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Combinatorial optimization of mRNA structure, stability, and translation for RNA-based therapeutics.
Leppek, Kathrin; Byeon, Gun Woo; Kladwang, Wipapat; Wayment-Steele, Hannah K; Kerr, Craig H; Xu, Adele F; Kim, Do Soon; Topkar, Ved V; Choe, Christian; Rothschild, Daphna; Tiu, Gerald C; Wellington-Oguri, Roger; Fujii, Kotaro; Sharma, Eesha; Watkins, Andrew M; Nicol, John J; Romano, Jonathan; Tunguz, Bojan; Diaz, Fernando; Cai, Hui; Guo, Pengbo; Wu, Jiewei; Meng, Fanyu; Shi, Shuai; Participants, Eterna; Dormitzer, Philip R; Solórzano, Alicia; Barna, Maria; Das, Rhiju.
Afiliación
  • Leppek K; Department of Genetics, Stanford University, Stanford, CA, 94305, USA.
  • Byeon GW; Department of Genetics, Stanford University, Stanford, CA, 94305, USA.
  • Kladwang W; Department of Biochemistry, Stanford University, Stanford, CA, 94305, USA.
  • Wayment-Steele HK; Department of Chemistry, Stanford University, Stanford, CA, 94305, USA.
  • Kerr CH; Department of Genetics, Stanford University, Stanford, CA, 94305, USA.
  • Xu AF; Department of Genetics, Stanford University, Stanford, CA, 94305, USA.
  • Kim DS; Department of Biochemistry, Stanford University, Stanford, CA, 94305, USA.
  • Topkar VV; Program in Biophysics, Stanford University, Stanford, CA, 94305, USA.
  • Choe C; Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA.
  • Rothschild D; Department of Genetics, Stanford University, Stanford, CA, 94305, USA.
  • Tiu GC; Department of Genetics, Stanford University, Stanford, CA, 94305, USA.
  • Wellington-Oguri R; Eterna Massive Open Laboratory, Stanford University, Stanford, CA, 94305, USA.
  • Fujii K; Department of Genetics, Stanford University, Stanford, CA, 94305, USA.
  • Sharma E; Department of Biochemistry, Stanford University, Stanford, CA, 94305, USA.
  • Watkins AM; Department of Biochemistry, Stanford University, Stanford, CA, 94305, USA.
  • Nicol JJ; Eterna Massive Open Laboratory, Stanford University, Stanford, CA, 94305, USA.
  • Romano J; Eterna Massive Open Laboratory, Stanford University, Stanford, CA, 94305, USA.
  • Tunguz B; Department of Computer Science and Engineering, State University of New York at Buffalo, Buffalo, New York, 14260, USA.
  • Diaz F; Department of Biochemistry, Stanford University, Stanford, CA, 94305, USA.
  • Cai H; NVIDIA Corporation, 2788 San Tomas Expy, Santa Clara, CA, 95051, USA.
  • Guo P; Pfizer Vaccine Research and Development, Pearl River, NY, USA.
  • Wu J; Pfizer Vaccine Research and Development, Pearl River, NY, USA.
  • Meng F; Pfizer Vaccine Research and Development, Pearl River, NY, USA.
  • Shi S; Pfizer Vaccine Research and Development, Pearl River, NY, USA.
  • Participants E; Pfizer Vaccine Research and Development, Pearl River, NY, USA.
  • Dormitzer PR; Pfizer Vaccine Research and Development, Pearl River, NY, USA.
  • Solórzano A; Eterna Massive Open Laboratory, Stanford University, Stanford, CA, 94305, USA.
  • Barna M; Pfizer Vaccine Research and Development, Pearl River, NY, USA.
  • Das R; GlaxoSmithKline, 1000 Winter St., Waltham, MA, 02453, USA.
Nat Commun ; 13(1): 1536, 2022 03 22.
Article en En | MEDLINE | ID: mdl-35318324
ABSTRACT
Therapeutic mRNAs and vaccines are being developed for a broad range of human diseases, including COVID-19. However, their optimization is hindered by mRNA instability and inefficient protein expression. Here, we describe design principles that overcome these barriers. We develop an RNA sequencing-based platform called PERSIST-seq to systematically delineate in-cell mRNA stability, ribosome load, as well as in-solution stability of a library of diverse mRNAs. We find that, surprisingly, in-cell stability is a greater driver of protein output than high ribosome load. We further introduce a method called In-line-seq, applied to thousands of diverse RNAs, that reveals sequence and structure-based rules for mitigating hydrolytic degradation. Our findings show that highly structured "superfolder" mRNAs can be designed to improve both stability and expression with further enhancement through pseudouridine nucleoside modification. Together, our study demonstrates simultaneous improvement of mRNA stability and protein expression and provides a computational-experimental platform for the enhancement of mRNA medicines.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: ARN / COVID-19 Límite: Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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PubMed Links
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: ARN / COVID-19 Límite: Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos