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

Pierzynowska, Kateryna LU orcid ; Deshpande, Aditi ; Mosiichuk, Nadiia LU ; Terkeltaub, Robert ; Szczurek, Paulina LU ; Salido, Eduardo ; Pierzynowski, Stefan LU and Grujic, Danica (2020) In Frontiers in Medicine 7.
Abstract

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... (More)

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.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
ABCG2, CKD, gout, urate-lowering therapy, urolithiasis
in
Frontiers in Medicine
volume
7
article number
569215
publisher
Frontiers Media S. A.
external identifiers
  • scopus:85097390705
  • pmid:33330529
ISSN
2296-858X
DOI
10.3389/fmed.2020.569215
language
English
LU publication?
yes
id
cdd7ba66-636e-418d-93e6-de813c415e66
date added to LUP
2020-12-22 10:01:45
date last changed
2024-06-13 02:43:11
@article{cdd7ba66-636e-418d-93e6-de813c415e66,
  abstract     = {{<p>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.</p>}},
  author       = {{Pierzynowska, Kateryna and Deshpande, Aditi and Mosiichuk, Nadiia and Terkeltaub, Robert and Szczurek, Paulina and Salido, Eduardo and Pierzynowski, Stefan and Grujic, Danica}},
  issn         = {{2296-858X}},
  keywords     = {{ABCG2; CKD; gout; urate-lowering therapy; urolithiasis}},
  language     = {{eng}},
  publisher    = {{Frontiers Media S. A.}},
  series       = {{Frontiers in Medicine}},
  title        = {{Oral Treatment With an Engineered Uricase, ALLN-346, Reduces Hyperuricemia, and Uricosuria in Urate Oxidase-Deficient Mice}},
  url          = {{http://dx.doi.org/10.3389/fmed.2020.569215}},
  doi          = {{10.3389/fmed.2020.569215}},
  volume       = {{7}},
  year         = {{2020}},
}