Johns Hopkins University

University of Florida Research Foundation Inc

Targeted Genetics Corporation

William B Guggino

Terence R Flotte

Barrie J Carter

Erik Schwiebert

Rikki Solow

Anna Kottgen

Jeffrey R Sirninger

Liudmila Cebotaru

Michael Kottgen

Owen Woodward

Christian Müller

Josef Coresh

Lihua Liang

Genome-wide association studies (GWAS) was recently used to identify SNPs in a genomic region on chromosome 4 that associate with serum urate levels and gout. The present disclosure shows that human ATP-binding cassette, subfamily G, 2 (ABCG2), encoded by the ABCG2 gene contained in this region, is a hitherto unknown urate efflux transporter. The present disclosure further shows that native ABCG2 is located in the brush border membrane of kidney proximal tubule cells, where it mediates renal urate secretion. Introduction of the mutation Q141K encoded by the common SNP rs2231142 by site-directed mutagenesis resulted in reduced urate transport rates compared to wild-type ABCG2. Data from a population-based study of 14,783 individuals support rs2231142 as the causal variant in the region and show highly significant associations with urate levels and gout.

Modulation of ABCG2-mediated urate transport to treat hyperuricemia and gout

Described herein are spiperone derivative compounds which have been found to be useful in methods of stimulating CaCC and treating disorders (or symptoms thereof) associated with CaCC including cystic fibrosis, wherein a compound of the invention is administered to a subject.

Spiperone derivatives and methods of treating disorders

The invention relates to compositions and methods of treating cystic fibrosis. More specifically, this invention relates to the use the AAV vectors and constructs to provide gene therapy to cystic fibrosis patients.

Compositions for treating cystic fibrosis

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

Growing community of inventors

Baltimore, MD, United States of America

William B Guggino