Uricases as therapeutic agents to treat refractory gout: Current states and future directions

Xiaolan Yang, Yonghua Yuan, Chang Guo Zhan, Fei Liao

Research output: Contribution to journalReview articlepeer-review

62 Scopus citations

Abstract

Strategy, Management and Health Policy Enabling Technology, Genomics, Proteomics Preclinical Research Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics Clinical Development Phases I-III Regulatory, Quality, Manufacturing Postmarketing Phase IV Treatment of refractory gout remains a challenge on drug development. While pegloticase, a recombinant mammalian uricase modified with monomethoxyl poly(ethylene glycol) (mPEG) is effective in treating refractory gout, after continued treatment for 3 months biweekly at a therapeutic dose of 0.14 mg/kg body weight, it elicits an immune response against mPEG in nearly 20% of patients. For continued treatment of refractory gout, PEGylated uricases at monthly therapeutic doses below 4 μg/kg body weight have promise. To formulate uricases to achieve monthly therapeutic regimens requires pharmacodynamics simulation and experimentation including molecular engineering of uricases based on rational design and evolution biotechnology in combination to improve their inherent catalytic efficiency, thermostability and selectivity for urate over xanthine and optimization of the number and distribution of accessible reactive amino acid residues in native uricases for site-specific PEGylation with poly(ethylene glycol) derivatives with lower of immunogenicity than mPEG to retain activity, minimize immunogenicity and enhance the pharmacokinetics of the PEGylated uricase. These issues are briefly reviewed as a means to stimulate the development of safer uricase formulations for continued treatment of refractory gout.

Original languageEnglish
Pages (from-to)66-72
Number of pages7
JournalDrug Development Research
Volume73
Issue number2
DOIs
StatePublished - Mar 2012

Keywords

  • hyperuricemia
  • molecular engineering
  • refractory gout
  • uricase

ASJC Scopus subject areas

  • Drug Discovery

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