Johns Hopkins University

Harry C Dietz

Hans Tomas Bjornsson

Daniel Philip Judge

David Kim

Alexander J Doyle

Jefferson J Doyle

Enid R Neptune

Joseph Shin

Benjamin Edward Kang

Ronald Cohn

Caitlin J Bowen

Juan Francisco Calderon Giadrosic

Joel Benjamin

Jennifer Habashi

Daniel P Judge

The present invention relates to compositions and methods for treating vascular Ehlers Danlos Syndrome and associated connective tissue disorders.

Compositions and methods for treating vascular Ehlers Danlos syndrome and associated disorders

The instant disclosure provides methods and compositions for the diagnosis, treatment and prevention of a TGF&#x3b2;2-associated disease, disorder and/or condition, including, e.g., Scleroderma, other fibrotic disease, grade 4 glioblastoma (GBM) and/or Primary Open-Angle Glaucoma (POAG). The disclosure further provides pharmaceutical compositions and kits for the diagnosis, treatment and prevention of TGF&#x3b2;2-associated diseases, disorders and/or conditions.

Targeted epigenetic therapy against distal regulatory element of TGF&#x3b2;2 expression

The instant disclosure provides methods and compositions for the diagnosis, treatment and prevention of Marfan syndrome and related diseases, disorders and conditions. The disclosure further provides pharmaceutical compositions and kits for the diagnosis, treatment and prevention of Marfan syndrome and related diseases, disorders and conditions.

Map kinase pathway targets for the treatment of Marfan syndrome

A method is provided for treating a Mendelian disorder of the epigenetic machinery in a subject in need thereof. In particular, the method comprises administering a therapeutically effective amount of an agent that restores balance between open and closed chromatin states at one or more target genes, wherein the agent that restores balance between open and closed chromatin states at one or more target genes is an agent that ameliorates the effect of a defective gene encoding a component of the epigenetic machinery.

Methods for treating mendelian disorders of the epigenetic machinery

Transforming growth factor &#x3b2; (TGF&#x3b2;) transcriptional responses are involved in the pathogenesis of aortic aneurism syndromes. Compositions that inhibit histone acetyltransferase activity normalize gene expression in the aorta, preserved aortic wall architecture and abrogated aneurism progression. Methods include the use of these compositions to epigenetically regulate abnormal expression and/or activity of TGF&#x3b2; genes.

Targeted epigenetic therapy for inherited aortic aneurysm condition

Provided herein are, inter alia, compositions and methods for identifying and using agents capable of inhibiting myofibroblast transition as well as methods for treating diseases associated with the same in a subject in need thereof.

Targeting CAPN9/CAPNS2 activity as a therapeutic strategy for the treatment of myofibroblast differentiation and associated pathologies

A method is provided for treating a Mendelian disorder of the epigenetic machinery (e.g., Kabuki syndrome) in a subject in need thereof. In particular, the method comprises administering to the subject a ketogenic composition in an amount sufficient to produce a physiologically acceptable ketosis in the subject. A method for selecting a subject for treatment of a Mendelian disorder of the epigenetic machinery (e.g., Kabuki syndrome) is also provided. Ketogenic compositions and kits useful for practicing the methods are also provided.

Compositions and methods for treating kabuki syndrome and related disorders

Non-FRET-based fusion protein reporter molecules are provided that can be used to monitor histone modifications in living cells. Transgenic animals, particularly non-human mammals, whose genomes comprise an expression cassette encoding a non-FRET-based fusion protein reporter, are also provided. Methods of using the fusion reporter molecules for diagnosing histone-modification-associated disorders and to identify candidate pharmaceutical agents that effect histone modification in cells and tissues are also provided.

Genetically encoded histone reporter allele constructs

The instant invention provides methods and compositions for the treatment and prevention of Marfan syndrome and related diseases, disorders and conditions. The invention further provides pharmaceutical compositions and kits for the treatment and prevention of Marfan syndrome and related diseases, disorders and conditions.

Methods and compositons featuring TGF-beta antagonists for the treatment of marfan syndrome and associated disorders

A novel nucleic acid construct for delivery of antisense targeting sequences is provided. The construct includes intact stem loop structures and an antisense nucleic acid. Optionally, a ribozyme nucleic acid is included in the construct. The construct is useful for inhibition of selected genes in a cell. This allele-specific targeting is also useful in combination with replacement gene therapy.

Delivery construct for antisense nucleic acids and methods of use

All eukaryotes that have been studied to date possess the ability to detect and degrade transcripts that contain a premature signal for the termination of translation. This process of nonsense-mediated RNA decay (NMRD) has been most comprehensively studied in the yeast, Saccharomyces cerevisiae where at least three trans-acting factors (Upf1p through Upf3p) are required. The present invention provides cDNAs encoding human and murine RENT1 (regulator of nonsense transcripts). rent1 is the first identified mammalian protein that contains all of the putative functional elements in Upf1p including zinc finger-like motifs and NTPase domains as well as all motifs common to members of helicase superfamily I. Moreover, expression of a chimeric protein, containing the central region of RENT1 flanked by the extreme N- and C-termini of Upf1p, complements the Up1p-deficient phenotype in yeast.

Mammalian regulator of nonsense-mediated RNA decay

All eukaryotes that have been studied to date possess the ability to detect and degrade transcripts that contain a premature signal for the termination of translation. This process of nonsense-mediated RNA decay (NMRD) has been most comprehensively studied in the yeast Saccharomyces cerevisiae where at least three trans-acting factors (Upf1 through Upf3) are required. The present invention provides cDNAs encoding human and murine RENT1 (reguiator of nonsense transcripts). RENT1 is the first identified mammalian protein that contains all of the putative functional elements in Upf1 including zinc finger-like motifs and NTPase domains as well as all motifs common to members of helicase superfamily I. Moreover, expression of a chimeric protein, containing the central region of RENT1 flanked by the extreme N- and C-termini of Upf1, complements the Upf1-deficient phenotype in yeast.

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Towson, MD, United States of America

Harry C Dietz