The J. David Gladstone Institutes

University of California

The J. David Gladstone Institutes, a Testamentary Trust Established Under the Will of J. David Gladstone

Xyphos Biosciences Inc.

Warner C Greene

Michael P Sherman

Peter Henklein

Ulrich Schubert

Kimberly S Stopak

Gilad Doitsh

Wesley M Yonemoto

Orlando Zepeda

Nicole Galloway

Romas Gelezuinas

Xin Lin

Eric M Verdin

Katerina Akassoglou

Vanessa Soros

Victor Wray

Jae Kyu Ryu

Kaman C Kim

Wolfgang Fischle

Carlos De Noronha

Mauricio Montano

Carlos M C deNoronha

Uwe Tessmer

Karsten Bruns

Samuel A F Williams

Lin-feng Chen

Nigel Killeen

Eytan Herzig

Andrea Gramatica

Carlos M deNoronha

Carlos Mc De Noronha

Ya-Lin Chiu

Parham Ganchi

Marielle Cavrois

Shao-Cong Sun

Kimberly Sue Stopak

Vanessa B Soros

Wesley Minoru Yonemoto

Carlos Manuel Clemm De Noronha

Described herein is an animal model useful for identifying therapeutic agents that can inhibit the physiological effects or symptoms of COVID-19 infection, including the effects of the following on one or more organs of the animal: inflammation, oxidative stress, fibrin deposition, blood brain barrier breakdown, clotting, and vascular problems.

Animal model for SARS-CoV-2-spike induced coagulopathy

The present disclosure provides compositions and methods for reactivating latent immunodeficiency virus using a glycogen synthase kinase 3&#x3b1; inhibitor, such as a glycogen synthase kinase 3&#x3b1; (GSK-3&#x3b1;) or a glycogen synthase kinase 3&#x3b2; (GSK-3&#x3b2;) inhibitor. In some embodiments, the glycogen synthase kinase 3 inhibitor is a glycogen synthase kinase antagonist, e.g., Tideglusib (4-benzyl-2-(naphthalen-1-yl)-1,2,4-thiadiazolidine-3,5-dione), or a pharmaceutically acceptable salt or derivative thereof. In other embodiments, the glycogen synthase kinase 3 inhibitor is a maleimide-based glycogen synthase kinase 3 inhibitor, e.g., SB-216763 (3-(2,4-Dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione) or a pharmaceutically acceptable salt or derivative thereof.

Compositions and methods for reactivating latent immunodeficiency virus using a GSK-3 inhibitor

This application relates generally to the production of modified, non-natural &#x3b1;1-&#x3b1;2 domains of NKG2D ligands with attached polypeptides having specific target-binding properties, for example, antibodies or variable fragments of antibodies, that are selectively delivered to Chimeric Antigen Receptors (CARs) comprised of modified, non-natural NKG2D receptors on engineered mammalian cells. The targeting of surface-expressed molecules includes those of virus-infected cells that can then be attacked and ablated by engineered cells of the immunity system expressing CARs cognate to the modified, non-natural &#x3b1;1-&#x3b1;2 domains of NKG2D ligands with attached polypeptides.

Modified non-natural NKG2D ligands that selectively deliver attached heterologous molecules to non-natural NKG2D receptors on car-cells

Provided herein are compositions and methods for the treatment of a patient having an HIV-1 infection and/or AIDS. More specifically this invention provides treatment of an HIV-1 infection and/or AIDS using small molecule compounds, such as inhibitors for the activation and/or activity of caspase-1. Inhibitors for the activation and/or activity of caspase-1 also prevent the cell death of CD4 T-cells in a population of CD4 T-cells comprising HIV-1 infected CD4 T-cells and uninfected CD4 T-cells, In addition, caspase-1 inhibitors inhibit inflammation, and pyroptosis.

Treatment of HIV-1 infection and AIDS

Provided herein are compositions and methods for the treatment of a patient having an HIV-1 infection and/or AIDS. More specifically this invention provides treatment of an HIV-1 infection and/or AIDS using small molecule compounds, such as inhibitors for the activation and/or activity of caspase-1. Inhibitors for the activation and/or activity of caspase-1 also prevent the cell death of CD4 T-cells in a population of CD4 T-cells comprising HIV-1 infected CD4 T-cells and uninfected CD4 T-cells. In addition, caspase-1 inhibitors inhibit inflammation, and pyroptosis.

The present invention provides methods of identifying an agent that inhibits an activity of a lentiviral Vif protein. The present invention provides methods of identifying an agent that increases the level of active APOBEC3G in a cell. The present invention provides agents identified by a subject screening method; and further provides methods for treating lentivirus infections.

Methods for treating lentivirus infections

The present invention provides methods and compositions useful for the elimination of latent HIV reservoirs that persist despite HAART. The methods and compositions overcome this latent barrier by inducing the replication of HIV in latently infected T cells while preventing the spread of the newly produced virions to uninfected cells by providing HAART simultaneously. Compositions of the invention comprise an activator of latent HIV expression, such as prostratin, and an inhibitor of histone deacetylase, such as TSA. A surprising finding of this invention is that the inhibitor of the histone deacetylase synergizes the effect of prostratin thus, allowing administering to a patient a lower, non-toxic dose of prostratin.

Methods and compositions for the synergistic activation of latent HIV

The present invention features methods and compositions relating to a virion-based fusion assay for detection of infection of a target cell by an enveloped retroviral virion such as HIV. The assay uses virions containing a chimeric viral protein comprising a viral accessory polypeptide (such as Vpr) fused to a reporter polypeptide (such as beta-lactamase). Fusion of the virion with a target cell membrane results in intracellular delivery of the chimeric protein to the target cell, which in turn provides for detection of a detectable signal mediated by the reporter polypeptide portion of the chimeric polypeptide. Significant detectable signal is only detected following intracellular delivery of the chimeric viral protein, thus providing for detection of productive viral entry to the exclusion of non-productive, endocytic entry of virions into the cell.

Virion-based fusion assay

The present invention provides screening methods for identifying a compound that induces loss of the lentiviral protein Vpr; screening methods for identifying compounds that inhibit the peptidyl-prolyl cis/trans isomerase (PPIase) activity of a protein that catalyzes cis-trans isomerization of cis-peptidylprolyl bonds in Vpr; and compounds identified by the screening methods. The compounds are useful for treating a lentiviral infection. The present invention further provides methods of inducing loss of the lentiviral protein Vpr; methods of inhibiting lentivirus viral replication; and methods of treating a lentivirus infection in an individual. The methods generally involve administering to an individual infected with the lentivirus an effective amount of a compound that induces Vpr loss and/or that inhibits PPIase activity of a protein that catalyzes cis-trans isomerization of cis-peptidylprolyl bonds in Vpr.

Methods of identifying agents for inhibiting lentivirus replication

The present invention provides methods for identification of agents that modulate NF-&#x3ba;B activity through modulation of the acetylation and deacetylation of the RelA subunit of NF-&#x3ba;B.

Methods for identifying modulators of NF-KB activity

Provided is a composition comprising a Vpr polypeptide conjugated to a therapeutic molecule. Preferably, the Vpr comprises synthetic Vpr. The therapeutic molecule can comprise any molecule capable of being conjugated to Vpr or a fragment thereof, including a polypeptide, a polynucleotide, and/or a toxin. The invention additionally provides a method for delivering a molecule into a cell. The method comprises contacting the cell with a conjugate comprising a Vpr polypeptide conjugated to the molecule. The invention further provides a method for modulating the expression of a transgene in a cell, a method for killing a target cell population in a subject, a method for increasing the sensitivity of cells to radiation therapy, and a method for inhibiting cell proliferation.

Compositions and methods for delivery of a molecule into a cell

The present invention provides the molecular basis for cytokine induction of NF-&kgr;B-dependent immune and inflammatory responses, emphasizing a role for both NIK-NIK and NIK-IKK protein&mdash;protein interactions. A relatively small region of NIK selectively impairs the NIK-IKK interaction. The present invention provides a novel and highly specific method for modulating NF-&kgr;B-dependent immune, inflammatory, and anti-apoptotic responses, based on interruption of the critical protein&mdash;protein interaction of NIK and IKK. The present invention provides methods for inhibiting NF-&kgr;B-dependent gene expression, using mutant NIK proteins. One embodiment of the present invention provides kinase-deficient NIK mutant proteins that inhibit activation of IKK. Another embodiment of the invention provides N-terminus NIK mutant proteins that bind IKK, thus inhibiting NIK/IKK interaction.

Inhibitor of the inflammatory response induced by TNF&agr; and IL-1

The present invention provides the molecular basis for cytokine induction of NF-&kgr;B-dependent immune and inflammatory responses, emphasizing a role for both NIK-NIK and NIK-IKK protein-protein interactions. A relatively small region of NIK selectively impairs the NIK-IKK interaction. The present invention provides a highly specific method for modulating NF-&kgr;B-dependent immune, inflammatory, and anti-apoptotic responses, based on interruption of the critical protein-protein interaction of NIK and IKK. The present invention provides methods for inhibiting NF-&kgr;B-dependent gene expression, using mutant NIK proteins. One embodiment of the present invention provides kinase-deficient NIK mutant proteins that inhibit activation of IKK. Another embodiment of the invention provides N-terminus NIK mutant proteins that bind IKK, thus inhibiting NIK/IKK interaction.

Inhibitor of the inflammatory response induced by the TNFA and IL-1

Methods and compositions for the inhibition of NF-&kgr;B activation are disclosed.

Growing community of inventors

Hillsborough, CA, United States of America

Warner C Greene