Yale University

Oklahoma Medical Research Foundation

Other

Alfred L Bothwell

Peter J Sims

Richard A Flavell

Scott A Rollins

Stephen P Squinto

Leonard Bell

Joseph A Madri

Eileen A Elliot

Sidney Altman

Alfred E Slanetz

Wook-Jin Chae

Choukri Mamoum

The present invention provides compositions and methods for inhibiting Dkk-1 for treating or preventing an inflammatory or inflammatory-related disease or disorder.

Compositions and methods for inhibiting Dkk-1

Antimicrobial compositions including a cell penetrating peptide (CPP) having the amino acid sequence Tyr-Ala-Arg-Val-Arg-Arg-Arg-Gly-Pro-Arg-Gly-Tyr-Ala-Arg-Val-Arg-Arg-Arg-Gly-Pro-Arg-Arg (SEQ ID NO:1) or variant thereof are disclosed. The CPP, which itself has antimicrobial properties, can be advantageously combined with or conjugated to a cargo to increase the delivery, efficacy, or combinations thereof, of the cargo into cells. In preferred embodiments, the CPP is combined with or conjugated to a functional nucleic acid, such as an external guide sequence (EGS) which can target and reduce expression of essential microbial genes or genes than impart resistance to antimicrobial drugs. Methods of using the compositions alone or in combination with traditional antimicrobial drugs to treat infections are also disclosed.

Antimicrobial compositions and methods of use thereof

Genetically engineered cells are provided which can serve as universal donor cells in such applications as reconstruction of vascular linings or the administration of therapeutic agents. The cells include a coding region which provides protection against complement-based lysis, i.e., hyperacute rejection. In addition, the cell's natural genome is changed so that functional proteins encoded by either the class II or both the class I and the class II major histocompatibility complex genes do not appear on the cell's surface. In this way, attack by T-cells is avoided. Optionally, the cells can include a self-destruction mechanism so that they can be removed from the host when no longer needed.

Universal donor cells

An intact, assembled T cell receptor (TcR) in soluble form is provided. The soluble TcR is prepared by splicing the extracellular domains of a T cell receptor to the glycosyl phosphatidylinositol (GPI) membrane anchor sequences of Thy-1. The molecule is expressed in the absence of CD3 on the cell surface, and can be cleaved from the membrane by treatment with phosphatidylinositol specific phospholipase C (PI-PLC). The .alpha. and .beta. chains of the soluble molecule are paired in the native conformation as judged by reactivity with the anti-V.sub..beta. 8 monoclonal antibody F23.1, and with the anti-clonotypic monoclonal antibody 1B2. The soluble TcR is a disulfide linked dimer with a molecular mass of 95 kDa on SDS-PAGE under nonreducing conditions, and 47 kDa after reduction.

Soluble T cell receptors

A method and means for protecting cells and transplanted organs from the effects of activated complement proteins generated in blood serum or plasma by introducing the gene for CD59 into the cells to be protected is described. In an example of the method, protection against the pore-forming activity of the human C5b-9 proteins was conferred on CHO cells by transfection with cDNA encoding the human complement regulatory protein CD59.

Genetic inhibition of complement mediated inflammatory response

A method and means for protecting cells and transplanted organs for the effects of activated complement proteins generated in blood serum or plasma by introducing the gene for CD59 into the cells to be protected is described. In an example of the method, protection against the pore-forming activity of the human C5b-9 proteins was conferred on CHO cells by transfection with cDNA encoding the human complement regulatory protein CD59.

Growing community of inventors

Guilford, CT, United States of America

Alfred L Bothwell