Abstract: Provided herein are AAV inverted terminal repeats (ITRs) comprising modifications that are useful for improved expression of a transgene to muscle cells/tissue. ITRs as described herein comprise a myoblast determination protein (MyoD) binding site and/or myocyte enhancer factor (MEF) binding site. to improve transgene expression in muscle cells/tissue. Provided herein are also AAV particles comprising modified ITRs. and method of making and using them.

Abstract: Provided herein are methods of site-specific integration of a heterologous sequence into a host genome (e.g., by administering a recombinant adeno-associated virus (rAAV) to a host cell in the presence of a Rep protein), and methods for treating diseases and disorders by delivering an rAAV that comprises a nucleic acid vector comprising a Rep protein. Also provided herein are methods and compositions for producing rAAV particles with improved titer and transduction efficiencies.

Abstract: Provided herein are AAVrh74 capsid proteins comprising one or more amino acid substitutions or deletions that confer a liver-detargeting property to AAV particles comprising them. Provided herein are AAVrh74 capsid proteins comprising one or more amino acid substitutions that confer an improved transduction efficiency (e.g., in muscle cells). Also provided herein are methods of using AAVrh74 capsid proteins comprising one or more amino acid substitutions or deletions.

Abstract: 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.

Abstract: The present invention provides optimized no-end adeno-associated virus (NE-AAV) DNA genomes comprising recombinant AAV inverted terminal repeats (ITRs), compositions comprising the same, and methods of use thereof to treat certain diseases or disorders. Such genomes and compositions may be useful in the delivery of therapeutic genes to subjects in need thereof, for example in the treatment of certain diseases or disorders known to be associated with the liver, such as hemophilia. The methods of the disclosure may be useful in the site-specific integration of NE-DNA and treatment of hemophilia in humans, including children.

Abstract: Provided herein are modified AAV capsid proteins, particles, nucleic acid vectors, and compositions thereof, as well as methods of their use.

Abstract: 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.

Abstract: Disclosed herein are novel methods for administration of rAAV particles having enhanced transduction properties, comprising the pre-incubation and co-administration of AAV capsids and polyvinyl alcohol (PVA). The disclosed methods of rAAV particle administration have improved efficiency in transducing mammalian liver and hematopoetic cells in vivo. The disclosed methods are suitable for use with a variety of AAV capsid serotypes and presudotypes and improve vector potency, thus lowering the concentration of rAAV particle required to achieve the desired effect. Further disclosed herein are buffers for storage and manufacturing of rAAV particles comprising PVA.

Abstract: 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.

Abstract: 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.

Abstract: Provided herein are modified AAV capsid proteins, particles, nucleic acid vectors, and compositions thereof, as well as methods of their use.

Abstract: 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.

Abstract: Provided herein are recombinant adeno-associated virus (rAAV) particles encoding microRNAs targeting the glucocorticoid receptor (GR) pathway, and in particular a microRNA17-92 (miR 17-92) cluster, and genes of interest. The modified genomes of these rAAV particles comprise heterologous nucleic acid sequences encoding microRNA structures. These particles exhibit enhanced transduction efficiencies in mammalian cells. Also provided herein are compositions of nucleic acids encoding the miR 17-92 cluster and nucleic acids encoding a gene of interest. Further provided herein are methods for administering these nucleic acid compositions to enhance transduction efficiencies.

Abstract: 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.

Abstract: Disclosed herein are compositions and methods for continuous AAV-based delivery of blocking anti-TSHR antibodies to a subject having a thyroid disease. The present disclosure is based, at least in part, on the realization that blocking anti-TSHR antibodies may be delivered in a continuous manner using rAAV, e.g., rAAVS, to effectively block the stimulating effects of TSAbs or TSH on TSHR, thereby blocking or reducing the synthesis of thyroid hormone. By blocking or reducing the synthesis of thyroid hormone, the presently described methods and compositions for rAAV-based delivery of blocking anti-TSHR antibodies (e.g., may be used to treat thyroid diseases, including Graves' disease, Graves' orbitopathy, and thyroid cancer without the requirement of repeated administrations.

Abstract: Provided herein are compositions of recombinant adeno-associated virus (rAAV) particles capable of dampening the humoral immune response against rAAV in the host into which the rAAV particles are introduced. The modified genomes of these rAAV particles comprise heterologous insert nucleic acid and/or inverted terminal repeat (ITR) sequences containing one or more sequences associated with the human leukocyte antigen gene complex DR (HLA-DR) promoter. Also provided herein are methods for transducing host cells with modified rAAV particles to induce a dampened humoral immune responses in order to improve transduction efficiencies. Also provided herein are complexes comprising a modified rAAV particle and a Regulatory Factor X (RFX) transcription factor.

Abstract: 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.

Abstract: 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.

Abstract: 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.

Abstract: Disclosed are next-generation multi-mutated capside protein-modified rAAV expression vector, 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 vector, 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.