Oncolytic adenovirus armed with therapeutic genes

Abstract

The present invention involves compositions and methods for treating cancer using a mutant adenovirus comprising a polynucleotide encoding a therapeutic polypeptide that is targeted to cells with a mutant retinoblastoma pathway. The mutant adenovirus is able to kill the tumor cells without harming cells with a wild type retinoblastoma pathway.

Description

[0001] The United States Government owns rights in this invention pursuant to funding by the National Institutes of Health. This application claims priority to co-pending U.S. patent application Ser. No. 10 / 124,608, filed Apr. 17, 2002 and to U.S. Provisional Patent application Ser. No. 60 / 551,932, filed Mar. 10, 2004, each of which is incorporated in their entirety herein by refernce.BACKGROUND OF THE INVENTION [0002] A. Field of the Invention [0003] The invention generally relates to the field of oncology and oncolytic adenoviruses. More particularly, it concerns compositions and methods of treating cancer of the brain in a patient using oncolytic adenoviruses armed with therapeutic transgenes. [0004] B. Description of Related Art [0005] The development of cancer is understood as the culmination of complex, multistep biological processes, occurring through the accumulation of genetic alterations. Many if not all of these alterations involve specific cellular growth-controlling gen...

AI Technical Summary

Benefits of technology

[0011] The present invention provides an oncolytic adenovirus capable of killing target cells, such as a tumor cells, with a greater efficiency. The invention takes advantage of the discovery that an adenovirus encoding an E1A polypeptide unable to bind the tumor suppressor protein Rb may not replicate in or kill a cell that has a functional Rb pathway, but may replicate in and kill a cell that has a defective Rb pathway. In various aspects of the invention the oncolytic adenovirus is armed or encodes a therapeutic or diagnostic polypeptide. “Armed” is a term that indicates that the virus contains a heterologous nucleic acid sequence encoding a polypepitde of interest or a nucleic acid comprising a polynucleotide of interest. In certain embodiments, the nucleic acid encoding a therapeutic polypeptide may encode angiopoietin 2 (Ang-2), humanized yeast cytosine deaminase polypeptide (hyCD) or a sodium-iodide symporter (NIS) polypeptide. In further embodimens, the NIS polypepitde may be used in detecting the location of oncolytic adenovirus within a subject. The adenovirus of the present invention can be delivered by a number routes including, but not limited to intracranial (into the skull cavity) or intravenous administration. The tumor may be a primary tumor or it may be a tumor resulting from a metastasis to the skull or brain.

Problems solved by technology

When a tumor suppressor gene is inactivated, for example by point mutation or deletion, the cell's regulatory machinery for controlling growth is upset.

However, treating human glioma tumors with existing adenovirus constructs realistically cannot affect significant portions of the tumor, mainly because replication-deficient adenoviral vectors are unable to replicate and infect other cells, thus transferring the exogenous nucleic acid to sufficient numbers of cancer cells (Puumalainen et al., 1998).

Although targeting the p16 / Rb / E2F pathway produces an anti-cancer effect in vitro, this imperfection of the vector system limits the therapeutic effect of the gene in vivo.

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