Dendrimer-based lipid nanoparticles deliver therapeutic fah mrna to normalize liver function and extend survival in a mouse model of hepatorenal tyrosinemia type i

Qiang Cheng, Tuo Wei, Yuemeng Jia, Lukas Farbiak, Kejin Zhou, Shuyuan Zhang, Hao Zhu, Daniel J. Siegwart

Research output: Chapter in Book/Report/Conference proceedingConference contribution

17 Scopus citations

Abstract

Statement of Purpose: mRNA-mediated protein replacement represents a promising concept for the treatment of liver disorders. Children born with fumarylacetoacetate hydrolase (FAH) mutations suffer from hepatorenal tyrosinemia type I resulting in renal dysfunction, liver failure, neurological impairments, and cancer. Protein replacement therapy using FAH mRNA offers tremendous potential to treat Hepatorenal Tyrosinemia Type I (HT-1), but is currently hindered by the development of efficacious mRNA carriers that can function in diseased livers. Structure-guided, rational optimization of 5A2-SC8 mRNA-loaded dendrimer lipid nanoparticles (mDLNPs) increased delivery potency of FAH mRNA, resulting in functional FAH protein and sustained normalization of body weight and liver function in FAH -/- knockout mice. Optimization using luciferase mRNA produced DLNP carriers that were efficacious at mRNA doses as low as 0.05 mg/kg in vivo. mDLNPs transfected >44% of all hepatocytes in the liver, yielded high FAH protein levels (0.5 mg/kg mRNA), and were well tolerated in a knockout mouse model with compromised liver function. Genetically engineered FAH -/- mice treated with FAH mRNA mDLNPs had statistically equivalent levels of TBIL, ALT, and AST compared to wild type C57BL/6 mice and maintained normal weight throughout the month-long course of treatment. This study provides a framework for the rational optimization of LNPs to improve delivery of mRNA broadly and introduces a specific and viable DLNP carrier with translational potential to treat genetic diseases of the liver. 1 .

Original languageEnglish (US)
Title of host publicationSociety for Biomaterials Annual Meeting and Exposition 2019
Subtitle of host publicationThe Pinnacle of Biomaterials Innovation and Excellence - Transactions of the 42nd Annual Meeting
PublisherSociety for Biomaterials
Number of pages1
ISBN (Electronic)9781510883901
DOIs
StatePublished - Jan 1 2019
Event42nd Society for Biomaterials Annual Meeting and Exposition 2019: The Pinnacle of Biomaterials Innovation and Excellence - Seattle, United States
Duration: Apr 3 2019Apr 6 2019

Publication series

NameTransactions of the Annual Meeting of the Society for Biomaterials and the Annual International Biomaterials Symposium
Volume40
ISSN (Print)1526-7547

Conference

Conference42nd Society for Biomaterials Annual Meeting and Exposition 2019: The Pinnacle of Biomaterials Innovation and Excellence
CountryUnited States
CitySeattle
Period4/3/194/6/19

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Biotechnology
  • Biomaterials
  • Materials Chemistry

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    Cheng, Q., Wei, T., Jia, Y., Farbiak, L., Zhou, K., Zhang, S., Zhu, H., & Siegwart, D. J. (2019). Dendrimer-based lipid nanoparticles deliver therapeutic fah mrna to normalize liver function and extend survival in a mouse model of hepatorenal tyrosinemia type i. In Society for Biomaterials Annual Meeting and Exposition 2019: The Pinnacle of Biomaterials Innovation and Excellence - Transactions of the 42nd Annual Meeting (Transactions of the Annual Meeting of the Society for Biomaterials and the Annual International Biomaterials Symposium; Vol. 40). Society for Biomaterials. https://doi.org/10.1002/adma.201805308