The United States of America, As Represented by the Secretary, Department of Health and Human Services

University of Iowa Research Foundation

University of Florida Research Foundation Inc

The United States of America As Represented by the Department of Health

Stephen M. Weiner

Robert M. Kotin

Brian Safer

John A. Chiorini

John A Chiorini

Robert Michael Kotin

Michael Schmidt

Ioannis Bossis

Giovanni Di Pasquale

Edoardo Mannucci

Melodie L Weller

Beverly L Davidson

Stephen M Wiener

Giovanni DiPasquale

Matthew D Weitzman

Roland A Owens

Michael J Welsh

Mavis Agbandje-McKenna

Charles P Venditti

Randy J Chandler

Mark F Stinski

Joseph Zabner

Lynda S Ostedgaard

Nikola A Kaludov

Sandra Wainer

Sujata Halder

Robert M Kotin

Elena Urcelay

Hongen Yin

Robert Kotin

Stephen M Weiner

The invention provides an adeno-associated viral (AAV) vector comprising a capsid comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 9, wherein the AAV vector further comprises a heterologous nucleic acid sequence, and wherein the heterologous nucleic acid sequence can encode the NGF-PTH fusion polypeptide or methylmalonyl CoA mutase enzyme. The invention also provides a polypeptide comprising nerve growth factor (NGF) signal peptide and parathyroid hormone (PTH), wherein the polypeptide can comprise, consist essentially of, or consist of the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 2. The invention provides a nucleic acid encoding the polypeptide, a vector comprising the nucleic acid, and a composition comprising the polypeptide, nucleic acid, or vector, as well as treatment methods comprising the polypeptide, nucleic acid, vector, or composition. The invention further provides a method of treating methylmalonic acidaemia (MMA) in a mammal comprising administering an AAV vector comprising a heterologous nucleic acid sequence encoding methylmalonyl CoA mutase enzyme to the mammal.

AAV with unique capsid protein VP1 and methods of using for treatment

The invention relates to a gene transfer-based method to protect a subject from diabetes or obesity. The method comprises administering to a salivary gland of the subject an AAV virion comprising an AAV vector that encodes an exendin-4 protein. Also provided are exendin-4 proteins and nucleic acid molecules that encode such exendin-4 proteins. Also provided are AAV vectors and AAV virions that encode an exendin-4 protein. One embodiment is an exendin-4 protein that is a fusion protein comprising an NGF secretory segment joined to the amino terminus of an exendin-4 protein domain.

AAV mediated exendin-4 gene transfer to salivary glands to protect subjects from diabetes or obesity

The finding that patients with Sj&#xf6;gren's syndrome exhibit a statistically significant increase in expression of BMP6 in the salivary gland relative to healthy control subjects is described. Also described is the finding that overexpression of BMP6 in the salivary glands of mice results in an increase in electrical potential across the salivary gland. Thus, methods of diagnosing a subject as having Sj&#xf6;gren's syndrome, or at risk for developing Sj&#xf6;gren's syndrome, by measuring the level of BMP6 expression in a salivary gland of a subject, measuring electrical potential in a salivary gland of a subject, or both, are disclosed. Also described are methods of treating a subject with Sj&#xf6;gren's syndrome by administering an agent that inhibits expression of BMP6 expression or activity. Further disclosed is the use of XIST and MECP2 as diagnostic and therapeutic targets for male Sj&#xf6;gren's syndrome patients.

Methods for the diagnosis and treatment of Sj&#xf6;gren's syndrome

Viral infection has been suspected in the development of primary Sj&#xf6;gren's syndrome (pSS). Using a custom viral microarray, hepatitis delta virus (HDV) genomes and antigens were detected in minor salivary glands of patients with pSS. Expression of HDV antigens in healthy mice led to a Sj&#xf6;gren's syndrome-like pathogenesis characterized by a reduction in salivary flow, increase in lymphocytic foci, and the development of an autoantibody profile similar to HDV-positive patients. Also described herein is the detection of HDV in patients diagnosed with lymphoma. Expression of HDV antigen in healthy mice resulted in the development of tertiary lymphoid structures characteristic of the early stages of lymphoma. A sensitive, nested qPCR assay to detect HDV transcript and/or HDV genome in patient samples is also described.

Detection of hepatitis delta virus (HDV) for the diagnosis and treatment of Sj&#xf6;gren's syndrome and lymphoma

The invention relates to a gene transfer-based method to protect a subject from Sjogren's syndrome. The method comprises administering to the subject an AAV virion comprising an AAV vector that encodes aquaporin-1 (AQP-1) protein. Also provided are AQP-1 proteins and nucleic acid molecules that encode such proteins. Also provided are AAV vectors and AAV virions that encode an AQP-1 protein.

AAV mediated aquaporin gene transfer to treat Sjogren's syndrome

A modified adeno-associated virus (AAV) capsid protein comprising at least one non-native amino acid that confers to the modified AAV particles new properties, such as increased transduction efficiency and reduced immunogenicity. These modified AAV proteins and particles are particularly useful for gene therapy and the treatment of various diseases and conditions.

Adeno-associated vectors for enhanced transduction and reduced immunogenicity

Described herein is the finding that patients with Sj&#xf6;gren's syndrome exhibit a statistically significant increase in expression of BMP6 in the salivary gland, relative to healthy control subjects. Also described herein is the finding that overexpression of BMP6 in the salivary glands of mice results in an increase in electrical potential across the salivary gland. Thus, provided herein are methods of diagnosing a subject as having Sj&#xf6;gren's syndrome, or at risk for developing Sj&#xf6;gren's syndrome, by measuring the level of BMP6 expression in a salivary gland of a subject, measuring electrical potential in a salivary gland of a subject, or both. Also provided herein are methods of treating a subject with Sj&#xf6;gren's syndrome by administering an agent that inhibits expression of BMP6 expression or activity. Also described herein is the use of XIST and MECP2 as diagnostic and therapeutic targets for male Sj&#xf6;gren's syndrome patients.

Methods for the diagnosis and treatment of sj&#xf6;gren's syndrome

Comparative gene analysis (CGA) was combined with pathway visualization software to identify a positive correlation between AAV6 transduction and epidermal growth factor receptor (EGFR) expression. It was found that EGFR is necessary for vector internalization and functions as a co-receptor for AAV6. The identification and characterization of AAV6's requirement of EGFR expression for high transduction activity has allowed construction of recombinant AAV6 vectors which are capable of targeting and killing specific types of head and neck tumors that because of this high EGFR activity, were until now, refractory to current therapies.

Epidermal growth factor receptor (EGFR) and methods of use in adenoviral-associated virus type 6 (AAV6) transduction

The present invention provides an Avian adeno-associated vims (AAAV) vims and vectors and particles derived therefrom. In addition, the present invention provides methods of delivering a nucleic acid to a cell using the AAAV vectors and particles. Methods of isolating the AAAV are provided.

Avian adenoassociated virus and uses thereof

The present invention provides a bovine adeno-associated virus (BAAV) virus and vectors and particles derived therefrom. In addition, the present invention provides methods of delivering a nucleic acid to a cell using the BAAV vectors and particles.

Bovine adeno-associated viral (BAAV) vector and uses thereof

The present invention provides an Avian adeno-associated virus (AAAV) virus and vectors and particles derived therefrom. In addition, the present invention provides methods of delivering a nucleic acid to a cell using the AAAV vectors and particles. Methods of isolating the AAAV are provided.

The present invention provides an adeno-associated virus 4 (AAV4) virus and vectors and particles derived therefrom. In addition, the present invention provides methods of delivering a nucleic acid to a cell using the AAV4 vectors and particles.

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Dayton, MD, United States of America

John A Chiorini