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

Genzyme Corporation

Targeted Genetics Corporation

Johns Hopkins University

Barrie J Carter

Rikki Solow

Sandra Afione

Terence Flotte

William B Guggino

Terence R Flotte

Jon D Tratschin

Recombinant viral vectors, especially parvovirus vectors such as adeno-associated virus (AAV) vectors; capable of enhanced expression of heterologous sequences, and methods for their construction and use, are provided. The vectors have a structure, or are capable of rapidly adopting a structure, which involves intrastrand base pairing of at least one region in a heterologous sequence.

Metabolically activated recombinant viral vectors and methods for their preparation and use

Recombinant viral vectors, especially parvovirus vectors such as adeno-associated virus (AAV) vectors, capable of enhanced expression of heterologous sequences, and methods for their construction and use, are provided. The vectors have a structure, or are capable of rapidly adopting a structure, which involves intrastrand base pairing of at least one region in a heterologous sequence.

Metabolically activated recombinant viral vectors and methods for the preparation and use

Described herein are constructions of recombinant DNA comprising modified adeno-associated virus (AAV) DNA sequences capable of functioning as a eukaryotic expression vector for expressing foreign DNA sequences using a novel transcription promoter comprising the termini of AAV DNA. It is shown that expression of a test reporter gene can be obtained from this vector in mammalian cells. It is further shown that this combination of vector and promoter can be used to introduce and express a human gene and correct a genetic defect in human cells resulting from malfunction of the mutant endogenous gene. Further, the vector can be used to correct the genetic defect by expressing a modified version of the human gene consisting of a fusion of part of the said gene and a synthetic sequence contained in the vector.

Modified adeno-associated virus vector capable of expression from a

Amino-terminally truncated cystic fibrosis transmembrane conductance

Adeno-associated virus (AAV) vectors may have utility for gene therapy but heretofore a significant obstacle has been the inability to generate sufficient quantifies of such recombinant vectors in amounts that would be clinically useful for human gene therapy application. Stable, helper-free AAV packaging cell lines have been elusive, mainly due to the activities of Rep protein, which down-regulates its own expression and reverses cellular immortalization. This invention provides packaging systems and processes for packaging AAV vectors that efficiently circumvent these problems by replacing the AAV p5 promoter with a heterologous promoter and that allow for substantially increased packaging efficiency.

Generation of high titers of recombinant AAV vectors

The present invention relates to a vector comprising part of AAV DNA contained in a plasmid and capable of being packaged into AAV particles and functioning as a vector for stable integration and expression of a gene in eukaryotic cells when under control of an AAV transcription promoter. A method of preparing such plasmids which are packagable and rescuable is also described.

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Seattle, WA, United States of America

Barrie J Carter