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, Yonglong Wei, Hao Zhu, Daniel J Siegwart

Research output: Contribution to journalArticle

Abstract

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 1 (HT-1) resulting in renal dysfunction, liver failure, neurological impairments, and cancer. Protein replacement therapy using FAH mRNA offers tremendous potential to cure HT-1, but is currently hindered by the development of effective mRNA carriers that can function in diseased livers. Structure-guided, rational optimization of 5A2-SC8 mRNA-loaded dendrimer lipid nanoparticles (mDLNPs) increases 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 produces DLNP carriers that are efficacious at mRNA doses as low as 0.05 mg kg−1 in vivo. mDLNPs transfect > 44% of all hepatocytes in the liver, yield high FAH protein levels (0.5 mg kg−1 mRNA), and are well tolerated in a knockout mouse model with compromised liver function. Genetically engineered FAH−/− mice treated with FAH mRNA mDLNPs have statistically equivalent levels of TBIL, ALT, and AST compared to wild type C57BL/6 mice and maintain 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.

Original languageEnglish (US)
Article number1805308
JournalAdvanced Materials
DOIs
StateAccepted/In press - Jan 1 2018

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Dendrimers
Hydrolases
Liver
Lipids
Nanoparticles
Messenger RNA
Proteins
fumarylacetoacetase
Luciferases

Keywords

  • gene therapy
  • lipid nanoparticles (LNPs)
  • mRNA delivery
  • nanoparticle formulations
  • protein replacement therapy

ASJC Scopus subject areas

  • Materials Science(all)
  • Mechanics of Materials
  • Mechanical Engineering

Cite this

Dendrimer-Based Lipid Nanoparticles Deliver Therapeutic FAH mRNA to Normalize Liver Function and Extend Survival in a Mouse Model of Hepatorenal Tyrosinemia Type I. / Cheng, Qiang; Wei, Tuo; Jia, Yuemeng; Farbiak, Lukas; Zhou, Kejin; Zhang, Shuyuan; Wei, Yonglong; Zhu, Hao; Siegwart, Daniel J.

In: Advanced Materials, 01.01.2018.

Research output: Contribution to journalArticle

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abstract = "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 1 (HT-1) resulting in renal dysfunction, liver failure, neurological impairments, and cancer. Protein replacement therapy using FAH mRNA offers tremendous potential to cure HT-1, but is currently hindered by the development of effective mRNA carriers that can function in diseased livers. Structure-guided, rational optimization of 5A2-SC8 mRNA-loaded dendrimer lipid nanoparticles (mDLNPs) increases 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 produces DLNP carriers that are efficacious at mRNA doses as low as 0.05 mg kg−1 in vivo. mDLNPs transfect > 44{\%} of all hepatocytes in the liver, yield high FAH protein levels (0.5 mg kg−1 mRNA), and are well tolerated in a knockout mouse model with compromised liver function. Genetically engineered FAH−/− mice treated with FAH mRNA mDLNPs have statistically equivalent levels of TBIL, ALT, and AST compared to wild type C57BL/6 mice and maintain 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.",
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