一种使用信使核糖核酸LNP的碱基编辑策略,用于体内校正最常见的苯丙酮尿症变体。

IF 3.3 Q2 GENETICS & HEREDITY
HGG Advances Pub Date : 2024-01-11 Epub Date: 2023-11-02 DOI:10.1016/j.xhgg.2023.100253
Dominique L Brooks, Madelynn N Whittaker, Hooda Said, Garima Dwivedi, Ping Qu, Kiran Musunuru, Rebecca C Ahrens-Nicklas, Mohamad-Gabriel Alameh, Xiao Wang
{"title":"一种使用信使核糖核酸LNP的碱基编辑策略,用于体内校正最常见的苯丙酮尿症变体。","authors":"Dominique L Brooks, Madelynn N Whittaker, Hooda Said, Garima Dwivedi, Ping Qu, Kiran Musunuru, Rebecca C Ahrens-Nicklas, Mohamad-Gabriel Alameh, Xiao Wang","doi":"10.1016/j.xhgg.2023.100253","DOIUrl":null,"url":null,"abstract":"<p><p>The c.1222C>T (p.Arg408Trp) phenylalanine hydroxylase (PAH) variant is the most frequent cause of phenylketonuria (PKU), an autosomal recessive disorder characterized by accumulation of blood phenylalanine (Phe) to neurotoxic levels. Here we devised a therapeutic base editing strategy to correct the variant, using prime-edited hepatocyte cell lines engineered with the c.1222C>T variant to screen a variety of adenine base editors and guide RNAs in vitro, followed by assessment in c.1222C>T humanized mice in vivo. We found that upon delivery of a selected adenine base editor mRNA/guide RNA combination into mice via lipid nanoparticles (LNPs), there was sufficient PAH editing in the liver to fully normalize blood Phe levels within 48 h. This work establishes the viability of a base editing strategy to correct the most common pathogenic variant found in individuals with the most common inborn error of metabolism, albeit with potential limitations compared with other genome editing approaches.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":3.3000,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10800763/pdf/","citationCount":"0","resultStr":"{\"title\":\"A base editing strategy using mRNA-LNPs for in vivo correction of the most frequent phenylketonuria variant.\",\"authors\":\"Dominique L Brooks, Madelynn N Whittaker, Hooda Said, Garima Dwivedi, Ping Qu, Kiran Musunuru, Rebecca C Ahrens-Nicklas, Mohamad-Gabriel Alameh, Xiao Wang\",\"doi\":\"10.1016/j.xhgg.2023.100253\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The c.1222C>T (p.Arg408Trp) phenylalanine hydroxylase (PAH) variant is the most frequent cause of phenylketonuria (PKU), an autosomal recessive disorder characterized by accumulation of blood phenylalanine (Phe) to neurotoxic levels. Here we devised a therapeutic base editing strategy to correct the variant, using prime-edited hepatocyte cell lines engineered with the c.1222C>T variant to screen a variety of adenine base editors and guide RNAs in vitro, followed by assessment in c.1222C>T humanized mice in vivo. We found that upon delivery of a selected adenine base editor mRNA/guide RNA combination into mice via lipid nanoparticles (LNPs), there was sufficient PAH editing in the liver to fully normalize blood Phe levels within 48 h. This work establishes the viability of a base editing strategy to correct the most common pathogenic variant found in individuals with the most common inborn error of metabolism, albeit with potential limitations compared with other genome editing approaches.</p>\",\"PeriodicalId\":34530,\"journal\":{\"name\":\"HGG Advances\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2024-01-11\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10800763/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"HGG Advances\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1016/j.xhgg.2023.100253\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2023/11/2 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"HGG Advances","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.xhgg.2023.100253","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/11/2 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0

摘要

c.1222C>T(p.Arg408Trp)苯丙氨酸羟化酶(PAH)变体是苯丙酮尿症(PKU)的最常见病因,这是一种常染色体隐性遗传疾病,其特征是血液苯丙氨酸(Phe)积累到神经毒性水平。在这里,我们设计了一种治疗性碱基编辑策略来纠正该变体,使用用c.1222C>T变体改造的原代编辑肝细胞系在体外筛选各种腺嘌呤碱基编辑物并引导RNA,然后在体内对c.1222C>T人源化小鼠进行评估。我们发现,在通过脂质纳米颗粒(LNPs)将选定的腺嘌呤碱基编辑器信使核糖核酸/引导核糖核酸组合递送到小鼠体内后,肝脏中有足够的PAH编辑,可以在48小时内使血液Phe水平完全正常化。这项工作确立了基础编辑策略的可行性,以纠正在具有最常见先天性代谢错误的个体中发现的最常见的致病性变体,尽管与其他基因组编辑方法相比存在潜在的局限性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A base editing strategy using mRNA-LNPs for in vivo correction of the most frequent phenylketonuria variant.

The c.1222C>T (p.Arg408Trp) phenylalanine hydroxylase (PAH) variant is the most frequent cause of phenylketonuria (PKU), an autosomal recessive disorder characterized by accumulation of blood phenylalanine (Phe) to neurotoxic levels. Here we devised a therapeutic base editing strategy to correct the variant, using prime-edited hepatocyte cell lines engineered with the c.1222C>T variant to screen a variety of adenine base editors and guide RNAs in vitro, followed by assessment in c.1222C>T humanized mice in vivo. We found that upon delivery of a selected adenine base editor mRNA/guide RNA combination into mice via lipid nanoparticles (LNPs), there was sufficient PAH editing in the liver to fully normalize blood Phe levels within 48 h. This work establishes the viability of a base editing strategy to correct the most common pathogenic variant found in individuals with the most common inborn error of metabolism, albeit with potential limitations compared with other genome editing approaches.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
HGG Advances
HGG Advances Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
4.30
自引率
4.50%
发文量
69
审稿时长
14 weeks
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信