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Methods and compositions related to adenoassociated virus-phage particlesRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Radionuclide Or Intended Radionuclide Containing; Adjuvant Or Carrier Compositions; Intermediate Or Preparatory Compositions, Attached To Or Within Viable Or Inviable Whole Micro-organism, Cell, Virus, Fungus Or Specified Sub-cellular Structure Thereof (e.g., Platelet, Red Blood Cell)Methods and compositions related to adenoassociated virus-phage particles description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070274908, Methods and compositions related to adenoassociated virus-phage particles. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application claims priority to U.S. Provisional Patent application Ser. No. 60/744,492 filed Apr. 7, 2006, which is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION [0003] I. Field of the Invention [0004] Embodiments of this invention are directed generally to biology and medicine. In particular the invention is directed to field of gene therapy using AAVP in combination with imaging for providing therapy to a subject. [0005] II. Background [0006] A limitation of many biological-based therapies has been an inability to achieve controlled and effective delivery of biologically active molecules to tumor cells or their surrounding matrix. The aim of employing gene-based therapy is to achieve effective delivery of biological products, as a result of gene expression, to their site of action within the cell. Gene-based therapy can also provide control over the level, timing, and duration of action of these biologically active products by including specific promoter/activator elements in the genetic material transferred resulting in more effective therapeutic intervention. Methods are being developed for controlled gene delivery to various somatic tissues and tumors using novel formulations of DNA, and for controlling gene expression using cell specific, replication activated, and drug-controlled expression systems. [0007] In one approach, gene therapy attempts to target cells in a specific manner. Thus, a therapeutic gene is linked in some fashion to a targeting molecule in order to deliver the gene into a target cell or tissue. Current methods typically involve linking up a targeting molecule such as a ligand or antibody that recognizes an internalizing receptor to either naked DNA or a mammalian cell virus containing the desired gene. When naked DNA is used it must be condensed in vitro into a compact geometry for entry into cells. A polycation such as polylysine is commonly used to neutralize the charge on DNA and condense it into toroid structures. This condensation process, however, is poorly understood and difficult to control, thus, making the manufacturing of homogeneous gene therapy drugs extremely challenging. [0008] Bacteriophage (phage), such as lambda and filamentous phage, have occasionally been used in efforts to transfer DNA into mammalian cells. In general, transduction of lambda was found to be a relatively rare event and the expression of the reporter gene was weak. In an effort to enhance transduction efficiency, methods utilizing calcium phosphate or liposomes (which do not specifically target a cell surface receptor) were used in conjunction with lambda. Gene transfer has been observed via lambda phage using calcium phosphate coprecipitation, or via filamentous phage using DEAE-dextran or lipopolyamine. However, these methods of introducing DNA into mammalian cells are not practical for gene therapy applications, as the transfection efficiency tends to be low, non-specific, and transfection is not only cumbersome, but is promiscuous regarding cell type. [0009] Currently, eukaryotic viruses unquestionably provide superior transgene delivery and transduction (Kootstra and Verma, 2003; Machida, 2003) but ligand-directed targeting of such vectors generally requires ablation of their native tropism for mammalian cell membrane receptors (Miller et al., 2003; Mizuguchi and Hayakawa, 2004; White et al., 2004). In contrast, prokaryotic viruses such as bacteriophage (phage) are generally considered poor vehicles for mammalian cell transduction. However, despite their inherent shortcomings as "eukaryotic" viruses, phage particles have no tropism for mammalian cells (Zacher et al., 1980; Barrow and Soothill, 1997; Barbas et al., 2001) and have even been adapted to transduce such cells (Ivanenkov et al., 1999; Larocca et al., 1999; Poul and Marks, 1999; Piersanti et al., 2004) albeit at low efficiency. [0010] More reliable means of targeting vectors to specific cells (or receptors) and of guaranteeing a therapeutically useful degree of gene delivery and expression are thus required, if vectors useful in therapeutic applications are to be achieved. SUMMARY OF THE INVENTION [0011] Embodiments of the invention are generally directed to compositions and methods of delivering one or more transgene to a target cell, such as a tumor cell, in a site-specific manner to achieve enhanced expression and to constructs and compositions useful in such applications. In certain aspects, expression from a therapeutic nucleic acid may be assessed prior to administration of a treatment or diagnostic procedure to or on a subject. In a further aspect, the determination or evaluation of expression in the region or location needed for therapeutic benefit is assessed and any unnecessary or marginal beneficial treatment can be with held in lieu of alternative treatments. [0012] Without being bound by any particular theory or mechanism, the present disclosure is based on the observation that transgene expression may be increased when the transgene is integrated into a genome with a multiplicity greater than one. Of particular interest is the ability of certain chimeric AAVP particles to transduce cells with more than one copy of the transgene, often as a concatamer. Transduced cells also may be monitored by the expression of a reporter gene carried by the chimeric AAVP particles. Any transgene may be included in and expressed from an AAVP particle of this disclosure. [0013] Certain embodiments of the invention include methods and compositions for detecting gene transfer to and/or gene expression in a target tissue of a subject comprising one or more of the following steps: [0014] (a) One step that may be used in the present methods includes delivering to the target tissue of a subject an AAVP vector containing a reporter gene, which may or may not be naturally present in the host subject. Typically, the reporter gene will not be expressed in location or region to be imaged and/or treated. In certain aspects, the reporter gene is a wild-type, a mutant, or a genetically engineered kinase. In a further aspect the kinase is a thymidine kinase. In still a further aspect, the kinase is a herpes simplex virus-thymidine kinase gene or human thymidine kinase type 2. Typically, the transfer vector or AAVP is introduced to cells of the target tissue, and the reporter gene is expressed in the cells of the target tissue, thereby generating a reporter gene product (protein) which accumulates only in the cells effectively transfected by the AAVP vector. [0015] (b) Another step that may be used is administering to the host subject a labeled reporter substrate where cells expressing a reporter gene product metabolize the labeled reporter substrate to produce a labeled reporter metabolite wherein the labeled reporter substrate comprises a radiolabeled nucleoside analogue. [0016] (c) Yet another step that may be used in the present methods includes non-invasively imaging a target tissue or cells containing a labeled metabolite of the reporter substrate. In certain aspects, the subject is subjected to imaging after clearance of residual reporter substrate not metabolized by the reporter gene product from the host subject thereby detecting gene transfer to and expression in the target tissue. In a further aspect the subject or subjects tissues are subjected to imaging after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more minutes, hours, days, or weeks, depending on the metabolism of clearance of non-metabolized reporter substrate. [0017] The methods can further comprise waiting for a period of time after step (b) sufficient to allow about, at least, or at most 60, 65, 67, 70, 75, 77, 80, 85, 87, 90, 95, 97% or more, including all values and ranges there between of non-metabolized (reporter substrate not metabolized by the expression product) by the reporter gene product to clear from the subject. The non-metabolized substrate may include non-specific label derived from residual reporter substrate not metabolized. AAVP vector can be introduced to the cells of the target tissue by in vitro or in vivo transfection (or transduction). In certain aspects, AAVP is administered intravenously, intratumorally, intrarterially, intrapleurally, intrabronchially, and/or orally. [0018] In certain aspects, a reporter substrate is labeled with a radioisotope suitable for imaging by positron emission tomography, gamma camera, or single-photon emission computed tomography. The reporter substrate and/or metabolite of the reporter substrate are compounds containing a stable-isotope nuclide including but not limited to .sup.2H, .sup.13C, .sup.15N and .sup.19F. In a further aspect, the labeled reporter metabolite is imaged by positron emission tomography. In still further aspects, the labeled reporter metabolite is imaged by gamma camera or single-photon emission computed tomography. In yet still further aspects, the labeled reporter substrate metabolite is imaged by magnetic resonance imaging. [0019] An AAVP vector may incorporate a reporter gene and suitable transcription promoter and enhancer elements, ensuring tissue-specific, tissue-selective, or transcription factor-specific, or signal transduction-specific transcriptional activation of reporter and therapeutic gene co-expression. In certain aspects, the organ, tissue, cells or a cell is transfected with a reporter gene operably coupled to transcription regulatory elements such as promoter and/or enhancer elements ex vivo (in vitro) prior to administration of the cells or a cell to a subject. A labeled 2'-fluoro-nucleoside analogue includes, but is not limited to 5-[.sup.123I]-2'-fluoro-5-iodo-1.beta.-D-arabinofuranosyl-uracil; 5-[.sup.124I]-2'-fluoro-5-iodo-1.beta.-D-arabinofuranosyl-uracil; 5-[.sup.131I]-2'-fluoro-5-iodo-1.beta.-D-arabinofuranosyl-uracil, 5-[.sup.18F]-2'-fluoro-5-fluoro-1-.beta.-D-arabinofuranosyl-uracil; 2-[.sup.131I]-2'-fluoro-5-methyl-1-.beta.-D-arabinofuranosyl-uracil; 5-([.sup.11C]-methyl)-2'-fluoro-5-methyl-1-.beta.-D-arabinofuranosyl-urac- il; 2-[.sup.11C]-2'-fluoro-5-ethyl-1-.beta.-D-arabinofuranosyl-uracil; 5-([.sup.11C]-ethyl)-2'-fluoro-5-ethyl-1-.beta.-D-arabinofuranosyl-uracil- ; 5-(2-[.sup.18F]-ethyl)-2'-fluoro-5-(2-fluoro-ethyl)-1-.beta.-D-arabinofu- ranosyl-uracil, 5-[.sup.123I]-2'-fluoro-5-iodovinyl-1-.beta.-D-arabinofuranosyl-uracil; 5-[.sup.124I]-2'-fluoro-5-iodovinyl-1-.beta.-D-arabinofuranosyl-uracil; 5 [.sup.131I]-2'-fluoro-5-iodovinyl-1-.beta.-D-arabinofuranosyl-uracil; 5-[.sup.123I]-2'-fluoro-5-iodo-1-.beta.-D-ribofuranosyl-uracil; 5-[.sup.124I]-2'-fluoro-5-iodo-1-.beta.-D-ribofuranosyl-uracil; 5-[.sup.131I]-2'-fluoro-5-iodo-1-.beta.-D-ribofuranosyl-uracil; 5-[.sup.123I]-2'-fluoro-5-iodovinyl-1-.beta.-D-ribofuranosyl-uracil; 5-[.sup.124I]-2'-fluoro-5-iodovinyl-1-.beta.-D-ribofuranosyl-uracil; 5-[.sup.131I]-2'-fluoro-5-iodovinyl-1-.beta.-D-ribofuranosyl-uracil; or 9-4-[.sup.18F]fluoro-3-(hydroxymethyl)butyl]guanine. [0020] The imaging data can embody, but is not limited to imaging obtained with magnetic resonance imaging (MRI), nuclear medicine, positron emission tomography (PET), computerized tomography (CT), ultrasonography (US), optical imaging, infrared imaging, in vivo microscopy and x-ray radiography. Imaging can be coupled with medical devices, drugs or compounds, contrast agents or other agents or stimuli that may be used to elicit additional information from the imaging. Images are obtained using these modalities of the lesion, tissue, specimen, system, organism, subject or patient and can be static or dynamic images both in time and/or space. [0021] The imaging can be matched to the tissue, specimen, system, organism, or patient from which the large scale biological data is obtained. Imaging information is extracted from each image, imaging study or studies or examinations, and can consists of quantitative or qualitative imaging features that may embody but are not limited to differences in morphology, composition, structure, physiology, gene expression, or function of a lesion, a tissue, specimen, system, organism, or patient. Examples of imaging information include but are not limited to imaging features that may be extracted from multi-phase contrast enhanced dynamic CT, functional imaging, magnetic resonance spectroscopy, diffusion tensor imaging, diffusion or perfusion based imaging as well as targeted imaging encapsulated by nuclear medicine or PET. For an example see U.S. Patent Publication 20030033616 and 20060223141, which are incorporated herein by reference in its entirety. [0022] In certain embodiments, the invention includes methods of treating a subject comprising one or more of the following steps: [0023] (a) administering a therapeutic AAVP encoding a reporter to a subject having, suspected of having or at risk of developing a pathologic or disease condition; and Continue reading about Methods and compositions related to adenoassociated virus-phage particles... Full patent description for Methods and compositions related to adenoassociated virus-phage particles Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Methods and compositions related to adenoassociated virus-phage particles patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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