Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-08-28
2003-03-11
Wehbe′, Anne M. (Department: 1632)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S320100, C435S235100, C435S455000, C424S199100, C424S093200
Reexamination Certificate
active
06531456
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to methods of treating solid tumors. More particularly, the invention relates to the use of recombinant adeno-associated virus (rAAV) virions to deliver a plurality of selected genes to cancerous cells and tissue. The method provides for the introduction of a drug-susceptibility gene and a second gene capable of providing an ancillary therapeutic effect into solid tumor cells. The invention also relates to rAAV virions that contain DNA useful in the treatment of neoplastic disease.
BACKGROUND OF THE INVENTION
Gene delivery is a promising method for the treatment of acquired and inherited diseases. A number of viral based systems for gene transfer purposes have been described, such as retroviral systems which are currently the most widely used viral vector systems for gene transfer. For descriptions of various retroviral systems, see, e.g., U.S. Pat. No. 5,219,740; Miller and Rosman (1989)
BioTechniques
7:980-990; Miller, A. D. (1990)
Human Gene Therapy
1:5-14; Scarpa et al. (1991)
Virology
180:849-852; Burns et al. (1993)
Proc. Natl. Acad. Sci. USA
90:8033-8037; and Boris-Lawrie and Temin (1993)
Cur. Opin. Genet. Develop
. 3:102-109.
A number of adenovirus based gene delivery systems have also been developed. Human adenoviruses are double-stranded DNA viruses which enter cells by receptor-mediated endocytosis. These viruses are particularly well suited for gene transfer because they are easy to grow and manipulate and they exhibit a broad host range in vivo and in vitro. Adenovirus is easily produced at high titers and is stable so that it can be purified and stored. Even in the replication-competent form, adenoviruses generally cause only low level morbidity and are not associated with human malignancies. For descriptions of various adenovirus-based gene delivery systems, see, e.g., Haj-Ahmad and Graham (1986)
J. Virol
. 57:267-274; Bett et al. (1993)
J. Virol
. 67:5911-5921; Mittereder et al. (1994)
Human Gene Therapy
5:717-729; Seth et al. (1994)
J. Virol
. 68:933-940; Barr et al. (1994)
Gene Therapy
1:51-58; Berkner, K. L. (1988)
BioTechniques
6:616-629; Rich et al. (1993)
Human Gene Therapy
4:461-476.
The in vivo transfer of specific tumor suppressor genes, apoptotic genes, or genes that encode a particular toxic product to cancer cells, using such known gene delivery systems, will provide an attractive alternative to conventional avenues in the treatment of neoplastic disease. Such approaches are particularly indicated in the treatment of cancers that are refractive to conventional procedures such as surgery, radiotherapy and chemotherapy. In this regard, advances in molecular biology have identified a number of mechanisms that control cell growth and differentiation. Experimental treatments which specifically target these pathways using gene therapy are currently underway. Particularly, a number of approaches involving somatic gene therapy in cancer treatment have been investigated, including drug sensitization, genetic immunomodulation, normal tissue protection, gene replacement and antisense strategies. Gutierrez et al. (1992)
Lancet
339:715-721, Anderson, W. F. (1994)
Hum. Gene Ther
. 5:1-2.
Of these approaches, drug sensitization has provided the most promising results to date. Drug sensitization involves the transfer of suicide genes (e.g., drug-susceptibility genes) to tumor cells to render those cells sensitive to compounds or compositions that are relatively nontoxic to normal cells. Moolten, F. L. (1994)
Cancer Gene Ther
. 1:279-287. Examples of suicide genes are thymidine kinase of herpes simplex virus (HSV-tk), cytochrome P450 (Manome et al. (1996) Gene
Therapy
3:513-520), human deoxycytidine kinase (Manome et al. (1996)
Nature Medicine
2(5):567-573) and the bacterial enzyme cytosine deaminase (Dong et al. (1996)
Human Gene Therapy
7:713-720). Cells which express these genes are rendered sensitive to the effects of the relatively nontoxic prodrugs ganciclovir (HSV-tk), cyclophosphamide (cytochrome P450 2B1), cytosine arabinoside (human deoxycytidine kinase) or 5-fluorocytosine (bacterial cytosine deaminase). Culver et al. (1992)
Science
256:1550-1552, Huber et al. (1994)
Proc. Natl. Acad. Sci. USA
91:8302-8306.
The HSV-tk gene is the most widely studied drug-susceptibility gene. HSV-tk converts specific protoxic nucleoside analogues, such as acyclovir and ganciclovir, to monophosphate intermediates that are then phosphorylated by cellular kinases to provide potent DNA synthesis inhibitors. Cells capable of expressing HSV-tk are rendered extremely sensitive to the toxic effect of ganciclovir, whereas non-HSV-tk expressing cells are much less sensitive, resulting in a large therapeutic index. Tumor modeling experiments using gene delivery of HSV-tk have demonstrated complete regression of established tumors and long-term animal survival, even though only a portion of the tumor cells were actually transduced with the HSV-tk gene. This so-called “bystander” cytocidal effect provides an important therapeutic advantage, as it avoids the need to transduce 100% of the tumor cells with the HSV-tk gene. For a detailed description of the bystander effect, see, e.g., Vrionis et al. (1995)
J. Neurosurg
. 83:698-704, Ishii et al. (1994)
J. Cell Biochem
. 18A:226, and Freeman et al. (1993)
Cancer Res
. 53:5274-5283.
In vivo transfer of drug-susceptibility genes is especially suited for treating solid tumors that are growing rapidly and invading normal tissue composed largely of nonproliferating or quiescent cells. Such therapies have thus been applied to the treatment of hepatocellular carcinoma (HCC). HCC is a common human malignancy that is particularly refractive to conventional cancer therapies. Modifications in conventional chemotherapeutic protocols, such as intrahepatic artery infusion of cytotoxic drugs, are able to improve tumor responses but fail to substantially improve patient prognosis or survival. Venook, A. P. (1994)
J. Clin. Oncol
. 12:1323-1334, Farmer et al. (1994)
Cancer
73:2669-2670. The most effective approach to date in the treatment of HCC entails complete surgical ablation of the tumor by partial hepatectomy or by total hepatectomy coupled with liver transplantation.
Recently, investigators have shown suppression of tumor growth and increased survival rates in transgenic murine subjects that express HSV-tk in HCC cells when those subjects were treated with ganciclovir. Macri et al. (1994)
Hum. Gene Ther
. 5:175-182. Retroviral vehicles have been used to transfer varicella-zoster virus thymidine kinase into HCC tumor cells to confer sensitivity to 6-methoxypurine arabino-nucleoside. Huber et al. (1991)
Proc. Natl. Acad. Sci. USA
88:8039-8043. Further, adenoviral vehicles have been used to transfer HSV-tk into HCC cells to confer sensitivity to ganciclovir. Qian et al. (1995)
Hepatology
22:118-123.
The use of replication-deficient retroviral vectors to transduce the HSV-tk gene into solid tumor cells is also being clinically investigated as a new approach in the treatment of human ovarian cancer. Ishii et al. (1994)
J. Cell Biochem
. 18A:226. Additionally, studies have been described wherein pancreatic cancer xenografts were successfully treated in severe combined immunodeficient (scid) mice using retrovirally-mediated HSV-tk transduction and ganciclovir treatment. DiMaio et al. (1994)
Surgery
116:205-213. Retroviral vectors have also been used to transduce lymphoma, fibrosarcoma and adenocarcinoma cells with the HSV-tk gene in culture and in vivo, rendering those cells conditionally sensitive to ganciclovir. Plautz et al. (1991)
New Biol
. 3:709-715, Freeman et al. (1991)
Federal Register
56 #138, p. 33174, Moolten et al. (1990)
Hum. Gene Ther
. 1:125-134, Moolten, F. L. (1986)
Cancer Res
. 46:5276-5281.
Drug sensitivity therapies are also being investigated in the treatment of malignant melanoma. The incidence of malignant melanoma in the United States continues to increase at a rate of about 2-3% annually, resulting in increased morbidit
Colosi Peter C.
Kurtzman Gary J.
Avigen, Inc.
Robins & Pasternak LLP
Wehbe′ Anne M.
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