02-10927. Government-Owned Inventions; Availability for Licensing

AGENCY:

National Institutes of Health, Public Health Service, DHHS.

ACTION:

Notice.

SUMMARY:

The inventions listed below are owned by agencies of the U.S. Government and are available for licensing in the U.S. in accordance with 35 U.S.C. 207 to achieve expeditious commercialization of results of federally-funded research and development. Foreign patent applications are filed on selected inventions to extend market coverage for companies and may also be available for licensing.

ADDRESSES:

Licensing information and copies of the U.S. patent applications listed below may be obtained by writing to the indicated licensing contact at the Office of Technology Transfer, National Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, Maryland 20852-3804; telephone: [phone]; fax: [phone]. A signed Confidential Disclosure Agreement will be required to receive copies of the patent applications.

HIV-1 Envelope Glycoproteins Stabilized by Flexible Linkers as Potent Entry Inhibitors and Immunogens

Dimitrov et al. (NCI).

Licensing Contact: Carol Salata; 301/496-7735 ext. 232; e-mail: [e-mail].

The technology relates to tethered constructs where flexible linkers join gp120 and the ectodomain of gp41. The HIV-1 envelope Glycoprotein (Env) undergoes conformational changes while driving entry. The inventors hypothesized that some of the intermediate Env conformations could be stably represented in tethered constructs where gp120 and the ectodomain of gp41 are joined by flexible linkers. Tethered Envs with long (15 to 26 amino acid) linkers were stable and potently inhibited fusion mediated by R5, X4 and R5X4 Envs, most likely by exposure of gp41 structures that bind DP178 and cluster II mAbs. A tethered Env with a short (4 amino acid) linker, gp120 or DP178 were 100, 20 or 10-fold less effective, respectively. The fusion proteins with long linkers exhibited enhanced exposure of DP178 and cluster II mAbs binding gp41 structures that are critical for entry. These findings suggest the existence of conserved structures that are critical for HIV-1 entry, and could be used as inhibitors and novel immunogens for elicitation of broadly neutralizing antibodies.

Construction of West Nile Virus and Dengue Virus Chimeras for Use in a Live Virus Vaccine to Prevent Disease Caused by West Nile Virus

Pletnev et al. (NIAID).

Licensing Contact: Carol Salata; 301/496-7735 ext. 232; e-mail: [e-mail].

A candidate live attenuated vaccine strain was constructed for West Nile virus (WN), a neurotrophic flavivirus that has recently emerged in the U.S. Considerable attenuation for mice was achieved by chimerization with dengue virus type 4 (DEN4). The genes for the structural premembrane and envelope proteins of DEN4 present in an infectious cDNA clone were replaced by the corresponding genes of WN strain NY99. Two of 18 cDNA clones of a WN/DEN4 chimera yielded full-length RNA transcripts that were infectious when transfected into susceptible cells. The WN/DEN4 chimera was highly attenuated in mice compared with its WN parent; the chimera was at least 28,500 times less neurovirulent in suckling mice inoculated intracerebrally and at least 10,000 times less virulent in adult mice inoculated intraperitoneally. Nonetheless, the WN/DEN4 chimera and a deletion mutant derived from it were immunogenic and provided complete protection against lethal WN challenge. These observations provide the basis for pursuing the development of a live attenuated WN vaccine.

MVA Expressing Modified HIV Envelope, Gag and Pol Genes

Bernard Moss and Linda S. Wyatt (NIAID).

Licensing Contact: Carol Salata; 301/496-7735 ext. 232; e-mail: [e-mail].

This technology relates to construction of a recombinant poxvirus using modified vaccinia Ankara (MVA). The recombinant MVA (rMVA) expresses HIV Gag, Pol and HIV-1 Env under the control of vaccinia virus early/late promoters. A related rMVA expressing SHIV genes was used in heterologous prime/boost regimens that raised high levels of immune responses. DNA priming followed by a recombinant modified vaccinia Ankara (rMVA) booster controlled a highly pathogenic immunodeficiency virus challenge in a rhesus macaque model. Both the DNA and rMNA components of the vaccine expressed multiple immunodeficiency virus proteins. Two DNA inoculations at 0 and 8 weeks effectively controlled an intrarectal challenge administered 7 months after the booster. These findings provide hope that a relatively simple multiprotein DNA/MVA vaccine can help to control the acquired immune deficiency syndrome epidemic. This research is described in Science 292(5514): 69-74, April 6, 2001 (originally published in Science Express as 10.1126/science.1058915 on March 8, 2001).

Specific Inhibition of Gene Expression by Small Double Stranded RNAs

Caplen et al. (NHGRI).

Licensing Contact: Fatima Sayyid; 301/496-7056 ext. 243; e-mail: [e-mail].

Double-stranded RNA (dsRNA) has been shown to trigger sequence-specific gene silencing in a wide variety of organisms, including plant, nematode and invertebrate species. Recent intense work in the field has shown that small dsRNAs mediate sequence specific RNA degradation in the process known as RNA interference (RNAi).

This invention provides for synthetic dsRNAs (20-25 nucleotides in length) and methods that can inhibit gene-specific expression in mammalian cells. The sequence of the dsRNAs are essentially identical to a portion of the coding region of the target gene for which interference or inhibition of expression is desired. This inhibition has been shown to be superior to single-stranded antisense oligonucleotides and opens the possibility of the use of dsRNAs as reverse genetic and therapeutic tools in mammalian cells.

Magnetic Labeling of Cells Using Transfection Agents

Joseph Frank and Jeff Bulte (CC).

Licensing Contact: Norbert Pontzer; 301/496-7736, ext. 284; e-mail: [e-mail].

Many therapeutic strategies, such as stem cell transplantation, are based upon introducing exogenous living cells or tissues into a patient or host. A problem common to all therapeutic strategies involving administration of exogenous cells is identifying and monitoring the cells in the host. It is currently difficult or impossible to monitor the location of such cells or tissues in the host after administration. It may also be difficult to establish the survival of these cells in the host. Currently available procedures to locate transplanted cells are invasive and destructive. This problem must be overcome before such cell therapies can achieve their full potential.

Magnetic Resonance Imaging (MRI) is a technique that allows whole body in vivo imaging in three dimensions at near-cellular (microscopic) resolution. MR image contrast is largely determined by the nuclear magnetic relaxation times of tissues. To allow detection of transplanted cells, this technology provides compositions and methods for labeling cells in vitro with a contrast agent prior to transplantation. These contrast agents are non-toxic, biodegradable and are prepared by mixing commercially available magnetic responsive coated iron oxides and transfection agents, some of which are FDA approved. Magnetically labeled cells will facilitate the use or MRI to monitor these cells following transplantation in a clinical setting.

Anti-sera Against Arylalkylamine N-acetyltransferase (AANAT)—The Melatonin Rhythm Enzyme

David C. Klein et al. (NICHD).

Licensing Contact: Pradeep Ghosh; 301/496-7736 ext. 211; e-mail: [e-mail].

Biological materials are important research tools that can be used for diagnostic purposes. In particular, antisera are of broad value in biomedical research and in clinical chemistry. The present invention comprises of unpurified and immunopurified antisera developed in rabbits against bovine, rat, pike-2, zebra fish, chicken, monkey, and human AANAT. AANAT is an important enzyme because it controls the production of melatonin and its rhythm in vertebrates. A daily rhythm of melatonin in the circulation serves as the hormonal signal of the daily light/dark cycle. AANAT protein is expressed at high levels in pineal gland and retina, and only at night. The antisera developed as part of this invention may serve as an important immunologic tool to detect and monitor the expression of AANAT protein. Expression of AANAT is important for the understanding of the biochemical and physiological role of melatonin and therefore, the antisera may have a wide use in research studies. In addition, antisera detecting human AANAT may be useful in pathological and histochemical analysis of human pineal and retinal tissues. Further, the use of antisera may be applicable in clinical testing and monitoring of the effects of drugs on AANAT protein and other biochemical modification procedures.

Research articles that describe the use of the antisera include: Invest Opthalmol. and Visual Science 43:564-572, 2002; Proc. Natl. Acad. Sci U.S.A. 98:8083-8088, 2001; Endocrinology 142:1804-1813, 2001; J. Biol. Chem. 276:24097-24107, 2001; J. Neurochem. 75:2123-2132, 2000; J. Neurochem. 74:2315-2321, 1999; Science 279:1358-1360, 1998; Recent Progress in Hormone Research 52:307-358, 1997.

Dated: April 24, 2002.

Jack Spiegel,

Director, Division of Technology Development and Transfer, Office of Technology Transfer, National Institutes of Health.