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, Hao Zhu

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

8 Citations (Scopus)

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

Fingerprint

Tyrosinemias
Dendrimers
Liver
Nanoparticles
Lipids
Hydrolases
Messenger RNA
Therapeutics
Proteins
Knockout Mice
Inborn Genetic Diseases
fumarylacetoacetase
Liver Failure
Luciferases
Inbred C57BL Mouse

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Biotechnology
  • Biomaterials
  • Materials Chemistry

Cite this

Cheng, Q., Wei, T., Jia, Y., Farbiak, L., Zhou, K., Zhang, S., ... Zhu, H. (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

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; Zhu, Hao; Zhu, Hao.

Society for Biomaterials Annual Meeting and Exposition 2019: The Pinnacle of Biomaterials Innovation and Excellence - Transactions of the 42nd Annual Meeting. Society for Biomaterials, 2019. (Transactions of the Annual Meeting of the Society for Biomaterials and the Annual International Biomaterials Symposium; Vol. 40).

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

Cheng, Q, Wei, T, Jia, Y, Farbiak, L, Zhou, K, Zhang, S, Zhu, H & Zhu, H 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, 42nd Society for Biomaterials Annual Meeting and Exposition 2019: The Pinnacle of Biomaterials Innovation and Excellence, Seattle, United States, 4/3/19. https://doi.org/10.1002/adma.201805308
Cheng Q, Wei T, Jia Y, Farbiak L, Zhou K, Zhang S et al. 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. Society for Biomaterials. 2019. (Transactions of the Annual Meeting of the Society for Biomaterials and the Annual International Biomaterials Symposium). https://doi.org/10.1002/adma.201805308
Cheng, Qiang ; Wei, Tuo ; Jia, Yuemeng ; Farbiak, Lukas ; Zhou, Kejin ; Zhang, Shuyuan ; Zhu, Hao ; Zhu, Hao. / Dendrimer-based lipid nanoparticles deliver therapeutic fah mrna to normalize liver function and extend survival in a mouse model of hepatorenal tyrosinemia type i. Society for Biomaterials Annual Meeting and Exposition 2019: The Pinnacle of Biomaterials Innovation and Excellence - Transactions of the 42nd Annual Meeting. Society for Biomaterials, 2019. (Transactions of the Annual Meeting of the Society for Biomaterials and the Annual International Biomaterials Symposium).
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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 .",
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