Oral Treatment With an Engineered Uricase, ALLN-346, Reduces Hyperuricemia, and Uricosuria in Urate Oxidase-Deficient Mice

Frontiers in Medicine

article

Kateryna Pierzynowska¹  Aditi Deshpande⁴  Nadiia Mosiichuk⁵  Robert Terkeltaub⁶  Paulina Szczurek⁷  Eduardo Salido⁸  Stefan Pierzynowski²  Danica Grujic⁴ 

[1] Department of Animal Physiology, Kielanowski Institute of Animal Nutrition and Physiology Polish Academy of Sciences;Department of Biology, Lund University;SGP+Group;United States;Department of Biochemistry and Biotechnology, Vasyl Stefanyk Precarpathian National University;VA Medical Center, University of California, United States;Department of Animal Nutrition and Feed Sciences, National Research Institute of Animal Production;Hospital Universitario de Canarias, Universidad La Laguna & Center for Rare Diseases (CIBERER);Department of Biology, Institute Rural Medicine

关键词: gout;    CKD;    urolithiasis;    urate-lowering therapy;    ABCG2;   

DOI  :  10.3389/fmed.2020.569215

学科分类：社会科学、人文和艺术（综合）

来源: Frontiers

【 摘 要 】

Limitations in efficacy and/or tolerance of currently available urate-lowering therapies (ULTs), such as oral xanthine oxidase inhibitors, uricosurics, and intravenous uricase agents contribute to the development of refractory gout. Renal excretion is the major route of uric acid elimination, but the intestinal tract plays an increasingly recognized role in urate homeostasis, particularly in chronic kidney disease (CKD) in which the renal elimination of urate is impaired. We targeted intestinal degradation of urate in vivo with ALLN-346, an orally administered, engineered urate oxidase, optimized for proteolytic stability, and activity in the gut. We tested ALLN-346 in uricase/urate oxidase deficient mice (URKO mice) with severe hyperuricemia, hyperuricosuria, and uric acid crystalline obstructive nephropathy. A total of 55 male and female URKO mice were used in the two consecutive studies. These seminal, proof-of-concept studies aimed to explore both short- (7-day) and long-term (19-day) effects of ALLN-346 on the reduction of plasma and urine urate. In both the 7- and 19-day studies, ALLN-346 oral therapy resulted in the normalization of urine uric acid excretion and a significant reduction of hyperuricemia by 44 and 28% when therapy was given with food over 24 h or was limited for up to 6 h, respectively. Fractional excretion of uric acid (FEUA) was normalized with ALLN-346 therapy. Oral enzyme therapy with engineered urate oxidase (ALLN-346) designed to degrade urate in the intestinal tract has the potential to reduce hyperuricemia and the renal burden of filtered urate in patients with hyperuricemia and gout with and without CKD.

【 授权许可】

CC BY