University of Pittsburgh

Other

The Scripps Research Institute

Paul David Robbins

Christopher H Evans

Joseph C Glorioso

Laura J Niedernhofer

Peter Wipf

Johnny Huard

Zhibao Mi

Raymond Frizzell

Mitra Lavasani

Richard C Mulligan

Theodore M Kamenecka

Nick Giannoukakis

Lawrence K Cohen

Andrea Gambotto

Alfred Blalock Bahnson

Lori F Rafield

Maliha Zahid

Brad Guild

Lina Lu

Isabelle Rivi&egrave;re

Gabriela Mustata Wilson

Richard Kane

Geethani Bandara

Steven C Ghivizzani

John A Barranger

Fei Sun

Axel W Baltzer

Richard Kang

The invention is directed to a method of inhibiting, within a living cell, the interaction between NF-&#x3ba;B essential modulator ('NEMO') with I&#x3ba;B kinase-&#x3b2; (IKK-&#x3b2;) at the NEMO binding domain (NBD), comprising exposing the cell to an effective amount or concentration of a compound of the invention, a NEMO-binding domain analog (NBDA). The invention is further directed to a method of treating a condition in a patient, wherein inhibiting the interaction between NF-&#x3ba;B essential modulator ('NEMO') with I&#x3ba;B kinase-&#x3b2; (IKK-&#x3b2;) at the NEMO binding domain (NBD) is medically indicated, comprising administering to the patient an effective dose of a compound of the invention. Conditions that can be treated by a method of the invention includes muscular dystrophy, asthma, inflammatory bowel disease, multiple sclerosis, Parkinson's Disease, arthritis, diabetes, graft versus host disease, accelerated aging, heart ischemia, cancer, UV-induced skin damage, or an age-related pathology.

Small molecule analogs of the nemo binding peptide

The present invention relates to methods of inhibiting one or more signs of aging and/or degenerative disorder in a subject in need of such treatment, which comprise administering, to the subject, an effective amount of one or more of the compounds as set forth herein. 'Inhibiting a sign of aging or degenerative disorder' means reducing the risk of occurrence, delaying the onset, slowing the progression, and/or reducing the severity and/or manifestation, of a sign of aging or degenerative disorder, and includes, but is not limited to, preventing the occurrence, development or progression of a sign of aging or degenerative disorder.

Compounds for the treatment of pathologies associated with aging and degenerative disorders

This invention relates to the use of autologous stem/progenitor cells to restore or rejuvenate adult stem cell function in a mammal, wherein the restoration or rejuvenating extends lifespan and/or improves health of the mammal. In addition, the invention also relates to compositions containing one or more regulatory factors secreted or released from isolated mammalian stem/progenitor cells and use of such compositions to extend lifespan and/or improve health of a mammal. Also provided are methods of treating, delaying, preventing or reversing progeria or related syndromes in a mammal using isolated autologous or allogeneic stem/progenitor cells and/or regulatory factors secreted or released therefrom.

Compositions and methods for restoring or rejuvenating stem/progenitor cell function

The present invention relates to Cardiac Targeting Peptides or CTPs that are able to transduce cardiomyocytes specifically in culture and in vivo, and to methods for using such peptides and their derivatives to deliver peptides, proteins or nucleic acids specifically to the heart. It is based, at least in part, on the discovery that the peptide APWHLSSQYSRT (SEQ ID NO:1) functioned as a cardiac-specific protein targeting peptide and was successful in delivering a number of different cargoes to cardiac muscle cells in vitro and in vivo.

Cardiac-specific protein targeting domain

The present invention provides methods and compositions for enhancing channel activity to the mutant cystic fibrosis trans-membrane conductance regulator protein (CFTR). The compositions of the invention comprise polypeptides containing CFTR sub-domains that are designed to mimic the folding defect of the full length mutant CFTR proteins, resulting in competitive binding to cytoplasmic chaperones such as Hsc/Hsp70 and Hdj2. The methods of the invention comprise transduction, or recombinant expression, of CFTR polypeptides in a cell expressing mutant CFTR. The presence of the CFTR polypeptide results in a dominant effect whereby the CFTR polypeptide competes with the endogenously expressed mutant CFTR for binding to cytoplasmic chaperones such as Hsc/Hsp70 and Hdj2. Mutant CFTR proteins include, but are not limited to, &#x394;F508 CFTR. The present invention is based on the discovery that reduced binding of cytoplasmic chaperones to the endogenous &#x394;F508 CFTR, mediated by the presence of CFTR polypeptides, results in restoration of plasma membrane localization and channel activity. The methods and compositions of the invention can be used to restore channel activity in cystic fibrosis subjects carrying genetic defects in the CFTR gene, such as for example, &#x394;F508 CFTR.

Polypeptides for increasing mutant CFTR channel activity

The present invention relates to a method for treating bone pathologies comprising delivering a viral or non-viral delivery vehicle comprising genetic information (e.g. a transgene) encoding a therapeutic osteoinductive factor to target cells in vivo enabling the cells to produce the osteoinductive factor at the site of the bone pathology. The delivery is achieved by a simplified method which does not require cumbersome ex vivo techniques or additional matrix or scaffolding agents. Such viral and non-viral delivery vehicles of the present invention are derived from the following nonlimiting examples: adenoviruses, adeno-associated viruses, retroviruses, herpes simplex viruses, liposomes, and plasmids. The osteoinductive factors include, but are not limited to, growth factors, cytokines, growth factor inhibitors and cytokine inhibitors.

Viral and non-viral vectors as vehicles for delivering transgenes for treating bone pathologies

Methods for introducing at least one gene encoding a product into at least one target cell of a mammalian host for use in treating the mammalian host are disclosed. These methods include employing recombinant techniques to produce a vector molecule that contains the gene encoding for the product, and infecting the target cells of the mammalian host using the DNA vector molecule. A method to produce an animal model for the study of connective tissue pathology is also disclosed.

Gene transfer for studying and treating a connective tissue of a mammalian host

The present invention relates to tolerogenic mammalian dendritic cells (DCs) and methods for the production of the tolerogenic DCs. In addition, the present invention provides a method for enhancing tolerogenicity in a host comprising administering the tolerogenic mammalian DCs of the present invention to the host. The tolerogenic DCs of the present invention comprise an oligodeoxyribonucleotide (ODN) which has one or more NF-&#x3ba;B binding sites. The tolerogenic DCs of the present invention may further comprise a viral vector, and preferably an adenoviral vector, which does not affect the tolerogenicity of the tolerogenic DCs when present therein. Enhanced tolerogenicity in a host is useful for prolonging foreign graft survival and for treating inflammatory related diseases, such as autoimmune diseases.

Use of tolerogenic dendritic cells for enhancing tolerogenicity in a host and methods for making the same

The present invention relates to internalizing peptides which facilitate the uptake and transport of cargo into the cytoplasm and nuclei of cells as well as methods for the identification of the peptides, and methods of use for the peptides. The internalizing peptides of the present invention are selected for their ability to efficiently internalize cargo into a wide variety of cell types both in vivo and in vitro.

Identication of peptides that facilitate uptake and cytoplasmic and/or nuclear transport of proteins, DNA and virues

Retroviral vectors are disclosed which include an insertion site for genes of interest and are capable of expressing high levels of the protein derived from the genes of interest in a wide variety of transfected cell types. Also disclosed are retroviral vectors lacking a selectable marker, thus rendering them suitable for human gene therapy in the treatment of a variety of disease states without the co-expression of a marker product, such as an antibiotic. These retroviral vectors are especially suited for use in certain packaging cell lines.

Retroviral gene therapy vectors and therapeutic methods based thereon

The subject invention concerns a method of introducing at least one DNA sequence expressing a protein or protein fragment which substantially alleviates articular cartilage defects. This method involves in vitro culture of chondrocytes, transfection of the chondrocytes with a recombinant vector housing the DNA sequence to be expressed, and delivery of the transfected chondrocytes to the damaged cartilage region. This method can also be used in tandem with synovial cell delivery techniques of the present invention. This method is also useful as a model in animal studies regarding joint pathologies.

Cartilage alterations by administering to joints chondrocytes comprising a heterologous polynucleotide

The subject invention concerns a method of introducing at least one gene encoding a product into at least one cell of a connective tissue of a mammalian host for use in treating the mammalian host including employing recombinant techniques to produce a DNA vector molecule which contains the gene encoding for the product and infecting the connective cell of the mammalian host using the DNA vector molecule using the gene coding for the product. A method is provided for introducing at least one gene encoding a product into at least one cell of a connective tissue of a mammalian host employing non-viral methods. A method to produce an animal model for the study of connective tissue pathology is also disclosed. Additionally, this invention provides a method of using in vivo a gene encoding and extracellular interleukin-1 binding domain of an interleukin-1 receptor.

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Pittsburgh, PA, United States of America

Paul David Robbins