Spirituality/Medicine Interface Project

Gene Therapy: Science Fiction or Reality?

Authors: Meredith A. Preuss, PhD, David T. Curiel, MD, PhD

Abstract

Gene therapy has been proposed to be the modern medical cure for multiple diseases such as cancer, genetic disorders, as well as a potentially potent mediator of behavior. In the early days of gene therapy, the primary purpose was to develop therapies that would cure monogenetic diseases. However, with rapid advances in DNA technologies, specifically in the discovery of genes associated with disease pathologies, gene therapy strategies have expanded to include more complex diseases such as cancer, cardiovascular disease, and metabolic disorders. Furthermore, due to new developments in gene therapy vehicles, novel gene therapy strategies have begun to encompass not only curative therapies but also palliative therapies. Currently, new roads in this research have also initiated debates as to whether behaviors such as promiscuity1 and alcoholism2 should be included into the candidate disorders for gene therapy application. Thus, in addition to extending or improving life, gene therapy may also allow manipulation of the distinct differences between nature and nurture and thus not only affect disorders of the body, but potentially those of the mind as well.

This content is limited to qualifying members.

Existing members, please login first

If you have an existing account please login now to access this article or view purchase options.

Purchase only this article ($25)

Create a free account, then purchase this article to download or access it online for 24 hours.

Purchase an SMJ online subscription ($75)

Create a free account, then purchase a subscription to get complete access to all articles for a full year.

Purchase a membership plan (fees vary)

Premium members can access all articles plus recieve many more benefits. View all membership plans and benefit packages.

References

1. Lim MM, Wang Z, Olazabal DE, et al. Enhanced partner preference in a promiscuous species by manipulating the expression of a single gene. Nature 2004;429:754–757.
 
2. Thanos PK, Rivera SN, Weaver K, et al. Dopamine D2R DNA transfer in dopamine D2 receptor-deficient mice: effects on ethanol drinking. Life Sci 2005;77:130–139.
 
3. Couzin J, Kaiser J. Gene therapy. As Gelsinger case ends, gene therapy suffers another blow. Science 2005;307:1028.
 
4. Douglas JT, Kim M, Sumerel LA, et al. Efficient oncolysis by a replicating adenovirus (ad) in vivo is critically dependent on tumor expression of primary ad receptors. Cancer Res 2001;61:813–817.
 
5. Bauerschmitz GJ, Guse K, Kanerva A, et al. Triple-targeted oncolytic adenoviruses featuring the cox2 promoter, E1A transcomplementation, and serotype chimerism for enhanced selectivity for ovarian cancer cells. Mol Ther 2006;14:164–174.
 
6. Borovjagin AV, Krendelchtchikov A, Ramesh N, et al. Complex mosaicism is a novel approach to infectivity enhancement of adenovirus type 5-based vectors. Cancer Gene Ther 2005;12:475–486.
 
7. Glasgow JN, Kremer EJ, Hemminki A, et al. An adenovirus vector with a chimeric fiber derived from canine adenovirus type 2 displays novel tropism. Virology 2004;324:103–116.
 
8. Kanerva A, Mikheeva GV, Krasnykh V, et al. Targeting adenovirus to the serotype 3 receptor increases gene transfer efficiency to ovarian cancer cells. Clin Cancer Res 2002;8:275–280.
 
9. Kawakami Y, Li H, Lam JT, et al. Substitution of the adenovirus serotype 5 knob with a serotype 3 knob enhances multiple steps in virus replication. Cancer Res 2003;63:1262–1269.
 
10. Krasnykh V, Dmitriev I, Mikheeva G, et al. Characterization of an adenovirus vector containing a heterologous peptide epitope in the HI loop of the fiber knob. J Virol 1998;72:1844–1852.
 
11. Le LP, Rivera AA, Glasgow JN, et al. Infectivity enhancement for adenoviral transduction of canine osteosarcoma cells. Gene Ther 2006;13:389–399.
 
12. Short JJ, Pereboev AV, Kawakami Y, et al. Adenovirus serotype 3 utilizes CD80 (B7.1) and CD86 (B7.2) as cellular attachment receptors. Virology 2004;322:349–359.
 
13. Stoff-Khalili MA, Rivera AA, Glasgow JN, et al. A human adenoviral vector with a chimeric fiber from canine adenovirus type 1 results in novel expanded tropism for cancer gene therapy. Gene Ther 2005;12:1696–1706.
 
14. Stoff-Khalili MA, Stoff A, Rivera AA, et al. Gene transfer to carcinoma of the breast with fiber-modified adenoviral vectors in a tissue slice model system. Cancer Biol Ther 2005;4:1203–1210.
 
15. Takayama K, Reynolds PN, Short JJ, et al. A mosaic adenovirus possessing serotype Ad5 and serotype Ad3 knobs exhibits expanded tropism. Virology 2003;309:282–293.
 
16. Uil TG, Seki T, Dmitriev I, et al. Generation of an adenoviral vector containing an addition of a heterologous ligand to the serotype 3 fiber knob. Cancer Gene Ther 2003;10:121–124.
 
17. Hedley SJ, Auf der Maur A, Hohn S, et al. An adenovirus vector with a chimeric fiber incorporating stabilized single chain antibody achieves targeted gene delivery. Gene Ther 2006;13:88–94.
 
18. Bilbao G, Contreras JL, Dmitriev I, et al. Genetically modified adenovirus vector containing an RGD peptide in the HI loop of the fiber knob improves gene transfer to nonhuman primate isolated pancreatic islets. Am J Transplant 2002;2:237–243.
 
19. Contreras JL, Wu H, Smyth CA, et al. Double genetic modification of adenovirus fiber with RGD polylysine motifs significantly enhances gene transfer to isolated human pancreatic islets.Transplantation 2003;76:252–261.
 
20. Garcia-Castro J, Segovia JC, Garcia-Sanchez F, et al. Selective transduction of murine myelomonocytic leukemia cells (WEHI-3B) with regular and RGD-adenoviral vectors. Mol Ther 2001;3:70–77.
 
21. Reynolds P, Dmitriev I, Curiel D. Insertion of an RGD motif into the HI loop of adenovirus fiber protein alters the distribution of transgene expression of the systemically administered vector. Gene Ther 1999;6:1336–1339.
 
22. Wang M, Hemminki A, Siegal GP, et al. Adenoviruses with an RGD-4C modification of the fiber knob elicit a neutralizing antibody response but continue to allow enhanced gene delivery. Gynecol Oncol 2005;96:341–348.
 
23. Wu H, Seki T, Dmitriev I, et al. Double modification of adenovirus fiber with RGD and polylysine motifs improves coxsackievirus-adenovirus receptor-independent gene transfer efficiency. Hum Gene Ther 2002;13:1647–1653.
 
24. Reynolds PN, Nicklin SA, Kaliberova L, et al. Combined transductional and transcriptional targeting improves the specificity of transgene expression in vivo. Nat Biotechnol 2001;19:838–842.
 
25. Adachi Y, Reynolds PN, Yamamoto M, et al. Midkine promoter-based adenoviral vector gene delivery for pediatric solid tumors. Cancer Res 2000;60:4305–4310.
 
26. Yamamoto M, Alemany R, Adachi Y, et al. Characterization of the cyclooxygenase-2 promoter in an adenoviral vector and its application for the mitigation of toxicity in suicide gene therapy of gastrointestinal cancers. Mol Ther 2001;3:385–394.
 
27. Zhu ZB, Makhija SK, Lu B, et al. Transcriptional targeting of tumors with a novel tumor-specific survivin promoter. Cancer Gene Ther 2004;11:256–262.
 
28. Zhu ZB, Makhija SK, Lu B, et al. Transcriptional targeting of adenoviral vector through the CXCR4 tumor-specific promoter. Gene Ther 2004;11:645–648.
 
29. Scott JM, Chamberlain JS. Gutted adenoviral vectors for gene transfer to muscle. Methods Mol Biol2003;219:19–28.
 
30. Wu H, Han T, Belousova N, et al. Identification of sites in adenovirus hexon for foreign peptide incorporation. J Virol 2005;79:3382–3390.
 
31. Yant SR, Ehrhardt A, Mikkelsen JG, et al. Transposition from a gutless adeno-transposon vector stabilizes transgene expression in vivo. Nat Biotechnol 2002;20:999–1005.
 
32. Lee CT, Lee YJ, Kwon SY, et al. In vivo imaging of adenovirus transduction and enhanced therapeutic efficacy of combination therapy with conditionally replicating adenovirus and adenovirus-p27.Cancer Res 2006;66:372–377.
 
33. Raben D, Buchsbaum DJ, Khazaeli MB, et al. Enhancement of radiolabeled antibody binding and tumor localization through adenoviral transduction of the human carcinoembryonic antigen gene. Gene Ther 1996;3:567–580.
 
34. Rogers BE, Rosenfeld ME, Khazaeli MB, et al. Localization of iodine-125-mIP-Des-Met14-bombesin (7–13)NH2 in ovarian carcinoma induced to express the gastrin releasing peptide receptor by adenoviral vector-mediated gene transfer. J Nucl Med 1997;38:1221–1229.
 
35. Zinn KR, Douglas JT, Smyth CA, et al. Imaging and tissue biodistribution of 99mTc-labeled adenovirus knob (serotype 5). Gene Ther 1998;5:798–808.
 
36. Wagner JA, Nepomuceno IB, Messner AH, et al. A phase II, double-blind, randomized, placebo-controlled clinical trial of tgAAVCF using maxillary sinus delivery in patients with cystic fibrosis with antrostomies. Hum Gene Ther 2002;13:1349–1359.
 
37. Moss RB, Rodman D, Spencer LT, et al. Repeated adeno-associated virus serotype 2 aerosol-mediated cystic fibrosis transmembrane regulator gene transfer to the lungs of patients with cystic fibrosis: a multicenter, double-blind, placebo-controlled trial. Chest 2004;125:509–521.
 
38. Goff SP. Retrovirus restriction factors. Mol Cell 2004;16:849–859.
 
39. Bieniasz PD. Restriction factors: a defense against retroviral infection. Trends Microbiol 2003;11:286–291.
 
40. Bieniasz PD. Intrinsic immunity: a front-line defense against viral attack. Nat Immunol 2004;5:1109–1115.
 
41. Kaneda Y, Tabata Y. Non-viral vectors for cancer therapy. Cancer Sci 2006;97:348–354.
 
42. Qian ZM, Li H, Sun H, et al. Targeted drug delivery via the transferrin receptor-mediated endocytosis pathway. Pharmacol Rev 2002;54:561–587.
 
43. Sudimack J, Lee RJ. Targeted drug delivery via the folate receptor. Adv Drug Deliv Rev 2000;41:147–162.
 
44. Sudimack JJ, Adams D, Rotaru J, et al. Folate receptor-mediated liposomal delivery of a lipophilic boron agent to tumor cells in vitro for neutron capture therapy. Pharm Res 2002;19:1502–1508.
 
45. Bainbridge JW, Mistry A, Schlichtenbrede FC, et al. Stable rAAV-mediated transduction of rod and cone photoreceptors in the canine retina. Gene Ther 2003;10:1336–1344.
 
46. Dinculescu A, Glushakova L, Min SH, et al. Adeno-associated virus-vectored gene therapy for retinal disease. Hum Gene Ther 2005;16:649–663.
 
47. Acland GM, Aguirre GD, Bennett J, et al. Long-term restoration of rod and cone vision by single dose rAAV-mediated gene transfer to the retina in a canine model of childhood blindness. Mol Ther 2005;12:1072–1082.
 
48. Jacobson SG, Acland GM, Aguirre GD, et al. Safety of recombinant adeno-associated virus type 2-RPE65 vector delivered by ocular subretinal injection. Mol Ther 2006;13:1074–1084.