A sort and sequence approach to dissect heterogeneity of response to a self-amplifying RNA vector in a novel human muscle cell line

Self-amplifying RNA (saRNA) is an extremely promising platform because it can produce more protein for less RNA. We used a sort and sequence approach to identify host cell factors associated with transgene expression from saRNA; the hypothesis was that cells with different expression levels would ha...

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Published inMolecular therapy. Nucleic acids Vol. 36; no. 1; p. 102400
Main Authors Barton, Rachel D., Tregoning, John S., Wang, Ziyin, Gonçalves-Carneiro, Daniel, Patel, Radhika, McKay, Paul F., Shattock, Robin J.
Format Journal Article
LanguageEnglish
Published Elsevier Inc 11.03.2025
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Abstract Self-amplifying RNA (saRNA) is an extremely promising platform because it can produce more protein for less RNA. We used a sort and sequence approach to identify host cell factors associated with transgene expression from saRNA; the hypothesis was that cells with different expression levels would have different transcriptomes. We tested this in CDK4/hTERT immortalized human muscle cells transfected with Venezuelan equine encephalitis virus (VEEV)-derived saRNA encoding GFP. Cells with the highest expression levels had very high levels of transgene mRNA (5%–10% total reads); the cells sorted with low and negative levels of GFP protein also had detectable levels of both VEEV and GFP RNA. To understand host responses, we performed RNA sequencing. Differentially expressed gene (DEG) patterns varied with GFP expression; GFP high cells had many more DEGs, which were associated with protein synthesis and cell metabolism. Comparing profiles by an unsupervised approach revealed that negative cells expressed higher levels of cell-intrinsic immunity genes such as IFIT1, MX1, TLR3, and MyD88. To explore the role of interferon, cells were treated with the Jak inhibitor ruxolitinib. This reduced the number of DEGs, but differences between cells sorted by expression level remained. These studies demonstrate the complex interplay of factors, some immune related, affecting saRNA transgenes. [Display omitted] Shattock and colleagues used a sort and sequence approach to identify factors that influence the expression of transgenes from self-amplifying RNA as a way to understand the vaccine platform. We observed a very high level of transgene transcripts (10%) as a proportion of total RNA in positive cells and altered transcriptomes.
AbstractList Self-amplifying RNA (saRNA) is an extremely promising platform because it can produce more protein for less RNA. We used a sort and sequence approach to identify host cell factors associated with transgene expression from saRNA; the hypothesis was that cells with different expression levels would have different transcriptomes. We tested this in CDK4/hTERT immortalized human muscle cells transfected with Venezuelan equine encephalitis virus (VEEV)-derived saRNA encoding GFP. Cells with the highest expression levels had very high levels of transgene mRNA (5%–10% total reads); the cells sorted with low and negative levels of GFP protein also had detectable levels of both VEEV and GFP RNA. To understand host responses, we performed RNA sequencing. Differentially expressed gene (DEG) patterns varied with GFP expression; GFP high cells had many more DEGs, which were associated with protein synthesis and cell metabolism. Comparing profiles by an unsupervised approach revealed that negative cells expressed higher levels of cell-intrinsic immunity genes such as IFIT1, MX1, TLR3, and MyD88. To explore the role of interferon, cells were treated with the Jak inhibitor ruxolitinib. This reduced the number of DEGs, but differences between cells sorted by expression level remained. These studies demonstrate the complex interplay of factors, some immune related, affecting saRNA transgenes.
Self-amplifying RNA (saRNA) is an extremely promising platform because it can produce more protein for less RNA. We used a sort and sequence approach to identify host cell factors associated with transgene expression from saRNA; the hypothesis was that cells with different expression levels would have different transcriptomes. We tested this in CDK4/hTERT immortalized human muscle cells transfected with Venezuelan equine encephalitis virus (VEEV)-derived saRNA encoding GFP. Cells with the highest expression levels had very high levels of transgene mRNA (5%–10% total reads); the cells sorted with low and negative levels of GFP protein also had detectable levels of both VEEV and GFP RNA. To understand host responses, we performed RNA sequencing. Differentially expressed gene (DEG) patterns varied with GFP expression; GFP high cells had many more DEGs, which were associated with protein synthesis and cell metabolism. Comparing profiles by an unsupervised approach revealed that negative cells expressed higher levels of cell-intrinsic immunity genes such as IFIT1, MX1, TLR3, and MyD88. To explore the role of interferon, cells were treated with the Jak inhibitor ruxolitinib. This reduced the number of DEGs, but differences between cells sorted by expression level remained. These studies demonstrate the complex interplay of factors, some immune related, affecting saRNA transgenes. [Display omitted] Shattock and colleagues used a sort and sequence approach to identify factors that influence the expression of transgenes from self-amplifying RNA as a way to understand the vaccine platform. We observed a very high level of transgene transcripts (10%) as a proportion of total RNA in positive cells and altered transcriptomes.
ArticleNumber 102400
Author Tregoning, John S.
McKay, Paul F.
Gonçalves-Carneiro, Daniel
Shattock, Robin J.
Patel, Radhika
Wang, Ziyin
Barton, Rachel D.
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Issue 1
Keywords vaccine
expression
RNA
innate immunity
alphavirus
MT: Delivery Strategies
self-amplifying
Language English
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Snippet Self-amplifying RNA (saRNA) is an extremely promising platform because it can produce more protein for less RNA. We used a sort and sequence approach to...
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SubjectTerms alphavirus
expression
innate immunity
MT: Delivery Strategies
RNA
self-amplifying
vaccine
Title A sort and sequence approach to dissect heterogeneity of response to a self-amplifying RNA vector in a novel human muscle cell line
URI https://dx.doi.org/10.1016/j.omtn.2024.102400
https://doaj.org/article/d1b2b2f835494133af392e85d66ba723
Volume 36
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