<?xml version="1.0" encoding="us-ascii"?><rss version="2.0"><channel><title>NIH OTT RSS Feed - Gene Based Therapies - </title><link>http://www.ott.nih.gov/rss/default.aspx</link><description>Office of Technology Transfer (OTT).</description><copyright>Copyright 2009 NIH Office of Technology Transfer (OTT). All rights reserved.</copyright><item><title>Retroviral Vector Packaging Cell Lines and Purification Methods for Gene Therapy</title><description><![CDATA[This invention relates to a novel gammaretroviral vector packaging cell line and method of producing gammaretroviral vectors suitable for gene therapy. The described vectors may contain the gibbon ape leukemia virus (GALV) envelope with a CD11D8 epitope tag enabling their purification on a monoclonal antibody conjugated column. These vectors have several advantages over existing systems, including a broader host range, higher infectivity, and lower potential for replication. Further, purification of retroviral vector particles via an epitope tag may remove cellular components and debris toxic to target cells and tissues, providing a safer method of delivery for patients receiving gene therapy.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=2562</link><pubDate>2013-05-10</pubDate></item><item><title>Induced Pluripotent Stem Cells Generated Using Lentivirus-based Reprogramming</title><description><![CDATA[Five human induced pluripotent stem cells (iPSC) lines are generated using lentivirus-based reprogramming technology.  These lines are pluripotent, meaning they have the potential to differentiate into all cells in the body, and theoretically can proliferate/self-renew indefinitely.  The iPSC lines are: NC1 (derived from female's fibroblasts), NC2 (derived from female's fibroblasts ), NC3 (derived from male's HUVECS), NC4 (derived from male's fibroblasts) and NC5 (derived from female's fibroblasts).  Further details of these cells are available upon request.  NC1 uses a retrovirus delivery system incorporating the following vectors:  pMIG-hKLF4, pMIG-hOCT4, pMIG-hSOX2, and MSCV h c-MYC IRES GFP.   NC2-NC5 use the hSTEMCCA-loxP lentivirus delivery system (a gift from Dr. Gustavo Mostoslavsky).  These cell lines will be useful for studies related to stem cell biology, understanding diseases, potential cell therapies, and small molecule screening.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=2558</link><pubDate>2013-05-07</pubDate></item><item><title>Novel Methods for Generating Retinal Pigment Epithelium Cells from Induced Pluripotent Stem Cells</title><description><![CDATA[High efficiency methods for producing retinal pigment epithelial cells (RPE) from induced pluripotent stem cells (iPSCs) are disclosed.  The RPE is a polarized monolayer in the vertebrate eye that separates the neural retina from the choroid, and performs a crucial role in retinal physiology by forming a blood-retinal barrier and closely interacting with photoreceptors to maintain visual function.  Many ophthalmic diseases, such as age-related macular degeneration, are associated with a degeneration or deterioration of the RPE.  The iPSCs are produced from somatic cells, including retinal pigment epithelial cells, such as fetal RPE.  These methods involve producing embryoid bodies from human iPSCs, culturing the embryoid bodies using specific media to induce differentiation into RPE and growing the differentiated RPE cells in a defined media to generate human RPE cells.  The investigators also developed methods for detecting RPE cells and authenticating RPE cells; determining agents that can affect the production of RPE cells from an iPSC; and identifying an agent that can increase RPE survival in response to a proteo toxic insult or stress.  The novel methods and RPE cells disclosed here can be useful for both pre-clinical and clinical studies involving RPE.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=2553</link><pubDate>2013-04-23</pubDate></item><item><title>Modulation of Leucine-rich Repeats and Calponin Homology Domain-containing Protein 4 (Lrch4) Activity for Therapeutic Applications</title><description><![CDATA[NIH Inventors have recently discovered a novel Leucine-rich repeat and calponin homology domain-containing protein 4 (Lrch4) in a proteomic screen of the plasma membrane of lipopolysaccharide (LPS)-exposed macrophages.  Expression data by RT-PCR revealed that all Lrch family members (1-4) are expressed in macrophages, but only Lrch4 was recruited into lipid rafts (signaling microdomains of the plasma membrane) by LPS.  Lrch4 is the most highly expressed Lrch family member in mouse tissues.  It is a predicted single-spanning transmembrane protein that is encoded by the Lrch4 gene in humans.  The Lrch4 ectodomain is predicted to have a series of leucine-rich repeats, the motifs by which Toll like Receptors (TLR) are thought to bind microbial ligands.  The human form of Lrch4 is 83% identical to murine Lrch4 and is predicted to have 680 amino acids and  a molecular weight of 73 kDa.

NIH inventors have shown that Lrch4 is expressed on the plasma membrane of macrophages.  They have determined that Lrch4 regulates pro-inflammatory signals (NF-kappaB activation, cytokine induction) emanating from all TLRs tested, and also regulates ligand-independent signals from MyD88.  Further, LPS-induced p38, JNK, and NFkappaB activation are attenuated following Lrch4 knockdown, indicating that Lrch4 regulates upstream LPS signaling events.  LPS-induced expression of the NF-kappaB-dependent cytokine TNFalpha was attenuated following Lrch4 knockdown at the level of both transcript and protein.  Based on these and other findings, the inventors of this technology propose that Lrch4 may be a novel component of TLR receptor complexes and that modulation of Lrch4 activity might open up new opportunities for developing novel therapeutics for inflammatory diseases.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=2243</link><pubDate>2013-04-17</pubDate></item><item><title>HIV Therapeutics Utilizing Peptide Secreting Commensal Bacteria</title><description><![CDATA[A patent estate covering genetically engineered commensal bacteria compositions and their methods of use that secrete HIV infectivity interfering peptides with the aid of co-expressed translocation mediators, such as HylB, HylD or tolC gene products. The bacteria can be, for example, Escherichia coli, and are preferably those that colonize the gastrointestinal or genitourinary tracts. The secreted anti-HIV peptide can be a functional inhibitory fragment from the C-terminus of HIV, SHIV or SIV, or an inhibitory peptide derived from the N-terminus receptor-binding domain of SIV gp41, HIV-1 gp41, or HIV-2 gp41. The secreted anti-HIV peptide can also be a peptide from the allosteric domain of gp120, an extracellular loop of CCR5, an anti-CD4 immunoglobulin, a mimetic of CD4, an alpha-defensin or theta-defensin, a CD38 fragment homologous to the V3 loop of gp120, polphemusin II (a CXCR4 antagonist), or a RANTES peptide that binds to CCR5 or an HIV surface binding peptide, such as cyanovirin.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=1000</link><pubDate>2013-02-13</pubDate></item><item><title>Cloning of a Genomic DNA Fragment Containing the Guinea Pig CXCR1 Gene, A Specific Receptor for Guinea Pig Interleukin-8</title><description><![CDATA[e present invention relates to cloning of a genomic DNA fragment containing the guinea pig CXCR1 gene, a specific receptor for guinea pig interleukin-8 (IL-8).

More specifically, the IL-8-CXCR1 axis is a major chemokine-chemokine receptor system that regulates the recruitment of neutrophils into sites of inflammation.  In this invention, the inventors cloned a genomic DNA clone containing the gene for guinea pig IL-8 receptor CXCR1.  Mice and rats are the most commonly used small animals to examine the efficacy of drugs developed for human use.  However, neither IL-8 nor CXCR1, a specific receptor for IL-8, is present in these animals, making it impossible to use them as a model to test the effects or IL-8 or CXCR1 antagonists.  Identification of CXCR1, along with IL-8, in the guinea pig may enable evaluation of the in vivo effects of the antagonists.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=1155</link><pubDate>2013-01-08</pubDate></item><item><title>DLC-1 Gene Deleted in Cancers</title><description><![CDATA[Chromosomal regions that are frequently deleted in cancer cells are thought to be the loci of tumor suppressor genes, which restrict cell proliferation.  Recurrent deletions on the short arm of human chromosome 8 in liver, breast, lung and prostate cancers have raised the possibility of the presence of tumor suppressor genes in this location.

The inventors have discovered the deletion of human DLC-1 gene in hepatocellular cancer (HCC) cells.  They have performed in vitro experiments demonstrating the deletion in over 40% of human primary HCC and in 90% of HCC cell lines.  The DLC-1 gene is located on human chromosome 8p21.3-22, a region frequently deleted in many types of human cancer. DLC-1 mRNA is expressed in all normal tissues tested, but it has either no or low expression in a high percentage of several types of human cancer, such as liver, breast, lung, prostate cancers.  Through in vitro and in vivo tumor suppression experiments, the inventors further demonstrated that DLC-1 acts as a new tumor suppressor gene for different types of human cancer.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=1559</link><pubDate>2012-08-01</pubDate></item><item><title>Rapid Methods for Human Artificial Chromosome (HAC) Formation</title><description><![CDATA[Human artificial chromosomes (HACs) provide a unique opportunity to develop a new generation of vectors for therapeutic use as gene expression and delivery systems.  The advantages of a high-capacity, non-integrating chromosome-based vector capable of autonomous replication and long-term gene expression are evident for potential use in gene therapy and this area is one of active research.  In particular, the generation of a functional centromere (a complex structure needed for segregation at cell division) has been recognized as key in the production of synthetic chromosomes.  However, a typical human centromere extends over many millions of base pairs containing mainly alphoid satellite DNA (171 bp repeating units) organized into higher order repeats (HORs), which have been difficult to fully characterize or modify readily.  There remains a need to elucidate the structural requirements of alphoid DNA arrays for efficient de novo assembly of centromere structure in order to construct HAC vectors able to carry intact mammalian genes capable of fully regulated gene expression and which can be stably maintained in the host nucleus for use in gene therapy.

The group of Dr. Larionov at the NCI and colleagues have recently developed a  novel strategy to rapidly construct large synthetic alphoid DNA arrays with a predetermined structure by in vivo recombination in yeast.  The invention is a two step method involving 1) rolling-circle amplification (RCA) of a short alphoid DNA multimer (e.g. a dimer) and 2) subsequent assembly of the amplified fragments by in vivo homologous recombination during transformation with a Transformation-Associated Recombination targeting vector (TAR-NV) into yeast cells.  This method or Recombinational Amplification of Repeats (RAR) has been used to construct sets of different synthetic alphoid DNA arrays varying in size from 30 to 120 kb which were shown to be competent in HAC formation.  Thus, these long arrays are engineered centromere-like regions that permit construction of mammalian artificial chromosomes with a predefined centromeric region structure.  As any nucleotide can be easily changed into an alphoid dimer before its amplification, this new system is optimal for identifying the critical regions of the alphoid repeat for de novo centromere seeding.

The Mammalian Artificial Chromosome Portfolio [HHS Ref. No. E-128-2005/0-US-01 and HHS Ref. No. E-253-2000/0-US-03], including methods of generating engineered centromeric sequences, mammalian artificial chromosomes and methods of their use is available for licensing and will be of direct use to those interested in vectors providing long-term regulated expression of genes used in therapy for human disease.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=1315</link><pubDate>2012-08-01</pubDate></item><item><title>Nanoprobes for Detection or Modification of Molecules</title><description><![CDATA[This invention describes "Rod-tether Nanoprobes", devices consisting of a rigid molecular rod with a flexible molecular tether attached at both ends that can detect and/or modify molecules. Each tether tip has a functional group, such as an antibody or oligonucleotide that recognizes a target molecule. In addition, one tip carries a donor fluorophore and the other carries an acceptor fluorophore. The fluorophores form a pair for Forster Resonance Energy Transfer (FRET). In the absence of the target molecule, the rod keeps the tether arms apart, while in the presence of the target molecule, both recognizers bind to the target. This binding holds the donor and acceptor fluorophores close together, allowing a FRET signal. By reducing an ELISA-like assay entirely to the molecular level, complex macroscopic or microfluidic washing and pumping systems can be eliminated. Rod-tether Nanoprobes can detect a wide variety of clinical and biowarfare reagents. The nanoprobes can also rapidly and simply detect, modify, and/or destroy endogenous molecules (e.g., proteins, mRNA) involved in a broad range of diseases. The simplest ssDNA-detecting nanoprobe has been created.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=1323</link><pubDate>2012-08-01</pubDate></item><item><title>The Medusa? Sequencer: A DNA or RNA Sequencing Machine the Size of a Molecule</title><description><![CDATA[Current high-throughput DNA sequencing methods suffer from several limitations. Many methods require multiple fluid handling steps, fixing of molecules on beads or a 2D surface, and provide very short read-lengths. The NIH inventors offer a DNA or RNA sequencing device that drastically simplifies the process by combining all elements for sequence detection in a single molecule, the Medusa? Sequencer.

The Medusa? Sequencer utilizes Forster Resonance Energy Transfer (FRET) to read a polynucleotide sequence while synthesizing a complementary strand. The device consists of a DNA (or RNA) polymerase labeled with a FRET donor fluorophore and attached to a set of four flexible arms. The tip of each arm carries a distinct set including one nonhydrolyzable nucleotide and one FRET acceptor fluorophore. While a Medusa? Sequencer synthesizes a complementary polynucleotide strand, the four different arms continuously "test" the polymerase pocket creating a characteristic FRET signal for the correct nucleotide. The series of FRET signals reveals the unknown polynucleotide sequence.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=1322</link><pubDate>2012-08-01</pubDate></item><item><title>The Whey Acidic Protein (WAP) Promoter and Its Use to Express Therapeutic Proteins in the Milk of Transgenic Mammals</title><description><![CDATA[Transgenic animals can be engineered to express complex human proteins at high concentrations in milk.  Protein replacement therapy is often the only treatment available for congenital diseases such as hemophilia or lysosomal storage disease, and the cost of treatment can be high with the therapeutic protein market estimated to reach more than $50 billion by 2010. 

U.S. Patent No. 6,727,405 provides for a non-human mammal such as mouse, sheep, pig, goat and cow whose genome contains a DNA sequence comprising a milk serum protein (whey acidic protein) promoter linked to a heterologous gene sequence and secretory peptide, as well as methods for producing a secreted protein into the transgenic animal?s milk and claims directed to the DNA construct.  The invention permits the production of any desired protein in an easily maintained, stable, mammalian bioreactor, which is capable not only of producing the desired protein in milk, but can also pass the ability to do so to its female offspring.  Although other methods of obtaining recombinant protein products are available, these require inefficient, expensive purification of the protein from the blood or from cell culture media and there remains a need for an efficient and cost effective method for producing therapeutic proteins. 

This WAP promoter platform technology provides a viable alternative to other milk protein promoters.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=1026</link><pubDate>2012-08-01</pubDate></item><item><title>Fluorescent Pteridine Nucleoside Analogs</title><description><![CDATA[Pteridines are naturally occurring, highly fluorescent compounds (Quantum yields 0.88-0.40) that are structurally similar to purines and that were first isolated from butterfly wings in 1889.  The pteridine nucleoside analogs developed by NCI scientist Hawkins and co-workers are structurally similar to guanosine (3-MI and 6-MI) or adenosine (6-MAP).  These analogs are stable, can be formulated as phosphoramidites and are incorporated into oligonucleotides as a direct substitute for a purine base using automated DNA synthesis.  The fluorescence properties of these probes are directly impacted by the chemistry of neighboring bases and reflect changes in tertiary structure due to interactions with proteins, RNA or DNA.  Even subtle changes in base stacking or base pairing can be observed through changes in fluorescence intensity, lifetimes, energy transfer or anisotropy, making these pteridines ideally suited for the study of DNA/DNA and DNA/protein interactions.

Several applications have been further developed using this technology and one such application causes the pteridine probe to "bulge" out of the base stacking environment as it anneals to a target sequence which does not contain a base pairing partner for the pteridine.  Prior to binding to the bulge-forming target strand the fluorescence of the probe is very quiet, only "lighting up" when bound to a specific sequence.  This highly specific technique results in a dramatic increase in fluorescence intensity of up to 27 fold, is very rapid, does not require separation of oligonucleotides in a mixture and has been used in the development of a PCR product detection system.  The specific nature of the "bulge hybridization" technique may be used to overcome some of the issues caused by non-specific probe binding in standard chip technology.  (For a review see: Hawkins, M. (2003) Fluorescent Nucleoside Analogues as DNA Probes, in DNA Technology. J. R. Lakowicz. New York, Kluwer Academic/Plenum Publishers Vol 7 151-175.)  More recent applications have shown that the stability and brightness of the guanosine analogy 3-MI are suitable for studies requiring probe detection at the single molecule level and studies using 6-MAP and 2-photon counting excitation demonstrate the adenosine analog's usefulness as a UV probe.

The pteridine nucleoside analogs provide a unique opportunity to use native-like, stable and highly fluorescent probes in the development of further refined, quantitative approaches to the study of DNA/DNA and DNA/protein interactions.  The pteridine nucleoside patent portfolio is available for licensing and provides composition and methods of use claims for these versatile fluorophores.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=835</link><pubDate>2012-08-01</pubDate></item><item><title>Novel Thermostable Y-Family DNA Polymerases</title><description><![CDATA[Y-family polymerases are able to bypass lesions in DNA that would otherwise block replication by high fidelity DNA polymerases and are key to the effective study of ancient DNA and for use in forensic medicine.  These enzymes are ubiquitous and are found in all kingdoms of life: bacteria, archaea and eukaryotes.  The number of proteins related to the Y-family polymerases is well over 200 orthologs and despite being closely related at the phylogenetic level, the few polymerases now characterized, each show a unique set of properties including processivity, fidelity, and the ability to bypass certain types of DNA.  Y-family polymerases from thermostable organisms are of particular interest because the enzymes isolated from such species tend to be more stable, easy to work with and may have more utility in assays at higher temperatures, such as Polymerase Chain Reaction (PCR). For example, the thermostable archeal Sulfolobus solfataricus DinB-like polymerase Dpo4 can bypass lesions by generally inserting the correct complementary nucleotide opposite a variety of damaged bases and can, under appropriate conditions substitute for Taq polymerase in PCR applications.  Additionally, functional and structural organization of this family of polymerases permits domain swapping designed to optimize specific properties of use in novel applications.

Dr. Woodgate's group at the National Institute of Child Health and Development have expanded their earlier work and have now discovered several additional thermostable dpo4 homologs from other strains found in the Sulfolobaceae family, some of which have optimal growth temperatures higher than 80oC.  These novel DinB-like proteins have thermostable DNA polymerase activity and are capable of: 1) PCR amplifications over 1kb in length, 2) replication past DNA lesions such as abasic sites and CPD (cis-syn cyclobutane pyrimidine dimer) lesions and 3) incorporation of several different labeled DNA nucleotides into DNA during replication.  These enzymes may therefore be a good substitute for Taq polymerase in applications utilizing fluorescent nucleoside triphosphate derivatives.  These lesion-bypassing Dpo4-like polymerases could also be included along with a conventional thermostable polymerase in a PCR protocol designed to amplify old or damaged DNA samples which could greatly increase recoverability, accuracy and length of products.  Other applications could include labelling or tagging DNA, real-time PCR, detection of SNPs, mismatches or DNA lesions, mutagenic PCR, directed-evolution methods and expanding the "DNA alphabet" utilizing non-natural nucleotides.

Available for licensing are seven novel Y-family polymerases.  Claims are directed to these sequences and chimeras, as well as to methods of identifying other Y-family polymerases and generating other chimeric Y-family polymerases and methods of use.  These enzymes and methods of identifying and generating novel Y-family polymerases should be of interest to forensic DNA service companies as well as to research reagent companies pursuing novel thermophlic enzymes for use in ancient and damaged DNA analysis and for novel applications with modified nucleotides.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=1025</link><pubDate>2012-07-31</pubDate></item><item><title>Transformation-Associated Recombination (TAR) Cloning</title><description><![CDATA[Transformation-Associated Recombination (TAR) cloning in yeast is a unique method for selective isolation of large chromosomal fragments or entire genes from complex genomes without the time-consuming step of library construction.1  The technique involves homologous recombination during yeast spheroplast transformation between genomic DNA and a TAR vector that has short (approximately 60bp) 5? and 3? gene targeting sequences (hooks).  Further, because up to 15% sequence divergence does not prevent recombination in yeast, TAR cloning is highly efficient for isolation of gene homologs and synthenic regions.  Using this technology, chromosomal regions up to 250kb can be rescued in yeast as circular YACs within 3-5 working days.

NIH researchers Drs. Larionov, Kouprina and Resnick have championed the use of this technology and TAR cloning has been used to efficiently isolate haplotypes, gene families4 as well as genomic regions which are not present in existing BAC libraries.  Known mutations and new modifications, including point mutations, deletions and insertions, can easily be introduced into DNA fragments hundreds of kilobases in size without introducing any unwanted alterations.  The modified DNAs can then be tested functionally in mammalian cells and transgenic mice. TAR has also been used for structural biology studies, long-range haplotyping, evolutionary studies, centromere analysis and analysis of other regions which cannot be cloned by a routine technique based on in vitro ligation.5  In particular, construction of human artificial chromosome vectors and the combining of a HAC vector with a gene of interest can be effectively performed using the TAR methodology.  Human genes isolated by TAR for expression in HACs include HPRT (60kb), BRCA1 (84kb), BRCA2 (90kb), PTEN (120kb), hTERT (60kb), KA11 (200kb), ASPM (70kb), SPANX-C (83kb) among others.  TAR is a flexible and efficient means for employing in vivo recombination in yeast in order to clone entire genomic loci which can then be used for structural and functional analysis and for expression in HAC vectors for a variety of uses including for potential use in gene therapy.

The TAR cloning portfolio, including methods of use and vectors, is available for licensing and will be of direct use to those using a functional genomics approach in their work.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=1316</link><pubDate>2012-07-31</pubDate></item><item><title>High Diversity/High Affinity Domain Antibody Library</title><description><![CDATA[Available for licensing and commercial development is a highly diverse domain antibody (dAb) library providing antibodies that bind with high affinity to variety of antigen targets.  Antibody diversity is inherently limited by using only three CDRs of either light chain variable domain (LCDRs) or heavy chain variable domain (HCDRs). This novel dAb library is designed using light chain variable domain 3 (LCDR3) and heavy chain variable domain (HCDR3), which are of primary importance for creating binding site diversity in the human immune system.  The library contains 2.5 x 1010 dAbs.  Human naturally occurring LCDR3s were grafted onto HCDR1 of m0.  These antibodies are of very small size (15-17 kDa), high stability and can be expressed at high levels as monomers.  The library can be used for the selection of antibodies to any antigen including cancer and viral antigens and exhibit such properties as good penetration, stability, solubility, high levels of expression (at potentially low cost), and low level of immunogenicity or toxicity.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=1986</link><pubDate>2012-07-31</pubDate></item><item><title>GLI-Similar 3(GLIS3) Knock Out (KO) Mice as Models to Screen Therapeutics for Diabetes, Polycystic Kidney Disease, and Hypothyroidism</title><description><![CDATA[GLI-similar (Glis) 1-3 proteins constitute a subfamily of the Kr?ppel-like zinc finger transcription factors that are closely related to the Gli family.  Mutations in human GLIS3 have been implicated in a syndrome characterized by neonatal diabetes and congenital hypothyroidism (NDH) and in some patients accompanied by polycystic kidney disease, glaucoma, and liver fibrosis.  To further identify and study the physiological functions of GLIS3, NIEHS investigators generated mice in which GLIS3 is ubiquitously knocked out (GLIS3-KO) or conditionally knocked out in a cell type-specific manner.  GLIS3-KO mice develop polycystic kidney disease, hypothyroidism, and neonatal diabetes, as indicated by the development of hyperglycemia and hypoinsulinemia.  The pancreatic endocrine cells, particularly insulin-producing pancreatic beta cells, are greatly diminished in these mice.   The pancreas-selective knockout mice GLIS3(Pdx1-Cre) develop severe diabetes within 2-3 months, much later than the GLIS3-KO mice.  The kidney-selective knockout of GLIS3 (GLIS3(Ksp-Cre) mice lack expression of GLIS3 in the collecting ducts and develop severe polycystic kidney disease within a period of 2-4 months. These mice can be used as models to screen therapeutics for diabetes, polycystic kidney disease, and hypothyroidism.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=2439</link><pubDate>2012-05-16</pubDate></item><item><title>Identification of EGFR as A Receptor for AAV6 Transduction</title><description><![CDATA[AAV vectors offer unique advantages in gene therapy applications.  Studies have shown that these replication deficient parvovirus vectors can deliver DNA to specific tissues and confer long-term transgene expression in a variety of systems.  Although many studies have looked at the tissue-specific expression elicited by each of the AAV serotypes, a true understanding of how AAV transduces these tissues is still unclear.  Of the large AAV family, only a few receptors or co-receptors have been identified.  The ability to better target transduction to specific tissues on the basis of the receptors that each serotype uses for entry is essential for selecting a serotype given the receptor expression in specific tissue, or to exploit altered receptor expression under disease conditions.

AAV6 has been reported to effectively transduce muscle, lung, brain, and multiple types of tumors, including gliomas and lung adenocarcinomas.  By using a bioinformatics based screen approach, the NIH investigators discovered that the epidermal growth factor receptor (EGFR) is a co-receptor for AAV6 infection in mammalian cells, and is necessary for efficient vector internalization.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=2238</link><pubDate>2012-04-30</pubDate></item><item><title>Stat5a Knockout (Stat5atm1Mam) Mouse Model for Mammopoietic and Lactogenic Signaling Studies</title><description><![CDATA[Stat 5a Knockout: Stat5a deficiency results in the loss of prolactin-dependent mammary gland development and lactogenesis.

Prolactin induces mammary gland development and lactogenesis.  Binding of Prolactin to its receptor leads to the phosphorylation and activation of STAT (signal transducers and activators of transcription) proteins.  Two Stat proteins, Stat 5a and Stat5b, are expressed in mammary tissues during pregnancy.  Stat5a null mice developed normally, and were indistinguishable from hemizygous and wild-type littermates in size, weight and fertility.  Mammary lobulo-alveolar outgrowth during pregnancy was reduced and females failed to lactate after parturition.  Stat5b, despite 96% similarity to Stat5a, could not compensate for the loss of Stat5a.  Stat5a is the principal and obligate mediator of mammopoietic and lactogenic signaling.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=2411</link><pubDate>2012-04-19</pubDate></item><item><title>Gs Alpha LoxP (Gnastm1Lsw) Mouse Model for Metabolism Studies</title><description><![CDATA[Generation of a floxed Gnsa gene for the G-protein Gs alpha (Gsalpha) for the construction of conditional knockout mice.

The heterotrimeric G protein Gsalpha couples many receptors to adenylyl cyclase and is essential for hormone-stimulated cAMP generation.  Previous mouse models with germ-line mutations in Gnas, the gene that encodes Gsalpha had limited usefulness in trying to decipher the role of Gsalpha pathways in specific tissues since only heterozygotes were viable and could be analyzed. Analysis was further complicated by the fact that Gsalpha is imprinted expressed in many metabolically active tissues.

Gsalpha-floxed mice were generated so that the metabolic effects of Gsalpha deficiency could be examined in specific tissues. Exon1, which is specific for Gsalpha, was surrounded with loxP recombination sites.  Liver-specific knockouts of Gsalpha were obtained by mating the Gsalpha-floxed mice with albumin promoter-Cre-transgenic mice.  Gsalpha exon1 was efficiently deleted. These mice have been used successfully to generate other tissue-specfic Gsalpha knockout mice.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=2412</link><pubDate>2012-04-19</pubDate></item><item><title>Sirt1 Knockout (Sirt1tm1.1Cxd) Mouse Model for Oncology and Metabolism Studies</title><description><![CDATA[Sirt1 knockout: Sirt1, a protein deacetylase, is a tumor suppressor that promotes genome stability and regulates proteins involved in energy metabolism.

Yeast Sir2, a nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase, has been implicated in chromatin silencing, longevity and genome stability.  Mammals contain a family of related deacetylases, the sirtuins, of which 7 have been identified.  Sirt1 is the closest mammalian orthologue of yeast Sir 2.  The Sirt1 gene in mice was disrupted by homologous recombination in embryonic stem cells.  The majority of Sirt1 (-/-) embryos die between E9.5 and E14.5, displaying altered histone modification, increased chromosomal aberrations, and impaired DNA damage repair. Tumor formation was increased in mutant tissues in Sirt1(+/-): p53(+/-) double heterozygotes, indicating that full levels of Sirt1 are necessary for tumor suppression.  Tumorigenesis is reduced by treatment with the polyphenol, resveratrol, which activates Sirt1.  Sirt1 may act as a tumor suppressor by promoting DNA damage repair and maintaining genome integrity.  Sirt1also is involved in the regulation of proteins involved in energy metabolism, and components of the circadian clock.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=2415</link><pubDate>2012-04-19</pubDate></item><item><title>ACSF3-based Diagnostics and Therapeutics for Combined Malonic and Methylmalonic Aciduria (CMAMMA) and Other Metabolic Disorders</title><description><![CDATA[Combined malonic and methylmalonic aciduria (CMAMMA) is a metabolic disorder in which malonic acid and methylmalonic acid, key intermediates in fatty acid metabolism, accumulate in the blood and urine.  This disorder is often undetected until symptoms manifest, which can include developmental delays and a failure to thrive in children, and psychiatric and neurological disorders in adults.  Once thought to be a very rare disease, CMAMMA is now thought to be one of the most common forms of methylmalonic acidemia, and perhaps one of the most common inborn errors of metabolism, with a predicted incidence of one in 30,000.

Investigators at the National Human Genome Research Institute (NHGRI) have identified the genetic cause of CMAMMA, an enzyme encoded by the ACSF3 (Acyl-CoA Synthetase Family Member 3) gene.  This enzyme is located in the mitochondrion, and appears to be a methylmalonyl-CoA and malonyl-CoA synthetase, which catalyzes the first step of intra-mitochondrial fatty acid synthesis.  As such, this discovery may not only be critical for the development of diagnostic tools and treatments for CMAMMA, but also holds promise for the treatment of other related metabolic disorders.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=2366</link><pubDate>2012-02-13</pubDate></item><item><title>Improved DNA-Protein Vaccination Protocols</title><description><![CDATA[Nucleic acid based vaccines are attractive alternatives to conventional vaccines for a number of reasons.  One of the issues with nucleic acid based vaccines is the poor immunogenicity in humans.  The subject technology is a method for eliciting improved immune responses with DNA based vaccines.  The method involves co-administration of a nucleic acid vaccine with a protein vaccine for the same antigen of interest that is encoded by the DNA vaccine in a prime-boost protocol.  This methodology increased the immune responses in a SIV macaque model to examine DNA based vaccines of HIV and vaccine protocols.   The methodology can potentially be applied to other disease indications to elicit greater immune responses.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=2363</link><pubDate>2012-02-08</pubDate></item><item><title>Use of Marrow-Derived Glial Progenitor Cells as Gene Delivery Vehicles into the Central Nervous System</title><description><![CDATA[The present disclosure relates to a method of treating Parkinson's disease by transfecting bone marrow cells with glial cell line-derived neurotrophic factor (GDNF) using a retroviral vector, and then administering the transfected cells intravenously to a mammal.  The results reported confirm that cells derived from the bone marrow can migrate into the brains of adult mice. The detection of marrow-derived cells in brains of adult mice within days of transplantation provides a method in which genetically altered hematopoietic cells could be used to treat acute diseases of the brain.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=2358</link><pubDate>2012-02-03</pubDate></item><item><title>Modulating Autophagy as a Treatment for Lysosomal Storage Diseases</title><description><![CDATA[Researchers at NIAMS have developed a technology for treatment of lysosomal storage diseases by inhibition of autophagy.  Pompe disease is an example of a genetic lysosomal storage disease caused by a reduction or absence of acid alpha-glucosidase (GAA).  Patients with Pompe disease have a lysosomal buildup of glycogen in cardiac and skeletal muscle cells and severe cardiomyopathy and skeletal muscle myopathy. Treatment of Pompe disease by GAA enzyme replacement therapy is quite  ineffective for the skeletal muscle myopathy. Skeletal muscle resistance to therapy is associated with increased cellular buildup of autophagic debris. Inactivation of autophagy results in effective GAA replacement therapy and a reduction in glycogen back to normal levels. This technology provides a novel approach for the treatment of Pompe disease as well as other diseases where autophagy is a critical contributor to disease development.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=2353</link><pubDate>2012-01-17</pubDate></item><item><title>LMNA Gene and Its Involvement in Hutchinson-Gilford Progeria Syndrome (HGPS) and Arteriosclerosis</title><description><![CDATA[Hutchinson-Gilford Progeria Syndrome (HGPS) is a very rare progressive childhood disorder characterized by premature aging (progeria).  The most common cause of death is from arteriosclerosis and few children affected by HGPS live beyond their teens.  The invention identifies point mutations in the LMNA gene, a gene which encodes a nuclear lamin protein, as the cause of HGPS.  These mutations activate a cryptic splice site within the LMNA gene which leads to the excision of a portion of an exon and the subsequent generation of a Lamin A protein with an internal deletion of fifty (50) amino acids.  The identification of mutations associated with HGPS could lead to breakthroughs in detection, diagnosis, and treatment of HGPS and related or similar conditions, including arteriosclerosis and aging.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=749</link><pubDate>2011-12-19</pubDate></item><item><title>Potent Inhibitory RNAs for Non-Surgical Treatment of Salivary Gland Cancers</title><description><![CDATA[In the U.S., approximately 40,000 cases of head and neck cancer, including salivary gland tumors, are diagnosed each year. Surgery with post-operative radiotherapy is the most common treatment for salivary gland tumors. However, complete removal is difficult  due to the three-dimensional growth pattern of these tumors which impedes a surgeon?s ability to determine once the tumor has been fully removed. Both surgeons and patients desire minimal surgical approaches for cosmetic reasons, as well as to preserve nerve function in the facial area. Thus a significant need exists for non-surgical approaches to treating salivary gland tumors.

Researchers at the National Cancer Institute, NIH, have discovered that mucoepidermoid (MEC) salivary gland tumors arise from a chromosomal rearrangement which generates a fusion oncogene, Mect1-Maml2, that functions to alter Notch and CREB signaling pathways. An RNAi vector has been developed that selectively suppresses the oncogene and inhibits growth of certain MEC tumor cell lines containing the oncogene by at least 90%. The RNAi vector has no effect on cells that do not express the oncogene. This ability of the RNAi vectors to block the "gain-of-function" activity of the acquired Mect1-Maml2 oncogene suggests new possibilities for the diagnosis and therapy of these cancers.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=2327</link><pubDate>2011-09-29</pubDate></item><item><title>Novel Osteobiologic Proteins for Treatment of Osteoporosis, Rheumatoid and Neurologic Diseases</title><description><![CDATA[In an effort to find effective strategies for treatment of body tissue and structural damage as the result of trauma, cancer and other diseases, scientists at the Food and Drug Administration (FDA) have identified Cartilage-Derived Morphogenetic Proteins (CDMP) and associated pathways instrumental in replacing or regenerating damaged tissue.  These proteins have unique activities likely to be useful as stand alone agents or in construction of engineered tissues.

CDMPs appear helpful in the healing of bone and joint surface lesions, and also for the repair or reconstruction of cartilaginous tissues, tendons and ligaments.  The invention identifies proteins belonging to TGF-Beta superfamily that promote repair of menisci, cruciate and collateral ligaments of the knee, and rotator cuff tendons.  The patent application claims nucleic acids encoding human Cartilage-Derived Morphogenetic Protein-1 (hCDMP-1) variant polypeptides.  Morphogenetic proteins are able to induce the proliferation and differentiation of progenitor cells into functional bone, cartilage, tendon, or ligament tissue.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=2298</link><pubDate>2011-07-27</pubDate></item><item><title>Novel Methods for the Reversible Incorporation of Functional Groups into RNA and DNA:  Synthesis and Uses for 2?-O-aminooxymethyl Nucleoside Derivatives</title><description><![CDATA[The delivery of DNA/RNA therapeutic drugs is still a major hurdle for the clinical application of DNA/RNA-based drugs. Also, developments in silencing the expression of specific genes, through RNA interference pathways, have led to an increased demand for synthetic RNA sequences and have created a pressing need for rapid and efficient methods for RNA synthesis.  Recently, FDA scientists have developed a novel phosphoramidite, 2?-O-aminooxymethyl ribonucleoside (2?-O-protected compounds).  The 2?-O-aminooxymethyl ribonucleoside can be modified with any type of functional group using an oximation reaction as long as the functional group contains an aldehyde, ketone, or acetal group.  Modification of the 2?-O-aminooxymethyl with an aldehyde results in a conjugated 2?-phosphoramidite that could be readily converted back to the native ribonucleoside and its corresponding by-product.  On the other hand, the oximation of 2?-O-aminooxymethy with a ketone results in an irreversible conjugated form of the phosphoramidite.

The 2?-O-protected compounds of the present technology have several advantages, for example, the 2?-O-protected compound is stable during the various reaction steps involved in oligonucleotide synthesis; and the protecting group can be easily removed after the synthesis of the oligonucleotide, for example, by reaction with tetrabutylammonium fluoride; and the O-protected groups do not generate DNA/RNA alkylating side products, which have been reported during removal of 2?-O-(2-cyanoethyl)oxymethyl or 2?-O-[2-(4-tolylsulfonyl)ethoxymethyl groups under similar conditions.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=2290</link><pubDate>2011-07-26</pubDate></item><item><title>The Human Nuclear Co-Repressor Gene:  Applications for Cancer Diagnostics/Therapeutics and Gene Expression Research</title><description><![CDATA[The human nuclear receptor co-repressor (huN-CoR) forms multimolecular complexes that alters chromatin structure, resulting in disrupted gene expression.  The huN-CoR complex is central to normal processes such as erythropoiesis and thymocyte development, but is also linked to multiple cancers including colorectal carcinomas, endometrial cancers and leukemia, particularly acute myeloid leukemia.  Thus, huN-CoR is a potentially-valuable tool for cancer diagnosis, as well as a target for the development of huN-CoR-based cancer therapeutics.  HuN-CoR is also an attractive research tool for the study of gene regulation, epigenetic modification and gene silencing.

The technology claims nucleic acid sequences comprising the huN-CoR gene and fragments thereof, as well as a gene chip array incorporating such fragments.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=461</link><pubDate>2011-07-21</pubDate></item><item><title>Production of Adeno-Associated Viruses in Insect Cells</title><description><![CDATA[Adeno-associated virus (AAV) is being developed for gene therapy applications.  This virus type presents several advantages over alternate vectors for therapeutic gene delivery.  AAV is not considered pathogenic and transduces stably dividing and non-dividing cells.  AAV also shows good serotype specificity to various cell types for targeted gene delivery.

The present invention describes a highly scalable adeno-associated virus (AAV) vector production method in insect cells.  The system for producing recombinant AAV (rAAV) uses the AAV Rep protein and an AAV ITR.  This production method produces virus particles much more efficiently than the standard mammalian cell culture system.  Yields of rAAV produced in Sf9 cells exceed 10e15 per liter for some constructs.  The improvement in production efficiency translates into lower production costs and potential for commercial scale manufacturing.  In addition, all serotypes of AAV can be produced, with the respective AAV serotype vectors available for the immediate scale up of AAV production.

This technology will give a company producing large quantities of AAV a significant competitive advantage over traditional AAV production methods.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=579</link><pubDate>2011-06-01</pubDate></item><item><title>Gene Expression Signature Predictive of Response to Chemotherapy</title><description><![CDATA[Combination cisplatin and fluorouracil (CF) is a reference chemotherapy regimen for metastatic gastric cancer.  However, to date, no genome-wide studies have identified distinctions in gene expression that predict which subjects with metastatic disease will benefit from this therapy and which subjects will not exhibit a therapeutic response to chemotherapy.  Given the toxicity of chemotherapy, however, defining parameters that identify those subjects who will likely benefit from chemotherapy is of paramount importance.  Early identification of non-responders would provide opportunities to explore alternate or novel therapeutic approaches.  Thus, a need exists to identify methods of predicting a subject's response to chemotherapy prior to receiving the treatment.

Scientists at the National Institutes of Health have discovered a three-gene signature that can be used to determine the chemotherapy response in patients with cancer.  By measuring the expression of three cancer-specific genes it can be determined if a patient with an epithelial cancer such as gastric, bladder, head and neck, esophageal or cervical cancers, will respond to CF treatment.  The inventors have demonstrated that examining these expression levels has high fidelity in identifying CF treatment non-responders.  Further, the invention describes a mechanism that can help patients identified as non-responders become responsive to treatment.  Therefore these methods have the potential to reduce fatalities caused by metastatic gastric cancer by identifying patients early on who are non-responsive to standard CF treatment and customizing a new treatment plan which may be better suited to their individual needs.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=1983</link><pubDate>2011-02-03</pubDate></item><item><title>Allele Specific shRNA for Nanog, and Its Use to Treat Cancer</title><description><![CDATA[Cancer stem cells are currently thought to be major participants in resistance to radiation therapy and chemotherapy; they are also thought to drive the spread of cancer through metastasis.  It has been postulated that genes involved in early embryogenesis, primarily transcription factor Nanog but also Oct4 and SOX2, may be reactivated to maintain the properties of cancer stem cells, any treatment that inhibits such genes may therefore inhibit the progression of cancer and lead to improved survival and other clinical outcomes.

The NIH investigators discovered that the expression of NanogP8, a pseudogene of Nanog, is upregulated in human colorectal cancer spheroids formed in serum-free medium. NanogP8 has also been reported to be upregulated in human prostate cancer and glioblastomas. An inhibitory RNA molecule was identified by the investigators to knock down expression of NanogP8, without interfering with expression of Nanog.  The discovery may improve the safety of a shRNA-based gene therapy and improve its chances for acceptance as a clinical therapy.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=2219</link><pubDate>2011-01-24</pubDate></item><item><title>Transplant and Autoimmune Therapy Using T-Cells Expressing Programmed Death Ligand-1 (PD-L1)</title><description><![CDATA[Transplant complications (graft rejection and graft-versus-host disease) and autoimmune diseases are primarily caused by T cell immune responses against normal host tissue or transplanted tissues.  These disorders can lead to serious complications and may be chronic, debilitating, and fatal.  Current treatment for these disorders is oftentimes not effective, and is typically associated with significant side effects, including global immune suppression, which increases the rate of infection and cancer. Hence, there is a need for new technologies to more specifically suppress the immune system for treatment of these diseases.

Programmed death (PD) ligand 1 (PD-L1) is an immune molecule present on regulatory T cells (Tregs), other suppressor cell populations, and tumor cells; the function of PD-L1 is to suppress the function of pathogenic T cells that express the PD1 receptor. Therefore, it has been hypothesized that the transfer of T cells that are enriched for PD-L1 expression might represent an effective method to suppress autoimmunity or transplant complications. Adoptive T cell therapy using Tregs is one such approach; however, this approach is limited due to the relative rarity of Tregs and their tendency to possess differentiation plasticity towards pathogenic T cell subsets such as the Th17 subset. Ex vivo co-stimulated and expanded effector T cells can be generated in sufficient numbers for cell therapy; however, such cells are not enriched for PD-L1 expression.

The current technology overcomes these limitations through transduction of co-stimulated T cells with a lentiviral expression vector that dictates T cell expression of PD-L1. In this method, the co-stimulated T cells acquire the immunosuppressant characteristics of Treg cells.  The PD-L1 gene expression construct co-expresses a cell surface molecule (i.e., CD19 or CD34) that allows enrichment of the gene-modified T cells to high purity.   Also the construct co-expresses another gene, TMPK, which acts as a safety cell fate switch because the TMPK can specifically activate the cytotoxic prodrug, AZT.  By incorporation of this TMPK/AZT cell fate safety switch, the current technology will allow for PD-L1 therapeutic delivery, with subsequent elimination of the therapeutic cells in the event of toxicity.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=2163</link><pubDate>2010-10-21</pubDate></item><item><title>A Rapid, Peripheral Blood Gene Expression Biomarker Panel for Diagnosis of Acute Ischemic Stroke</title><description><![CDATA[There are presently no rapid, accurate diagnostic procedures or methods that can be used to determine whether a patient has suffered an acute ischemic stroke (AIS).  Current technologies for diagnosis of AIS are limited by speed and resources as well as inaccuracy and generally require a high level of training to interpret the results for medical technicians.  In contrast, this invention may lead to the development of a rapid and accurate clinical diagnostic kit that would require very little training for proper use and could be used in the field or the emergency room setting.

Scientists at the National Institutes of Health have discovered that expression levels of a set of nine genes may be used as biomarkers for diagnosis of AIS as well as outcome prediction.  These biomarkers may be rapidly identified using peripheral whole blood and may form the basis of a rapid and accurate clinical point of care diagnostic kit.

Further, if validation is positive, this technology may enable rapid differential diagnosis between acute ischemic stroke and hemorrhagic stroke, transient ischemic attack, or any pathology mimicking a stroke.  Not only can this be used to identify stroke earlier in the course of treatment, this panel may also help to better characterize stroke subtype, and identify new pathways for stroke treatment. This is important as the only FDA approved treatment for acute ischemic stroke is tissue plasminogen activator (tPA) and tPA must not be given to hemorrhagic stroke patients since it could increase intracranial bleeding.  To effectively treat AIS, tPA must be administered intravenously within 3-4 hours of known stroke onset.  Because the differential diagnosis of AIS versus hemorrhagic stroke is difficult without specialized imaging equipment such as a CT scan with contrast or an MRI image, only a small percentage of stroke patients (3-5%) are ever given tPA.  So, a rapid and accurate clinical diagnostic kit based on this invention would have a profound public health benefit and likely a large commercial potential.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=2168</link><pubDate>2010-09-20</pubDate></item><item><title>A Mouse Model of von Hippel-Lindau Disease</title><description><![CDATA[The current invention embodies a mouse model which has been rendered a conditional homozygous knockout at the murine chromosome 6 VHL locus, homologous to the human VHL locus at chromosome 3p25. Mutations in VHL, a tumor suppressor gene, lead to the clinical manifestations of von Hippel-Lindau disease, a rare autosomal dominant syndrome characterized by tumor formation in multiple organs, including the brain and kidneys.  Using Cre/lox site-specific recombination, this invention allows for homozygous deletion of wild-type VHL only in specified tissues, thereby circumventing the embryonic lethality seen in the VHL knockout mouse.  The model embodied in this invention therefore appears to represent a valuable research tool for understanding how inactivation of both copies of the VHL gene lead to tumor formation, and ultimately should aid in the testing of possible therapeutic approaches to von Hippel-Lindau disease.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=1280</link><pubDate>2010-06-16</pubDate></item><item><title>Method for Predicting and Detecting Tumor Metastasis</title><description><![CDATA[Detecting cancer prior to metastasis greatly increases the efficacy of treatment and the chances of patient survival.  Although numerous biomarkers have been reported to identify aggressive tumor types and predict prognosis, each biomarker is specific for a particular type of cancer, and no universal marker that can predict metastasis in a number of cancers have been identified.  In addition, due to a lack of reliability, several markers are typically required to determine the prognosis and course of therapy. 

Available for licensing are carboxypeptidase E (CPE) inhibitor compositions and methods to prognose and treat cancer as well as methods to determine the stage of cancer.  The inventors discovered that CPE expression levels increase according to the presence of cancer and metastasis wherein CPE is upregulated in tumors and CPE levels are further increased in metastatic cancer.  This data has been demonstrated both in vitro and in vivo experiments and in liver, breast, prostate, colon, and head and neck cancers.  Metastatic liver cells treated with CPE siRNA reversed the cells from being metastatic and arrested cells from further metastasis.  Thus, CPE as a biomarker for predicting metastasis and its inhibitors have an enormous potential to increase patient survival.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=1539</link><pubDate>2010-06-16</pubDate></item><item><title>Novel DNA Liposome Complexes for Increased Systemic Delivery and Gene Expression</title><description><![CDATA[Improved liposomes have been created that could increase the efficacy of treatments for cancer, cardiovascular diseases, and HIV-1 related diseases in small and large animal models.  These liposomes efficiently condense nucleic acids, proteins, viruses, drugs, and mixtures of these agents on the interior of bilamellar invaginated structures produced by a novel extrusion procedure.  This technology is an improved delivery system for all biologically active reagents.  By using extruded DOTAP:Cholesterol liposomes to form complexes with DNA encoding specific proteins, expression has been improved dramatically.  These nucleic acid:liposome complexes have extended half-life in the circulation, are stable in serum, have broad biodistribution, efficiently encapsulate various sizes of nucleic acids and other molecules including viruses and drugs, are targetable to specific organs and cell types, penetrate through tight barriers in several organs, are fusogenic with cell membranes and avoid endosomes, are optimized for nucleic acid:lipid ratio and colloidal suspension in vivo, can be size fractionated to produce a totally homogenous population of complexes prior to injection; are non-toxic, non-immunogenic and can be repeatedly administered, and liquid suspensions and freeze-dried formulations are stable.  These complexes have been injected into mice, rats, rabbits, pigs, nonhuman primates, and humans.  Currently, these complexes are injected intravenously into patients in clinical trials to treat lung cancer and will be used in upcoming trials to treat breast, pancreatic, head and neck cancers; and Hepatitis B and C.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=1165</link><pubDate>2010-06-16</pubDate></item><item><title>Insect Cell Production of Recombinant Adeno-Associated Virus that Produce Cytotoxic Gene Products and Applications for Solid Tumor Therapy</title><description><![CDATA[Cancer is the second leading cause of death in United States and it is estimated that there will be approximately 600,000 deaths caused by cancer in 2006.  Due to the high incidence of death from cancer despite the use of current therapies, there is a strong need for targeted therapeutic approaches such as gene therapy. 

This technology describes a new method for targeting solid tumors using gene therapy.  More specifically, mammalian HEC-1 has a critical role in chromosome segregation and thus cell division.  This technology involves targeted depletion of HEC-1 using shRNA against the HEC-1 mRNA inhibiting cancer cell growth in cell culture models (in vitro) as well as regressed tumor size in mouse model (in vivo).  Additionally, this is the sole technology using an insect cell based recombinant adeno-associated virus (rAAV) gene transfer vehicle with high titer containing the shRNA of interest thus enabling high dosing during therapeutic intervention if necessary.  This technology platform has the potential to treat a broad spectrum of cancers and related diseases.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=1333</link><pubDate>2010-06-16</pubDate></item><item><title>Human Erythropoietin Receptor Transgenic Mice</title><description><![CDATA[The inventors have developed a transgenic mouse which expresses the human erythropoietin receptor. Erythropoietin is a cytokine or hormone required for the production of red blood cells and acts by binding on early, undifferentiated blood progenitor cells to stimulate red blood cell formation.  The model is particularly useful as human infectious agents or gene therapy vectors that selectively target human cells expressing the erythropoietin receptor can be studied. 

Background scientific detail may be found in Liu, C., Liu, Z.Y., Shen, K. and Noguchi, C. T. (1997), "Regulated human erythropoietin receptor expression in mouse brain", J. Biol. Chem. 272:32395-32400.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=185</link><pubDate>2010-06-16</pubDate></item><item><title>A Novel and Efficient Technology for Targeted Delivery of siRNA</title><description><![CDATA[The biological phenomenon of RNA interference (RNAi) has much promise for developing therapeutics to a variety of diseases.  However, development of RNAi therapies remains mainly in preclinical stages largely because of difficulties in delivering small inhibitory RNAs (siRNA) and short hairpin RNAs (shRNA) into target cells.  Although viral vector-based siRNA delivery systems have been widely used, their specificity and safety remains significant issue.  Without a solution to this delivery problem, RNAi cannot fulfill its therapeutic promise. 

Investigators at the National Institutes of Health have developed novel compositions and methods for delivering inhibitory oligonucleotides to cells in a targeted and efficient manner.  The compositions and methods are based on utilizing a cell surface receptor targeting ligand, such as cytokine or chemokine, and a domain that binds an inhibitory oligonucleotide, to efficiently deliver the inhibitory oligonucleotide to the cell that expresses the cell surface receptor targeting ligand.  Chemokine receptors are differentially expressed on various cells, including tumors; hence this technology allows targeting siRNA to aberrant cells.  Gene silencing can also be achieved in variety of immune cells by targeting cytokine receptors.  This technology has great potential for developing into a safe and effective means of delivering therapeutic siRNAs.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=1868</link><pubDate>2010-06-16</pubDate></item><item><title>Attenuated Salmonella as a Delivery System for siRNA-Based Tumor Therapy</title><description><![CDATA[The discovery that genes vectored by bacteria can be functionally transferred to mammalian cells has suggested the possible use of bacterial vectors as vehicles for gene therapy. Genetically modified, nonpathogenic bacteria have been used as potential antitumor agents, either to elicit direct tumoricidal effects or to deliver tumoricidal molecules. Bioengineered attenuated strains of Salmonella enterica serovar typhimurium (S. typhimurium) have been shown to accumulate preferentially greater than one-thousand fold in tumors than in normal tissues and to disperse homogeneously in tumor tissues. Preferential replication allows the bacteria to produce and deliver a variety of anticancer therapeutic agents at high concentrations directly within the tumor, while minimizing toxicity to normal tissues. These attenuated bacteria have been found to be safe in mice, pigs, and monkeys when administered intravenously, and certain live attenuated Salmonella strains have been shown to be well tolerated after oral administration in human clinical trials. The S. typhimurium phoP/phoQ operon is a typical bacterial two-component regulatory system composed of a membrane-associated sensor kinase (PhoQ) and a cytoplasmic transcriptional regulator. phoP/phoQ is required for virulence, and its deletion results in poor survival of this bacterium in macrophages and a marked attenuation in mice and humans. phoP/phoQ deletion strains have been employed as effective vaccine delivery vehicles. More recently, attenuated salmonellae have been used for targeted delivery of tumoricidal proteins. 

This technology comprises live, attenuated Salmonella strains as a delivery system for small interfering double-stranded RNA (siRNA)-based tumor therapy.  The inventors' data provide the first convincing evidence that Salmonella can be used for delivering plasmid-based siRNAs into tumors growing in vivo. Claimed in the related patent application are methods of inhibiting the growth or reducing the volume of solid cancer tumors using the si-RNA constructs directed against genes that promote tumor survival and cancer cell growth. The Stat3-siRNAs carried by an attenuated S. typhimurium described in the application exhibit tumor suppressive effects not only on the growth of the primary tumor but also on the development of metastases, suggesting that an appropriate attenuated S. typhimurium combined with the RNA interference (RNAi) approach may offer a clinically feasible method for cancer therapy.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=1878</link><pubDate>2010-06-16</pubDate></item><item><title>A Transgenic Mouse Model for Tetracycline Regulated Gene Expression in the Mouse Epidermis</title><description><![CDATA[This technology relates to the creation of several transgenic mouse lines that will produce conditional overexpression of foreign genes in the mouse epidermis.  Foreign genes are frequently expressed in mice to create models of human disease by using a promoter or regulatory region that is tissue specific.  In previous models expression of the target gene is always on.  In these new models expression is conditional such that timing and level of expression can be completely controlled by the investigator.  The inventor has taken advantage of the bigenic tetracycline regulatory system first described by Grossen and Bujard to create the present transgenic mouse lines.  The system utilizes two transgenic lines that are then bred together to create a double transgenic mouse.  One transgenic line expresses the tetracycline regulated transcriptional transactivator tTA or rTA linked to a keratin 5 (K5) promoter.  These transgenic lines have been designated K5/tTA and K5/rTA.  The K5 promoter is expressed in the epidermis hair follicles and several other squamous epithelia such as tongue trachea and forestomach.  The second transgenic line carries the target gene linked to the tetO binding sites for the tTA or rTA proteins.  In double transgenic mice, the tTA binds to the tetO sequence and causes high levels of expression of the target gene.  However, the ability of the tTA to bind to DNA is prevented by the antibiotic tetracycline.  If animals are maintained on tetracycline in the drinking water or feed, the expression of the target gene is suppressed; upon removal of the antibiotic, gene expression is induced.  In contrast tetracyclines are required to induce expression of the target gene by the rTA.  The ability of  this bigenic system to suppress expression of the target gene is crucial for a functional analysis of genes which produce an embryonic or neonatal lethal phenotype when expressed at high levels during gestation.   In addition, different levels of gene expression can be achieved through titration of the tetracycline dose.  Studies in the inventor's laboratory have confirmed that the K5/tTA and rTA can transactivate expression of target genes in the epidermis at high levels, uniformly throughout the tissue, and that transactivation is tightly controlled by tetracycline analogues.  The mouse epidermis is a useful system for modeling for human fibrotic and blistering skin diseases, dissecting the critical factors in wound healing and multistage carcinogenesis in lining epithelia.  This conditional expression system should greatly enhance the ability to assess function of specific target genes in these processes, and to create useful in vivo models for the development of novel therapeutics.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=189</link><pubDate>2010-06-16</pubDate></item><item><title>Novel Oligonucleotides for Treatment of Human Cancer</title><description><![CDATA[Human endogenous retroviruses (HERVs) are remnants of retroviruses that invaded and integrated into the human genome 6-15 million years ago.  One significant type of HERV is ERV-9; approximately 5% of the total human genome comprises sequences from this retrovirus family.  The human genome contains approximately 50 copies of ERV-9 along with 3000-4000 copies of solitary elements of ERV-9 regulatory regions, called long terminal repeats (LTRs).  The solitary LTRs contain promoter and enhancer elements that drive expression of genes located proximally to the LTR.  Therefore, insertion of an ERV-9 LTR proximal to an oncogene could initiate carcinogenesis. 

This invention relates to the use of antisense and sense oligonucleotides (oligos) targeting the RNAs of ERV-9 LTR as a treatment for various cancers, including human breast, liver, prostate, and myeloid cancers and fibrosarcomas.  The inventors have shown that the ERV-9 LTR sense and antisense oligos can inhibit cancer cell proliferation in vitro more efficiently than the antisense oligos of Bcl-2 (G3139) and telomerase (GRN163), both of which are currently in cancer clinical trials.  The oligos have minimal effects on the proliferation of primary normal human cells in vitro.  These oligos have potential as a new therapeutic agent to suppress tumor cell growth, either when used alone or in conjunction with other antisense oligos or with chemotherapeutic agents such as VePesid.  Furthermore, sense and antisense RNA transcripts of ERV-9 LTR were detected in many human normal and tumor cells in this invention.  The sense and antisense RNA may form double stranded RNA and act as siRNA to regulate gene expression.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=1942</link><pubDate>2010-06-16</pubDate></item><item><title>Modified Growth Hormone</title><description><![CDATA[This invention described and claimed in this patent application provides for an improved method for producing human growth hormone (hGH) in vitro or in vivo.  In particular, the patent application describes compositions and methods which are based on a modified form of human growth hormone where the regulated secretory pathway (RSP) sorting signal has been modified to provide for the constitutive secretion of human growth hormone via the nonregulated secretory pathway (NRSP) in a mammalian cell.  One particular modified hGH composition, has been demonstrated to be biologically active and able to be secreted into the bloodstream in an animal model providing proof-of-concept.  This invention can be applied to a non-invasive method of gene therapy to achieve sustained delivery of this therapeutic protein.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=492</link><pubDate>2010-06-16</pubDate></item><item><title>Preventing Oral Mucositis with Hybrid Adenoretroviral Vectors</title><description><![CDATA[Researchers at the National Institutes of Health have recently developed a novel method utilizing adenoretroviral vectors to safely and swiftly prevent oral mucositis induced by radiotherapy. This clever new method developed by National Institute of Dental and Craniofacial Research (NIDCR) researchers combines the advantages of adenoviral and retroviral vectors to efficiently shuttle into salivary glands a non-integrating vector that can produce a therapeutic protein for intermediate to long-term treatment. This approach is anticipated to result in fewer side-effects than current therapies.

The market for the treatment of mucositis, the painful inflammation and ulceration of the mucous membranes lining the digestive tract, is estimated to be in excess of $5 billion world-wide. Up to 80% of all patients receiving radiotherapy and approximately 40% of all chemotherapy patients develop oral mucositis, and almost all patients receiving radiotherapy for head and neck cancer and those undergoing stem cell transplantation develop mucositis.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=2054</link><pubDate>2010-06-14</pubDate></item><item><title>Parkin and PINK1-Based Therapies for Parkinson's Disease and Other Mitochondrial Diseases</title><description><![CDATA[This technology provides methods for treating Parkinson's disease and other diseases associated with mitochondrial dysfunction.

Mutations in mitochondrial DNA (mtDNA) are responsible for a broad spectrum of inherited diseases, with symptoms that can range from mild to very severe.  Accumulated mutations in mtDNA have also been linked to the pathogenesis of common diseases such as cancer, diabetes mellitus, and neurodegenerative disorders.  In Parkinson's disease, for example, the accumulation of defective mitochondria appears to be responsible for the loss of midbrain neurons that produce dopamine neurotransmitter, which is a key feature of this disease.

In their recent work, Dr. Richard Youle and co-investigators have linked the fields of mitochondrial quality control and the genetics of Parkinson's disease.  They have discovered that the Parkin protein is selectively recruited to damaged mitochondria, and promotes autophagic degradation of these mitochondria; ablation of Parkin increases levels of damaged mitochondria in cells.  They have also discovered that another protein associated with mitochondrial disease, the mitochondrial PTEN-induced kinase-1 (PINK1), accumulates on the surface on damaged mitochondria, and that the presence of full-length PINK1 is necessary and sufficient for Parkin recruitment to the mitochondria.   Thus, both Parkin and PINK1 play specific and important roles in mitochondrial quality control and disposal.

This technology describes methods of treating Parkinson's disease or other mitochondrial diseases such as KSS (Kearns Sayre syndrome), MERRF (Myoclonus epilepsy ragged-red fibers), MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes), NARP (Neuropathy ataxia, retinitis pigmentosa), and LHON (Leber hereditary optic neuropathy) by increasing PINK1 or Parkin expression or activity, as well as methods of reducing the number of defective mitochondria in a cell by increasing PINK1 or Parkin expression or activity.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=2121</link><pubDate>2010-06-14</pubDate></item><item><title>Improved Expression Vectors for Mammalian Use</title><description><![CDATA[This technology relates to improving levels of gene expression using a combination of a constitutive RNA transport element (CTE) with a mutant form of another RNA transport element (RTE).  The combination of these elements results in a synergistic effect on stability of mRNA transcripts, which in turn leads to increased expression levels.  Using HIV-1 gag as reporter mRNA, one mutated RTE in combination with a CTE was found to improve expression of unstable mRNA by about 500-fold.  Similarly this combination of elements led to synergistically elevated levels of HIV-1 Env expression.  The function of CTEs and RTEs is conserved in mammalian cells, so this technology is a simple and useful way of obtaining high levels of expression of otherwise poorly expressed genes and can be used in a number of applications such as but not limited to improvements of gene therapy vectors, expression vectors for mammalian cells.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=870</link><pubDate>2010-06-14</pubDate></item><item><title>Methods to Increase Stability of Recombinant Vaccinia-Vectored Vaccines and Increase Expression of a Foreign Gene Inserted in Such Vaccines</title><description><![CDATA[The technology offered for licensing is in the field of vaccinia-based recombinant vaccines. In particular the invention relates to methods of stabilizing the recombinant virus, thus resulting in efficient production of the vaccine and efficient expression of the inserted gene.  Stabilization of the recombinant virus is achieved by the insertion of the exogenous gene into an intergenic region (IGR) of the viral genome (i.e. Modified Vaccinia Ankara, MVA), where the IGR is flanked by open reading frames of conserved poxvirus genes. Furthermore, the invention relates to plasmids vectors useful to insert the exogenous DNA into the genome of a vaccinia virus. Stability can be further enhanced by incorporating silent mutations that decrease the lengths of homopolynucleotide runs in the foreign gene.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=2068</link><pubDate>2010-03-01</pubDate></item><item><title>Novel Inhibitors of Interleukin-6 for Kaposi Sarcoma Therapy</title><description><![CDATA[The cancer therapy market is forecast to reach $40.9 billion by 2012. With immunosuppressant drugs set for phenomenal growth over the next six years, revenues could reach $26.2 billion by 2014. One market for which there is a significant need for new therapies is cancers induced by Kaposi Sarcoma-associated Herpesvirus (KSHV).

Researchers at the National Cancer Institute have identified novel nucleic acid sequences that act through a unique mechanism to inhibit the expression of interleukin-6 that occurs in cancerous cells transformed by KSHV infection and which promotes cancer cell proliferation. The researchers have also identified a key protein involved in the mechanism which could be inhibited using antibodies.

These inhibitors are likely to be accepted in the marketplace because their unique specificity in mechanism of action gives them a distinct advantage over the mechanisms of other existing therapies.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=2026</link><pubDate>2009-10-28</pubDate></item><item><title>Rapid Diagnostic Applications of Phage</title><description><![CDATA[The NIH has available for licensing two techniques for rapid detection of a particular bacteria strain.  Similar detection using currently available technologies take 1-2 days; this technology reduces the time to less than one hour.  These technologies utilize phage, which has no pathogenic effect on higher plants and animals and are part of approved food-preparation formulations, indicating their known safety profile and an existing regulatory pathway.  The first technique involves a phage that incorporates a reporter gene (e.g., luciferase) that will be expressed only when the phage successfully infects a bacterium.  This technique is particularly useful where only bacteria-killing ("lytic") phages are known because the method also deactivates the lytic genes, enabling infection and subsequent detection.  The second technique involves an engineered phage that will bind with quantum dots upon infection of bacteria; if a sample is treated first with this phage and then with quantum dots, the sample will only respond if the bacteria are present.  Both techniques can be used to diagnose a clinical sample (tissue, blood, etc.) or an environmental isolate.]]></description><link>http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=2012</link><pubDate>2009-09-03</pubDate></item></channel></rss>