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  Adenoviruses mutated in the va genes for cancer treatmentRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Whole Live Micro-organism, Cell, Or Virus Containing, Genetically Modified Micro-organism, Cell, Or Virus (e.g., Transformed, Fused, Hybrid, Etc.)The Patent Description & Claims data below is from USPTO Patent Application 20080089864. Brief Patent Description - Full Patent Description - Patent Application Claims
CLAIM OF PRIORITY [0001] This application is a continuation of U.S. application Ser. No. 10/509,194, filed Sep. 23, 2004, which is the National Phase of PCT/ES03/00140, filed Mar. 25, 2003, the contents of which are incorporated herein by reference. AIM OF THE INVENTION [0002] The field of the invention relates in general terms to the field of tumor biology. In particular, the invention refers to adenoviruses mutated in the VA RNA genes and their use in inhibiting cancer. STATUS OF THE PRIOR ART [0003] Current cancer treatment is based mainly on chemotherapy, radiation therapy, and surgery. In spite of a high cure rate for early stages of cancer, most advanced cases of cancer are incurable because they cannot be surgically removed or because the doses of radiation or chemotherapy administered are limited by their toxicity to normal cells. The transfer-of genetic material to inhibit or destroy tumors is a very promising therapeutic alternative. Compared to conventional strategies, this gene therapy strategy seeks to target malignant cells more specifically, attacking genetic defects in tumor cells. There are several strategies that use DNA as a therapeutic agent: the transfer of genes that stimulate antitumor immune response, the transfer of toxic genes that activate the toxicity of drugs, and the transfer of DNA to block or reestablish the expression of genes involved in tumor development (oncogenes, tumor suppressor genes, antiangiogenic genes, etc.). In addition to therapeutic DNA, the other component of gene therapy is the vehicle that transports this DNA: the vector. Synthetic vectors and viral derivatives have been used to increase the transfer of DNA to the target cells. The latter are generally more efficient in transferring DNA or transducing tumor cells. Viral vectors have been developed from various types of viruses, including retroviruses, Herpes Simplex virus, adeno-associated viruses, and adenoviruses, among others. In cancer gene therapy, the adenovirus is preferred for its high capacity to infect epithelial cells, which are the cause of most solid tumors. Other advantages of adenoviral vectors are that the DNA can be transferred to cells not yet in division, that the vector DNA is not integrated into the genome of the transduced cell, that these vectors can be purified up to concentrations of 1013 viral particles per milliliter, and that they are stable in the bloodstream because they lack lipid envelopes. [0004] The adenovirus is a DNA virus without a lipid envelope, characterized by an icosahedral capsid enclosing a linear, double-stranded DNA of approximately 36 kilobases. There are 50 serotypes of human adenovirus, which are classified into six subgroups (A to F) based on their structural and functional properties, such as erythrocyte agglutination. In gene therapy, adenovirus type 5 is preferred because it is molecularly well defined and because of its low pathogenicity in humans. In fact, 85% of the population has been infected with adenovirus and is seropositive for the presence of adenovirus antibodies. In particular, type 5 adenovirus causes colds in children that in most cases are asymptomatic. [0005] Various E1-deleted adenoviral vectors have been used with little success to treat cancer in clinical trials. Their limited effectiveness is due to the scant number of cells that the vector reaches. The large size of the viral particle, 80 nm in diameter, makes it difficult to diffuse and the vector reaches only a few layers of tumor cells beyond the injection site or the blood vessels. This limitation is particularly relevant in therapeutic strategies based on the introduction of cytotoxic genes or tumor suppressors, in spite of the fact that a collateral cytotoxic effect was found in nontransduced cells that were near transduced ones. Even when multiple high doses of the vector were injected, most of the tumor cells remained unaffected by the vector. In recent years, the selective propagation of the vector in tumor cells has been proposed as strategy to solve this limitation (R. Alemany et al., Nature Biotechnology 2000, Vol. 18, pp. 723-7). Viral replication per se is cytopathic; therefore, cytotoxic genes or tumor suppressors are not necessary to obtain an antitumor effect. In a way, the concept of an adenovirus that selectively replicates itself in tumor cells without carrying a nonviral gene belongs more precisely to the field of viral therapy or virotherapy of cancer than to the field of gene therapy. However, since cytotoxic genes, immunostimulants, or tumor suppressors may increase the selective toxicity of the replicative adenovirus; said genes have been inserted into the genome of the replicative adenovirus. These selective replication vectors thus link the concepts of virotherapy and gene therapy. [0006] Virotherapy, or the use of viruses in cancer treatment, is much older than gene therapy. The first observations of tumor treatments using viruses date from the beginning of the last century. Some viruses are naturally oncotropic. For example, parvovirus replication seems to be linked to the malignant transformation of the cell by a mechanism that is still unknown. The vesicular stomatitis virus (VSV) has an oncotropism associated with the antiviral effects of interferon. VSV is very sensitive to inhibition by interferon and tumor cells are often unresponsive to the effects of interferon, causing them to have a deficient antiviral response. Another virus that has been identified recently as oncotropic is the reovirus (Norman and Lee, Journal of Clinic Investigation, 2000. Vol. 105, pp. 1035-8). Infected cells react to the production of double-strand RNA (dsRNA) produced during infection with reovirus or other viruses activating a dsRNA-dependent kinase (PKR). The PKR, thus activated, blocks protein synthesis through the phosphorylation of the alpha unit of the eIF2 translation factor. This block of the messenger RNA translation also blocks the viral RNA translation and, with it, replication of the virus. Many types of virus express genes that render the PKR inactivate, but not the reovirus. However, PKR can be rendered inactivated by other proteins found in the Ras signal transduction pathway. Therefore, in cells with an active Ras, as in the case of many tumor cells, the reovirus can propagate. Other viruses show no natural oncotropism but can be genetically manipulated so that they replicate selectively in tumors. For example, the Herpes Simplex virus (HSV) has been made oncotropic by deleting the ribonucleotide reductase gene, an enzymatic activity dispensable in cells in active proliferation, such as tumor cells. HSV has also been made oncotropic by deleting the protein ICP34.5, which counteracts the active translation block by the PKR. Its deletion results in an oncotropism by a mechanism similar to that of the revirus. Recently, the Influenza A virus has been manipulated to be oncotropic (Bergmann et al., Cancer Research 2001, Vol. 61, pp. 8188-93). The viral protein NS1 of this virus also counteracts the translation block by PKR and its deletion results in a virus that depends on an active Ras. However, it is with adenoviruses that the most genetic manipulations have been performed to obtain selective replication in tumors. The central role of adenoviruses in cancer gene therapy, together with the experience accumulated in clinical trials, has contributed to the popularity of these new replicative adenoviral vectors. [0007] Two methods have been used to restrict adenovirus replication to tumor cells: the replacement of viral promoters with tumor selective promoters and deletion of viral functions that are unnecessary in tumor cells. In both strategies, the preferred gene to be regulated or mutated is Ela because it controls the expression of the remaining genes. Many tissue- or tumor-specific promoters have been used to control Ela expression. With respect to the strategy of deleting viral functions that are unnecessary in tumor cells, the first mutant proposed for selective replication had a E1b-55K deletion. This protein binds with and inactivates p53 to induce the infected cell to enter the S-phase of the cell cycle and to inhibit p53-mediated apoptosis triggered as a result of this induction. An adenovirus with an E1b-55K mutation known as dl1520 or Onyx-015 has been used to treat tumors with p53 defects. Another mutation performed on the adenovirus genome to obtain selective replication in tumors affects the CR1 and CR2 domains of Ela. These domains of Ela mediate the binding of proteins in the Retinoblastoma (RB) family. The RB proteins block the transition from the Go/G1 phase to the S phase of the cycle, forming a complex inhibitor of the transcription together with E2F. When Ela binds with RB, the E2F transcription factor is released from the RB-E2F complex and E2F acts as a transcription activator of the genes responsible for the transition to the S phase and viral genes such as E2. The release of E2F is thus a key step in the replication of the adenovirus. In tumor cells, the cell cycle is out of control because the RB is absent or inactivated by hyperphosphorylation and E2F is released. In these cells, the RB-inactivating function of Ela is no longer needed. Therefore, an adenovirus with an Ela mutant that prevents binding with the RB can be propagated normally in cells with inactive RB. The selective replication of these mutants has been demonstrated (Fueyo et al., Oncogene 2000, Vol. 19, pp. 2-12). [0008] This invention describes a new type of mutation for achieving selective replication in tumor cells with a determined genetic defect that is distinct from the p53 and RB pathways. Unlike other constructions existing in the field, in this invention the target DNA of the mutation does not produce any viral protein, but a virus-associated (VA) RNA, and it does not belong to the early adenovirus genes but to the late ones. Without any experimental data, WO 01/35970 mentions the use of a modified adenovirus in which the VAI gene is not transcribed; however, in regard to this technique, the combined use of adenoviruses with simultaneous mutations of the VAI gene and the VAII gene has never been mentioned. The genetic defect being attacked in this invention is the signal transduction pathway of the Ras oncogene, a pathway that has not bee previously attacked with adenovirus. Many growth factor receptors activate Ras proteins (H-Ras, N-Ras, K-Ras A and K-Ras B) to transduce a proliferative signal from the cell's exterior to the nucleus. Ras proteins are small GTPases that, when bound to GTP, are able to activate a series of effectors. The activation of the effectors creates a mitogenic signal. Ras is mutated into a permanently active form in 90% of pancreas tumors, 50% of colon tumors, 30% of lung tumors, and in other proportions in many other types of tumors. In addition to a large number of tumors with mutated Ras, the Ras pathway is activated in other cases by the constitutive activation of Ras-regulating proteins or vectors of the Ras pathway. For example, the c-erbB gene that encodes the EGF receptor is overexpressed in 50% of glioblastomas and its homologue c-erbB2 is frequently overexpressed in breast and ovarian cancer. Generally speaking, it is considered that 80% of tumors have an activated Ras pathway. Many of these types of tumors, as in the case of pancreatic cancer, need new therapies given the lack of response to conventional therapy. DESCRIPTION OF THE INVENTION [0009] This invention refers to the use of an adenovirus defective in its VAI and VAII virus-associated RNAs for the treatment of cancer. [0010] It also refers to the use of an adenovirus for the treatment of cancer wherein said adenovirus has a mutation in the sequences of the VAI and VAII RNA genes. [0011] Another objective of the invention is the use of an adenovirus for the treatment of cancer wherein said adenovirus has a mutation in the sequences of the genes that control the expression of the VAI and VAII RNA genes. [0012] Another objective of the invention is the use of an adenovirus for the treatment of cancer wherein said adenovirus has mutations in the VA RNA genes in one or more genes of the group Ela, Elb, and E4 to obtain selective replication in tumors. [0013] Another objective of the invention is the use of an adenovirus for the treatment of cancer wherein said adenovirus has mutations in the VA RNA genes and promoters that regulate one or more genes in the group Ela, Elb, and E4 to obtain selective replication in tumors. [0014] Yet another objective of this invention is the use of an adenovirus for the treatment of cancer wherein said adenovirus has mutations in the VA RNA genes to obtain selective replication in tumor cells with an active Ras pathway or unresponsive to the action of interferon. [0015] Yet another objective of this invention is the use of an adenovirus for the treatment of cancer wherein said adenovirus has mutations in the VA RNA genes to obtain selective replication in tumor cells and modifications in its capsid to increase its infectivity or to direct it to a receptor present on a tumor cell. [0016] Yet another objective of this invention is the use of an adenovirus for the treatment of cancer wherein said adenovirus has mutations in the VA RNA genes that confer selective replication on tumor cells and that, in turn, contain other genes commonly used in the field of cancer gene therapy such as prodrug activators, tumor suppressors, or immunostimulants. [0017] Yet another objective of this invention is the use of an adenovirus for the treatment of cancer wherein said adenovirus is a human adenovirus derived from a serotype between 1 and 50 with genetic mutations in the VA RNAs genes that confer selective replication on tumor cells. [0018] Yet another objective of this invention is the use of an adenovirus for the treatment of cancer wherein said adenovirus is a human adenovirus derived from serotype 5. [0019] Yet another objective of this invention is the use of an adenovirus for the treatment of cancer wherein said adenovirus is a mutant adenovirus d1331. [0020] This invention describes the use of mutant adenoviruses from VA RNA genes in cancer treatment. The VA RNA mutation allows replication of the adenovirus subject to the existence of an active Ras pathway or on the lack of PKR activation due to insensitivity to interferon. The invention is aimed at the need to find better treatments for pancreatic cancer, colon cancer, lung cancer, and other types of tumors. Continue reading... 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