Beth Israel Deaconess Medical Center, Inc.

Dartmouth College

Massachusetts Institute of Technology

The University of Texas System

Localmed, Inc.

Michael Simons

Arie Horowitz

Youhe Gao

Robert Samuel Langer

Aaron V Kaplan

Elazer Reuven Edelman

Robert D Rosenberg

Youche Gao

Rudiger Volk

Sudha Veeraraghavan

Kiflai Bein

Jean-Luc DeKeyser

Daniella Tirziu

Ruediger Volk

The present invention relates to mutant proline-and-arginine rich (PR) peptides with defined structural characteristics for use in inhibiting mammalian 20S proteasome activity and modulating expression of genes regulating the NF-&#x3ba;B pathway. Mutant PR peptides of the present invention differ from wild-type PR peptides by having at least one to three amino acid substitutions, wherein at least one of the amino acid residues at position one, two or three of the mutant PR peptide is positively charged.

Mutant proline-and-arginine rich peptides and methods for using the same

The present invention relates to methods of using a proline/arginine-rich peptide such as PR11 or PR39 for increasing cardiac mass or performance and in the treatment of heart failure.

Method for increasing cardiac mass and performance

The present invention provides both a method and means for regulating angiogenesis within living cells, tissues, and organs in-situ. The regulation is performed using native PR-39 peptide or one of its shorter-length homolog, for interaction with such proteasomes as one present in the cytoplasm of viable cells. The result of PR-39 peptide interaction with proteasomes is a decrease in the intracellular degradation of active peptides such as HIF-1&#x3b1; and a consequential stimulation of angiogenesis in-situ.

Method for PR-39 peptide regulated stimulation of angiogenesis

The present invention provides both a method and means for regulating I&#x3ba;B&#x3b1; degradation, NF&#x3ba;B activity, and NF&#x3ba;B-dependent gene expression within living cells, tissues, and organs in-situ. The selective regulation is performed using native PR-39 peptide or one of its shorter-length homologs, for interaction with such I&#x3ba;B&#x3b1; and proteasomes as are present in the cytoplasm of viable cells. The result of PR-39 peptide interaction with I&#x3ba;B&#x3b1; is a selective alteration in the intracellular proteolytic activity of proteasomes, which in turn, causes a reduction of I&#x3ba;B&#x3b1;, a decrease of NF&#x3ba;B activity, and a down-regulation of NF&#x3ba;B-dependent gene expression.

Method for PR-39 peptide mediated selective inhibition of l&#x3ba;B&#x3b1; degradation

The present invention provides both a method and means for regulating angiogenesis within living cells, tissues, and organs in-situ. The regulation is performed using native PR-39 peptide or one of its shorter-length homologs, for direct interaction with the &#x3b1;7 subunit of such proteasomes as one present in the cytoplasm of viable cells. The result of PR-39 peptide interaction with proteasomes is a decrease in the intracellular degradation of active peptides such as HIF-1&#x3b1; and a consequential stimulation of angiogenesis in-situ.

Method for PR-39 peptide mediated selective inhibition of I&#x3ba;B&#x3b1; degradation

The present invention provides tangible means and methods for stimulation of angiogenesis via enhanced endothelial expression of core proteins having a syndecan-4 cytoplasmic region intracellularly. The tangible means include a prepared DNA sequence fragment having separate and individual DNA sequenced portions coding for an heparan sulfate binding extracellular domain, a central transmembrane domain, and a cytoplasmic domain coding for the syndecan-4 polypeptide. The prepared DNA sequence unitary fragment may be delivered to endothelial cells in-situ, both under in-vivo and/or in-vitro conditions, using suitable expression vectors including plasmids and viruses. The resulting transfected endothelial cells overexpress heparan sulfate binding, core proteins; and the resulting overexpression of these proteoglycan entities causes stimulation of angiogenesis in-situ.

Stimulation of angiogenesis via enhanced endothelial expression of syndecan-4 core proteins

Stimulation of angiogenesis via enhanced endothelial expression of syndecan-4 core

The present invention provides a methodology and compositions for stimulating angiogenesis in-situ within viable cells, tissues and organs comprising endothelial cells. The methodology focuses upon and controls the phosphorylation of the 183rd amino acid residue, serine, within the cytoplasmic domain and intracellular tail of transmembrane syndecan-4 proteoglycans which are then positioned at and through the cellular membrane of viable endothelial cells. By intervening and maintaining the 183rd residue in a non-phosphorylated state, a consequential cascade of intracellular events is initiated which result in a stimulation of angiogenesis in-situ.

Stimulation of angiogenesis via syndecan-4 cytoplasmic domain signaling pathway

The present invention is directed to peptides that interacts with thrombospondin 2 and inhibit matrix metalloproteinase 9 (MMP-9) activity. Consequently, the invention provides peptides that inhibit MMP-9 activity and are useful as inhibitors of angiogenesis and metastasis, among other diseases regulated by MMP-9. The peptides of the invention and their methods of use are therapeutic against diseases, such as cancer and arthritis, which are characterized by neovascularization.

Peptide inhibitor of MMP activity and angiogenesis

Angiogenesis in cardiac and other tissues is promoted by the transmural delivery of angiogenic factors such as VEGF, FGF, EGF, and PDGF, through blood vessels and other body lumens into the surrounding tissue. Usually, the angiogenic factor is delivered using a catheter having infusion parts at its distal end. Optionally, the distal end of the catheter is radially expanded to engage the infusion parts directly against the blood vessel wall.

Localized intravascular delivery of growth factors for promotion of

Disclosed is a method for localized application of antisense oligonucleotides, which has been found to be effective in inhibiting expression and translation of a variety of genes. The method utilizes antisense oligonucleotides which are specific for the mRNA transcribed from the gene of interest. The antisense oligonucleotides are applied directly to the desired locus of the cells to be treated, where they hybridize with the mRNA and inhibit expression of the gene. Devices for localized antisense application and methods for making them also are described.

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Chestnut Hill, MA, United States of America

Michael Simons