167:Diphtheria Toxin; D007145:Immunoglobulin kappa-Chains; D008024:Ligands; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; C029795:diphtheria toxin fragment A; D011107:Polylysine; D001710:Biotin