University of Florida Research Foundation, Incorporated

Research Corporation Technologies, Inc.

Arun Srivastava

Mavis Agbandje-McKenna

George Vladimirovich Aslanidi

Kim M Van Vliet

Li Zhong

Sergei Zolotukhin

Lakshmanan Govindasamy

Chen Ling

William W Hauswirth

David A Ostrov

Sanford Leon Boye

Shannon Elizabeth Boye

Peter W Stacpoole

Scott A Rivkees

Sanford L Boye

Laura A Small

Jacqueline A Hobbs

Shannon E Boye

Yuan Lu

Disclosed are capsid-modified rAAV expression vectors, as well as infectious virions, compositions, and pharmaceutical formulations containing them. Also provided are methods of preparing and using the disclosed capsid-protein-mutated rAAV constructs in a variety of diagnostic and therapeutic modalities, including, inter alia, as mammalian cell-targeting delivery agents, and as human gene therapy vectors. Also disclosed are large-scale production methods for capsid-modified rAAV expression vectors, viral particles, and infectious virions having improved transduction efficiencies over those of the corresponding, un-modified, rAAV vectors, as well as use of the disclosed compositions in the manufacture of medicaments for a variety of in vitro and/or in vivo applications.

Capsid-modified rAAV vector compositions and methods therefor

The present invention provides AAV capsid proteins comprising modification of one or a combination of the surface-exposed lysine, serine, threonine and/or tyrosine residues in the VP3 region. Also provided are rAAV virions comprising the AAV capsid proteins of the present invention, as well as nucleic acid molecules and rAAV vectors encoding the AAV capsid proteins of the present invention. Advantageously, the rAAV vectors and virions of the present invention have improved efficiency in transduction of a variety of cells, tissues and organs of interest, when compared to wild-type rAAV vectors and virions.

High-transduction-efficiency rAAV vectors, compositions, and methods of use

Provided herein are nucleic acids, recombinant adeno-associated virus (rAAV) particles, and compositions, as well as methods of use thereof for transducing medullary thyroid carcinoma cells and in treatment of disease, such as medullary thyroid carcinoma. In some aspects, the nucleic acid comprises a truncated calcitonin promoter, which is optionally encapsidated within a rAAV particle. In other aspects, the rAAV particle is a rAAV particle having a mutation in a surface-exposed amino acid, such as tyrosine, threonine, or serine, that enhances transduction of the particle into medullary thyroid carcinoma cells.

Recombinant adeno-associated virus vectors to target medullary thyroid carcinoma

AAV vectors with high transduction efficiency and uses thereof for gene therapy

The present invention provides novel mRNA elements capable of forming hairpin, double-stranded RNA structures independent of other non-coding RNAs. These mRNAs are stably expressed, lack polyadenylation tails, and allow minimal protein translation except when in the presence of specific proteins. Also provided, are compositions and kits comprising the mRNA element, as well as methods for its use in the regulation of protein translation. Advantageously, the disclosed elements represent a novel tool useful in regulating the expression of a wide variety of proteins of interest.

Hairpin MRNA elements and methods for the regulation of protein translation

Disclosed are next-generation multi-mutated capsid protein-modified rAAV expression vectors, as well as infectious virions, compositions, and pharmaceutical formulations that include them. Also disclosed are methods of preparing and using these high transduction efficiency vector constructs in a variety of therapeutic applications including, inter alia, as delivery agents for the treatment or amelioration of one or more diseases or abnormal conditions in an affected mammal using in vivo and/or ex situ viral vector-based gene therapy protocols. Also disclosed are large-scale production methods for the multi-mutated, capsid-modified rAAV expression vectors, viral particles, and infectious virions, as well as use of the disclosed compositions in the manufacture of medicaments for use in a variety of in vitro and/or in vivo therapeutic methodologies.

Capsid-modified, RAAV3 vector compositions and uses in gene therapy of human liver cancer

Provided herein are modified recombinant adeno-associated virus (rAAV) capsid proteins, such as modified rAAV1, rAAV5, and rAAV6 capsid proteins, rAAV particles comprising such capsid proteins, nucleic acid molecules encoding such capsid proteins, as well as compositions, kits and methods of use thereof.

Recombinant AAV1, AAV5, and AAV6 capsid mutants and uses thereof

Provided herein are recombinant adeno-associated virus (rAAV) nucleic acid vectors that comprise one or more modifications within at least one inverted terminal repeat (ITR) region. Exemplary modifications include ITR sequences comprising a glucocorticoid responsive element and/or a transcription factor binding site. Also provided are plasmids, libraries, rAAV particles, compositions, kits, and methods related to such vectors.

Genome-modified recombinant adeno-associated virus vectors

Disclosed are tyrosine-modified rAAV vectors, as well as infectious virions, compositions, and pharmaceutical formulations that comprise them. Also disclosed are methods of preparing and methods for using the disclosed tyrosine-phosphorylated capsid protein mutant rAAV vectors in a variety of diagnostic and therapeutic applications including in vivo and ex vivo gene therapy, and large-scale production of rAAV vectors.

Capsid modified rAAV vectors and methods of use

Disclosed are capsid-mutated rAAV vectors and methods for their use in gene therapy, and particularly for use in delivering therapeutic transgenes to treat a variety of mammalian diseases and disorders, including dysfunctions and abnormal conditions of the human eye. VP3 capsid proteins comprising a modification of one or more of the surface-exposed tyrosine residues are disclosed, and in particular, VP3 capsid protein comprising tyrosine-to-phenylalanine mutations at positions corresponding to Y444F, Y500F, and Y730F of the wild-type AAV2 sequence. Also provided are rAAV virions and viral particles that comprise such a mutated AAV capsid protein and a nucleic acid molecule that expresses one or more selected therapeutic or reporter transgenes in one or more mammalian cells of interest. Advantageously, the capsid-mutated rAAV vectors and virions disclosed herein afford improved transduction efficiency in a variety of cells, tissues and organs of interest, when compared to their unmodified (i.e., wild-type) rAAV vector counterparts.

Capsid-mutated rAAV vectors and methods of use

Disclosed are capsid-modified rAAV particles and expression vectors, as well as compositions and pharmaceutical formulations that comprise them. Also disclosed are methods of preparing and using novel capsid-protein-mutated particle or rAAV vector constructs in a variety of diagnostic and therapeutic applications including, inter alia, as delivery agents for diagnosis, treatment, or amelioration of one or more diseases, disorders, or dysfunctions of the mammalian eye. Also disclosed are methods for subretinal delivery of therapeutic gene constructs to mammalian photoreceptors and retinal pigment epithelial cells, as well as use of the disclosed compositions in the manufacture of medicaments for a variety of in vitro and/or in vivo applications including the treatment of a variety of inherited retinal diseases.

Growing community of inventors

Gainesville, FL, United States of America

Arun Srivastava