Atavistic strategy for the treatment of hyperuricemia via ionizable liposomal mRNA.
Nat Commun
; 15(1): 6463, 2024 Jul 31.
Article
in En
| MEDLINE
| ID: mdl-39085241
ABSTRACT
Hyperuricemia is associated with an increased risk of gout, hypertension, diabetes, and cardiovascular diseases. Most mammals maintain normal serum uric acid (SUA) via urate oxidase (Uox), an enzyme that metabolizes poorly-soluble UA to highly-soluble allantoin. In contrast, Uox became a pseudogene in humans and apes over the long course of evolution. Here we demonstrate an atavistic strategy for treating hyperuricemia based on endogenous expression of Uox in hepatocytes mediated by mRNA (mUox) loaded with an ionizable lipid nanoparticle termed iLAND. mUox@iLAND allows effective transfection and protein expression in vitro. A single dose of mUox@iLAND lowers SUA levels for several weeks in two female murine models, including a novel long-lasting model, which is also confirmed by metabolomics analysis. Together with the excellent safety profiles observed in vivo, the proposed mRNA agent demonstrates substantial potential for hyperuricemia therapy and the prevention of associated conditions.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Urate Oxidase
/
Uric Acid
/
RNA, Messenger
/
Hyperuricemia
/
Liposomes
Limits:
Animals
/
Female
/
Humans
Language:
En
Journal:
Nat Commun
/
Nature communications
Journal subject:
BIOLOGIA
/
CIENCIA
Year:
2024
Document type:
Article
Country of publication:
Reino Unido