|
|
|
|
| LEADER |
01000naa a22002652 4500 |
| 001 |
NLM290029457 |
| 003 |
DE-627 |
| 005 |
20231225063837.0 |
| 007 |
cr uuu---uuuuu |
| 008 |
231225s2018 xx |||||o 00| ||eng c |
| 024 |
7 |
|
|a 10.1002/adma.201805308
|2 doi
|
| 028 |
5 |
2 |
|a pubmed24n0966.xml
|
| 035 |
|
|
|a (DE-627)NLM290029457
|
| 035 |
|
|
|a (NLM)30368954
|
| 040 |
|
|
|a DE-627
|b ger
|c DE-627
|e rakwb
|
| 041 |
|
|
|a eng
|
| 100 |
1 |
|
|a Cheng, Qiang
|e verfasserin
|4 aut
|
| 245 |
1 |
0 |
|a Dendrimer-Based Lipid Nanoparticles Deliver Therapeutic FAH mRNA to Normalize Liver Function and Extend Survival in a Mouse Model of Hepatorenal Tyrosinemia Type I
|
| 264 |
|
1 |
|c 2018
|
| 336 |
|
|
|a Text
|b txt
|2 rdacontent
|
| 337 |
|
|
|a ƒaComputermedien
|b c
|2 rdamedia
|
| 338 |
|
|
|a ƒa Online-Ressource
|b cr
|2 rdacarrier
|
| 500 |
|
|
|a Date Completed 04.06.2019
|
| 500 |
|
|
|a Date Revised 30.09.2020
|
| 500 |
|
|
|a published: Print-Electronic
|
| 500 |
|
|
|a Citation Status MEDLINE
|
| 520 |
|
|
|a © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
|
| 520 |
|
|
|a 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
|
| 650 |
|
4 |
|a Journal Article
|
| 650 |
|
4 |
|a gene therapy
|
| 650 |
|
4 |
|a lipid nanoparticles (LNPs)
|
| 650 |
|
4 |
|a mRNA delivery
|
| 650 |
|
4 |
|a nanoparticle formulations
|
| 650 |
|
4 |
|a protein replacement therapy
|
| 650 |
|
7 |
|a Dendrimers
|2 NLM
|
| 650 |
|
7 |
|a RNA, Messenger
|2 NLM
|
| 650 |
|
7 |
|a Hydrolases
|2 NLM
|
| 650 |
|
7 |
|a EC 3.-
|2 NLM
|
| 650 |
|
7 |
|a fumarylacetoacetase
|2 NLM
|
| 650 |
|
7 |
|a EC 3.7.1.2
|2 NLM
|
| 700 |
1 |
|
|a Wei, Tuo
|e verfasserin
|4 aut
|
| 700 |
1 |
|
|a Jia, Yuemeng
|e verfasserin
|4 aut
|
| 700 |
1 |
|
|a Farbiak, Lukas
|e verfasserin
|4 aut
|
| 700 |
1 |
|
|a Zhou, Kejin
|e verfasserin
|4 aut
|
| 700 |
1 |
|
|a Zhang, Shuyuan
|e verfasserin
|4 aut
|
| 700 |
1 |
|
|a Wei, Yonglong
|e verfasserin
|4 aut
|
| 700 |
1 |
|
|a Zhu, Hao
|e verfasserin
|4 aut
|
| 700 |
1 |
|
|a Siegwart, Daniel J
|e verfasserin
|4 aut
|
| 773 |
0 |
8 |
|i Enthalten in
|t Advanced materials (Deerfield Beach, Fla.)
|d 1998
|g 30(2018), 52 vom: 30. Dez., Seite e1805308
|w (DE-627)NLM098206397
|x 1521-4095
|7 nnns
|
| 773 |
1 |
8 |
|g volume:30
|g year:2018
|g number:52
|g day:30
|g month:12
|g pages:e1805308
|
| 856 |
4 |
0 |
|u http://dx.doi.org/10.1002/adma.201805308
|3 Volltext
|
| 912 |
|
|
|a GBV_USEFLAG_A
|
| 912 |
|
|
|a SYSFLAG_A
|
| 912 |
|
|
|a GBV_NLM
|
| 912 |
|
|
|a GBV_ILN_350
|
| 951 |
|
|
|a AR
|
| 952 |
|
|
|d 30
|j 2018
|e 52
|b 30
|c 12
|h e1805308
|