Cincinnati Children's Hospital Medical Center

University of Cincinnati

University of Illinois

Institut National De La Sante Et De La Recherche Medicale

The University of Chicago

Xi Jason Jiang

Ming Tan

Jianjun Chen

Seungpyo Hong

Xufu Zhang

Zejuan Li

Jacques Le Pendu

Leyi Wang

A method of treating a subject suffering from a condition characterized by over-expression of Ten-eleven translocation 1 (TET1) is provided, the method including administering to the subject an effective amount of a compound, or a pharmaceutically acceptable salt thereof, having the Formula I: wherein: R, R, R, R, and Rare each independently selected from the group consisting of H, hydroxyl, alkyl, alkoxy, amine, halo, and trifluoromethyl, and wherein any two adjacent moieties of R, R, R, R, and Rmay come together to form a heterocyclic ring; Ris H or hydroxyl; and Ris selected from H, wherein Ris C or O. Also provided are methods for selectively suppressing transcription of TET1 and/or reducing a level of 5-hydroxymethylcytosine in a subject by administering an effective amount of a Formula I compound and pharmaceutical compositions comprising Formula I compounds.

Methods, agents, and compositions for the treatment of acute myeloid leukemia

A nanoparticle delivery system designed for sustained delivery of microRNA-150 (miR-150) to FLT3-overexpressing acute myeloid leukemia (AML) cells, the delivery system comprising poly(amidoamine) (PAMAM) dendrimers complexed with miR-150, wherein at least one dendrimer is surface-functionalized with a ligand specific for FLT3 receptor, and methods for treating AML characterized by FLT3-overexpression are provided.

Methods for treating subjects suffering from acute myeloid leukemia with FLT3 ligand-targeted miR-150 nanoparticles

Disclosed herein are vaccine compositions, in particular, polyvalent icosahedral compositions for antigen presentation. The disclosed compositions may contain an S particle made up of recombinant fusion proteins. The recombinant fusion proteins may include a norovirus (NoV) S domain protein, a linker protein domain operatively connected to the norovirus S domain protein, and an antigen protein domain operatively connected to said linker.

Norovirus S particle based vaccines and methods of making and using same

Compositions and methods for treating acute myeloid leukemia (AML) based on upregulating expression of microRNA-22 (miR-22), and a nanoparticle delivery system that utilizes FLT3-functionalized polyamidoamine (PAMAM) dendromirs for targeted delivery of miR-22 and/or agents that upregulate expression of miR-22 to AML cells.

Methods for treating acute myeloid leukemia and nanoparticle complexes of miR-22 utilized therein

A composition for use in inhibiting the binding of a Norovirus to the histo-blood group antigen on the surface of epithelia is disclosed. The composition may contain a therapeutically effective amount of a binding-inhibiting compound and a carrier and/or excipient. The compounds may competitively bind a Norovirus that has the capability of binding with the histo-blood group antigens of secretor blood type, including A, B, AB, and O blood types. The compositions may be administered to a human prior to or after infection by a Norovirus, to prevent, ameliorate, or reduce the effects of an infection.

Compositions and methods for inhibiting norovirus infection

Genes for proteins which spontaneously form dimers and/or oligomers can be recombinantly linked together, which upon expression inproduces stable dimeric fusion proteins that spontaneously self-assemble into enormous, polyvalent complexes having increased immunogenicity and functionality. Linear, network and agglomerate complexes with enormous sizes and polyvalences are constructed using glutathione S-transferase, Norovirus P domains (NoV Pand NoV), the protruding (P) domain of hepatitis E virus (HEV P), the astrovirus P domain (AstV), a monomeric peptide epitope (M2e of influenza virus), and/or a protein antigen (VP8* of rotavirus) fused in different combinations. The resulting complexes can contain hundreds to thousands NoV P-protein, HEV, AstV, M2e and/or VP8* copies and exhibit higher immunogenicity than the individual proteins alone. The large size and multivalent nature of the complexes are candidates as a bivalent or multivalent vaccines against Norovirus and other pathogens, and for generation of antibodies for diagnosis and research purposes.

Protein complex system for increased immunogenicity and functionality, and methods making and use

A substituted Norovirus capsid protein monomer, having only the P-domain, includes a foreign antigen inserted into one or more of three surface loops present on each P-domain monomer by molecular cloning. The antigen-P-domain monomer can assemble spontaneously into an octahedral, antigen-Norovirus P-particle, composed of 24 copies of the monomer. Each substituted P-domain monomer can contain one to three copies of the foreign antigen, for a total of 24-72 antigen copies on each antigen-P-particle. The antigen-P-particle is useful in methods for diagnosing, immunizing and treating individuals infected with a foreign virus and as a carrier for development of vaccines against many infectious and non-infectious diseases. The substituted monomer can be readily produced inand yeast, are highly stable and tolerate a wide range of physio-chemical conditions. The P-particle-VP8 chimeras may also serve as a dual vaccine, for example, against both rotavirus and norovirus.

Antigen-Norovirus P-domain monomers and dimers, antigen Norovirus P-particle molecules, and methods for their making and use

A substituted Norovirus capsid protein monomer, having only the P-domain and called an antigen-Norovirus P-domain monomer, includes a foreign antigen inserted into one or more of three surface loops present on each P-domain monomer by molecular cloning. The antigen-P-domain monomer can assemble spontaneously into an octahedral form, called an antigen-Norovirus P-particle, that is composed of 24 copies of the antigen-P-domain monomer. Each substituted P-domain monomer will contain one to three copies of the foreign antigen, for a total of 24-72 antigen copies on each antigen-P-particle. The antigen-P-particle is useful in methods for diagnosing, immunizing and treating individuals infected with a foreign virus, for example Rotavirus, and can serve as a carrier for presentation of foreign antigens for development of novel vaccines against many infectious and non-infectious diseases. The substituted Norovirus P-particles can be readily produced inand yeast, are highly stable and tolerate a wide range of physio-chemical conditions. A modified Norovirus P-domain monomer includes one or more restriction recognition sites inserted within one or more of the three loops of the P-domain monomers, to provide user-friendly cloning cassettes for conveniently inserting candidate foreign antigens into the surface loops. The P-particle-VP8 chimeras may also serve as a dual vaccine against both rotavirus and norovirus.

Antigen-norovirus P-domain monomers and dimers, antigen-norovirus P-particle molecules, and methods for their making and use

Norovirus capsid protein monomers having only the P domain, and not the hinge or S domain, can assemble spontaneously into an icosahedral form herein called the P-particle. Factors affecting the formation and stability of the P-particle, as well as providing methods for diagnosing and treating Norovirus-infected individuals and creating a vaccine for prevention of Norovirus infection are presented.

Norovirus particle for use as an antiviral or vaccine

A method for detecting a Norwalk-Like Virus (NLV) in a biological sample, comprising the steps of: obtaining a biological sample suspected of containing a NLV; contacting the biological sample with at least one human histo-blood group antigen to allow formation of a complex of the NLV with the antigen; and detecting the antigen-NLV complex. The antigen-NLV complex can be detected by contacting the NLV-antigen complex with a NLV antibody that binds at an epitope of the NLV, and detecting the NLV antibody. The invention also includes a method for identifying compounds, and the compounds, that can inhibit the binding between a Norwalk-Like Virus (NLV) and a histo-blood group antigen. The method includes the steps of contacting the NLV target with a compound; subsequently contacting the NLV with a standard compound that is known to be bound at a determinant binding site of the NLV; and determining whether the binding of the standard compound is decreased in the presence of the test compound, the decrease in binding being an indication that the test compound inhibits the binding activity of the NLV with the standard compound. In preferred embodiments, the standard compound is a histo-blood group antigen.

Method, composition and kit for antigenic binding of norwalk-like viruses

The invention provides a compound which competitively inhibits the binding of a norovirus with a native blood antigen of a human host, as well as a kit for determining whether an individual has been infected by a norovirus. Also provided is a method for determining the susceptibility of an individual to infection by a particular, known strain of norovirus. The invention is based on the determination that noroviruses recognize human blood antigens such as human histo-blood group antigens (HBGAs) as a receptor in seven specific binding patterns. The invention allows one to predict that a particular strain of norovirus can infect humans who have a particular human histo-blood type, as well as blood antigens that can bind the particular strain of infecting norovirus. The invention also allows one to predict that a particular strain of norovirus will bind with one or more particular histo-blood group antigens, but will not bind with other blood group antigens.

Growing community of inventors

Cincinnati, OH, United States of America

Xi Jason Jiang