Screening Splice-Switching Antisense Oligonucleotides in Pancreas-Cancer Organoids
Open accessAbstract
Aberrant alternative splicing is emerging as a cancer hallmark and a potential therapeutic target. It is the result of dysregulated or mutated splicing factors, or genetic alterations in splicing-regulatory cis -elements. Targeting individual altered splicing events associated with cancer-cell dependencies is a potential therapeutic strategy, but several technical limitations need to be addressed. Patient-derived organoids are a promising platform to recapitulate key aspects of disease states, and to facilitate drug development for precision medicine. Here, we report an efficient antisense-oligonucleotide (ASO) lipofection method to systematically evaluate and screen individual splicing events as therapeutic targets in pancreatic ductal adenocarcinoma organoids. This optimized delivery method allows fast and efficient screening of ASOs, e.g., those that reverse oncogenic alternative splicing. In combination with advances in chemical modifications of oligonucleotides and ASO-delivery strategies, this method has the potential to accelerate the discovery of antitumor ASO drugs that target pathological alternative splicing.
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Written from the paper’s full text.
TL;DR
The paper reports an optimized lipofection protocol for delivering splice-switching antisense oligonucleotides (ASOs) into patient-derived pancreatic ductal adenocarcinoma (PDAC) organoids, enabling reproducible screening of splicing targets. It shows that free uptake is inefficient in organoids, whereas lipofection preserves organoid features and supports functional ASO effects, including PKM splice switching and growth suppression.
Key findings
- Free ASO uptake in PDAC organoids was inefficient: ASO-S increased SMN2 exon 7 inclusion by only ~25% at 5 µM in hF23 organoids, versus >80% in HEK293T cells; ASO-P had minimal effect on PKM splicing.
- Matrigel-diluted free-uptake culture did not significantly improve ASO-S activity and ASO-P failed to elicit significant PKM splice switching.
- Optimized lipofection of dissociated organoids markedly improved ASO activity: ASO-S produced SMN2 splicing changes in hF23 comparable to HEK293T cells, and ASO-P induced dose-dependent PKM splice switching in both hF23 and hT60 organoids.
- With 125 nM ASO-P, hF23 and hT60 organoids showed 4–8-fold elevated PKM1 protein, increased pyruvate kinase activity, and decreased cell growth; ASO-S did not decrease growth. At 100 nM, TMO-modified PKM ASOs enhanced exon 9 inclusion compared with MOE in both organoid lines.
Methods
- Human PDAC organoids hF23 (classical subtype) and hT60 (basal subtype) were cultured, along with HEK293T cells for 2D comparisons. ASOs targeted SMN2 (ASO-S) or PKM (ASO-P), with MOE, LNA, or TMO chemistries.
- ASO delivery was tested by free uptake in Matrigel, free uptake in Matrigel-diluted culture, and optimized lipofection: organoids were dissociated to single cells, incubated with Lipofectamine 3000–ASO mix for 8 h, centrifuged, resuspended in Matrigel, and cultured for 72 h before assays.
- Readouts included radioactive RT-PCR with DdeI or PstI digestion and percent spliced-in quantification, RT-qPCR, western blotting, pyruvate kinase activity, CellTiter-Glo 3D viability, and confocal imaging. Most splicing and viability experiments used n = 3; western blots used n = 2.
Limitations
- The paper states that free ASO uptake in organoids is limited by Matrigel properties: high ASO concentrations caused Matrigel domes to collapse or dissolve, and organoid cultures could not withstand high ASO concentrations without losing 3D architecture.
- The paper notes that SMN2 expression was detected in hF23 but not hT60 organoids, reflecting absence of this nonessential paralog in some individuals, and that Matrigel-diluted free-uptake results had large variance and were not statistically significant.
- Evident from the text: the study uses only two PDAC organoid lines and does not report in vivo validation; the optimized lipofection protocol requires organoid dissociation and an 8 h incubation, and the paper does not include a formal limitations section.
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Claims the paper makes
0 of 34 cited sources checked · 0 supported · 0 flagged
- Findingown data
The authors report an efficient antisense-oligonucleotide (ASO) lipofection method to systematically evaluate and screen individual splicing events as therapeutic targets in pancreatic ductal adenocarcinoma organoids.
“Here, we report an efficient antisense-oligonucleotide (ASO) lipofection method to systematically evaluate and screen individual splicing events as therapeutic targets in pancreatic ductal adenocarcinoma organoids.”
- Also stated in: § Abstract · plain
“Here, we report a versatile lipofection-based method that can be applied for systematic evaluation and screening of ASO candidates and their splicing targets in human PDAC organoid model systems.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Findingown data
ASO-P failed to elicit significant splice-switching of PKM in Matrigel-diluted PDAC organoid cultures.
“In addition, ASO-P failed to elicit significant splice-switching of PKM (Fig. 3D, E, Supplementary Fig. S2C, D), further highlighting the need for an improved and standardized method for efficiently delivering ASOs into PDAC organoids, while preserving their functional and clinically relevant features.”
Quote in the paperSubstantial claim - Findingown data
The efficiency of ASO-S in the Matrigel-diluted culture was slightly less than by free uptake in undiluted organoid cultures.
“The efficiency of ASO-S in the Matrigeldiluted culture was slightly less than by free uptake in undiluted organoid cultures (Fig. 3B, C).”
Quote in the paperSubstantial claim - Findingown data
Lipofection gave comparable splice-switching of SMN2 and PKM pre-mRNAs by ASO-S and ASO-P, respectively, at equivalent low-dose levels in 2D cells.
“We found that lipofection gave comparable splice-switching of SMN2 and PKM pre-mRNAs by ASO-S and ASO-P, respectively, at equivalent low-dose levels in 2D cells.”
Quote in the paperNot a substantial claim - Findingown data
PKM1/2 splicing was minimally affected by ASO-P free uptake in hF23 and hT60 organoids.
“In addition, PKM1/2 splicing was minimally affected by ASO-P free uptake in hF23 and hT60 organoids (Fig. 2E, F, and Supplementary Fig. S2A, B).”
Quote in the paperSubstantial claim- Rests on an assumption: The ASO concentrations used in the splicing experiments (up to 5 µM) do not cause general toxicity that could affect splicing.
- Findingreasoning
This optimized delivery method allows fast and efficient screening of ASOs, e.g., those that reverse oncogenic alternative splicing.
“This optimized delivery method allows fast and efficient screening of ASOs, e.g., those that reverse oncogenic alternative splicing.”
- Also stated in: § Abstract · plain
“This delivery protocol allows fast and efficient screening of ASO candidates against oncogenic alternative-splicing targets.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Findingown data
The optimized lipofection protocol in hF23 organoids markedly improved the SMN2 splicing change induced by ASO-S, comparable to lipofection in HEK293T cells.
“The optimized lipofection protocol in hF23 organoids markedly improved the SMN2 splicing change induced by ASO-S, which was comparable to that of lipofection in HEK293T cells (Fig. 4D, 4E, Supplementary Fig. S3A, B).”
Quote in the paperSubstantial claim - Findingown data
ASOs uniformly modified with TMO resulted in enhanced inclusion of exon 9 (PKM1 isoform) in both hF23 and hT60 organoids compared to MOE.
“Using our lipofection-based protocol, we observed that ASOs uniformly modified with TMO resulted in enhanced inclusion of exon 9 (PKM1 isoform) in both hF23 (Fig. 6A, B) and hT60 (Fig. 6C, D) organoids compared to MOE (cf.lanes 6 and 2).”
Quote in the paperSubstantial claim - Findingown data
Both ASOs promoted >50% inclusion at 500 nM for their respective targeted splicing events in HEK293T cells.
“In addition, both ASOs promoted >50% inclusion at 500 nM for their respective targeted splicing events in HEK293T cells (Supplementary Fig. S3A-D).”
Quote in the paperNot a substantial claim - Findingreasoning
ASO-P transfection of PDAC organoids resulted in a robust increase in PK activity.
“we observed a robust increase in PK activity (Fig. 5C, D).”
Quote in the paperSubstantial claim - Findingown data
Lipofection of ASO-P induced significant dose-dependent splice-switching in PKM in both hF23 and hT60 organoid lines.
“Furthermore, lipofection of ASO-P likewise induced significant splice-switching in PKM in a dose-dependent manner (Fig. 4F, G, and Supplementary Fig. S5A, B) in both hF23 and hT60 organoid lines.”
Quote in the paperSubstantial claim - Findingown data
The i9 PKM ASO with TMO modifications produced the expected splice-switching effects in hF23 and hT60 organoids.
“We also tested another PKM ASO (i9) targeting a separate element in intron 9, 34 with TMO modifications, and observed the expected splice-switching effects (Fig. 6A-D) (lane 7).”
Quote in the paperSubstantial claim - Findingown data
hF23 and hT60 organoid lines transfected with 125 nM ASO-P exhibited 4-8-fold elevated protein levels of PKM1.
“hF23 and hT60 lines transfected with 125 nM ASO-P exhibited 4-8-fold elevated protein levels of PKM1 (Fig. 5A, B).”
Quote in the paperSubstantial claim - Findingcitation
Extensive splice-switching between PKM1/2 isoforms was accompanied by the appearance of the PKMds (double-skipped) isoform lacking both exons 9 and 10 in the spliced mRNA.
“In line with our previous reports, 23,24 the extensive splice-switching between PKM1/2 isoforms was accompanied by the appearance of the PKMds (doubleskipped) isoform lacking both exons 9 and 10 in the spliced mRNA (Supplementary Fig. S3C).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [23]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [24]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
Targeting individual alternative splicing events is currently hampered by insufficient knowledge about pivotal alternative-splicing events in cancer.
“ii) targeting individual alternative splicing events is currently hampered by insufficient knowledge about pivotal alternative-splicing events in cancer.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [2]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [8]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [9]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
Altered expression of several RNA-binding proteins involved in splicing is a distinguishing feature for the most aggressive subtype of pancreatic cancer, in conjunction with mutations in KRAS and TP53.
“Altered expression of several RNA-binding proteins involved in splicing is a distinguishing feature for the most aggressive subtype of pancreatic cancer, in conjunction with mutations in KRAS and TP53.6,7”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [6]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [7]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
Organoid cultures are limited in their ability to withstand high ASO concentrations without losing important 3D features, which, in practice, results in inefficient ASO uptake and/or effectiveness.
“We conclude that organoid cultures are limited in their ability to withstand high ASO concentrations without losing important 3D features, which, in practice, results in inefficient ASO uptake and/or effectiveness.”
Quote in the paperSubstantial claim - Premisecitation
Organoid models have been used in drug development as a platform for accurately assessing the efficacy and specificity of precision-medicine-based experimental drugs.
“Additionally, these organoid models have been used in drug development as a platform for accurately assessing the efficacy and specificity of precision-medicine-based experimental drugs.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [11]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [12]
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- cites [13]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
PDAC organoids preserve clinically relevant features.
“Given that PDAC organoids preserve clinically relevant features 10”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
The lipofection-based method enables the identification and lead optimization of ASO candidates using PDAC organoid model systems.
“These results exemplify how our method enables the identification and lead optimization of ASO candidates using PDAC organoid model systems.”
Quote in the paperSubstantial claim - Interpretationreasoning
The optimized platform makes it possible to interrogate physiologically and pathologically relevant alternative splicing events in PDAC.
“With its optimized efficiency, this platform makes it possible to interrogate physiologically and pathologically relevant alternative splicing events in PDAC.”
Quote in the paperSubstantial claim - Interpretationown data
We established a method for efficiently and cost-effectively delivering splice-switching ASOs to human PDAC organoids.
“Here, we established a method for efficiently and cost-effectively delivering splice-switching ASOs to human PDAC organoids”
Quote in the paperSubstantial claim - Premisecitation
Modulating PKM alternative splicing and the corresponding increase in PK activity result in tumor suppressor activity by reprogramming cancer-cell metabolism through re-activation of the Krebs cycle and oxidative phosphorylation.
“Modulating PKM alternative splicing and the corresponding increase in PK activity result in tumor suppressor activity, by reprograming cancer-cell metabolism through re-activation of the Krebs cycle and oxidative phosphorylation.42”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [42]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
Single-cell dissociation does not affect these organoid features.
“indicating that singlecell dissociation does not affect these organoid features.”
Quote in the paperSubstantial claim
- May combine two claims. 16
- Classified as probably not a substantial claim. 15
May combine two claims.
Findingown dataA slight increase in SMN2 exon 7 inclusion was observed after treatment with ASO-S in the hF23 organoid line, but the increase was not statistically significant, which the authors attribute to large variance between samples.
“We observed a slight increase in SMN2 exon 7 inclusion after treatment with ASO-S in the hF23 organoid line.However, the increase was not statistically significant, which we attribute to the large variance between samples.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingnone givenIn general, lipofection markedly improves ASO uptake and effectiveness in 2D-cultured cells.
“In general, lipofection markedly improves ASO uptake and effectiveness in 2D-cultured cells.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S4 (based).
Findingnone givenFree uptake of ASOs is frequently hindered by very slow uptake and endosome-escape kinetics, the high ASO concentrations required, and cell-type variability, making it impractical for initial ASO-screening purposes.
“Free uptake of ASOs is frequently hindered by very slow uptake and endosome-escape kinetics, the high ASO concentrations required, and cell-type variability, making it impractical for initial ASO-screening purposes.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataASO-P elicited modest splice-switching of PKM only at the highest concentration tested, whereas ASO-S showed marked splice-switching starting at 0.3125 μM.
“ASO-P elicited modest splice-switching of PKM only at the highest concentration tested (Fig. 1E, F, and Supplementary Fig. S1A, B), whereas the above ASO-S showed marked splice-switching starting at 0.3125 lM.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataASO-S promoted SMN2 exon 7 inclusion in a dose-dependent manner, with 5 μM ASO-S resulting in around 90% full-length SMN2 isoform expression, compared to a baseline level of ~7%.
“Consistent with our previous studies, ASO-S promoted SMN2 exon 7 inclusion in a dose-dependent manner, with 5 lM ASO-S resulting in around 90% fulllength SMN2 isoform expression, compared to a baseline level of *7% (Fig. 1D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataFree uptake of ASO-S in organoids resulted in only slight splicing changes in SMN2; exon 7 inclusion increased by ~25% at 5 μM ASO in hF23 organoids, whereas it increased by >80% in HEK293T cells.
“We found that the free uptake of ASO-S in organoids resulted in only slight splicing changes in SMN2.Exon 7 inclusion increased by *25% at 5 lM ASO in hF23 organoids, whereas it increased by >80% in HEK293T cells (Fig. 1C, D, and Fig. 2C, D).”
Quote in the paperSubstantial claim- Rests on an assumption: HEK293T cells are a valid baseline for comparing ASO delivery efficiency to PDAC organoids.
- Rests on an assumption: The ASO concentrations used in the splicing experiments (up to 5 µM) do not cause general toxicity that could affect splicing.
May combine two claims.
FindingcitationExpression of the SMN2 gene was detected in hF23 but not in hT60 organoids, reflecting the absence of this nonessential paralog in some individuals.
“Expression of the SMN2 gene was detected in hF23 but not in hT60 organoids, reflecting the absence of this nonessential paralog in some individuals.37”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
FindingreasoningOur method optimizes the uptake efficiency of ASOs to facilitate effective preclinical evaluation of their therapeutic potency, while preserving the physiologically relevant organoid characteristics.
“Our method optimizes the uptake efficiency of ASOs to facilitate effective preclinical evaluation of their therapeutic potency, while preserving the physiologically relevant organoid characteristics.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDuring incubation, the Matrigel domes collapsed at high ASO concentrations, and even in the absence of organoids, concentrated ASO resulted in loose or dissolved Matrigel.
“During the incubation, we noticed the collapse of the Matrigel domes at high ASO concentrations.Even in the absence of organoids, incubation with concentrated ASO resulted in loose or dissolved Matrigel, as shown by crystalviolet staining (Fig. 2B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataASO-P, but not ASO-S, decreased cell growth of both hF23 and hT60 patient-derived PDAC organoid lines.
“ASO-P, but not ASO-S, resulted in decreased cell growth of both the hF23 and hT60 organoid lines (Fig. 5E, F).”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationAberrant alternative splicing is associated with various diseases, notably cancer, and is attributable to dysregulated or mutated splicing factors, or to mutations in splicing-regulatory cis-elements.
“Aberrant alternative splicing is associated with various diseases, notably cancer, and is attributable to dysregulated or mutated splicing factors, or to mutations in splicingregulatory cis-elements.3,4”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [3]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [4]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S4 (based).
Interpretationnone givenThe baseline efficiency of these ASOs in 2D cell culture is not affected by variables associated with the use of Matrigel and the 3D architecture of organoids.
“These results establish the baseline efficiency of these ASOs in 2D cell culture, which is not affected by variables associated with the use of Matrigel and the 3D architecture of organoids.”
Quote in the paperNot a substantial claim- Rests on an assumption: HEK293T cells are a valid baseline for comparing ASO delivery efficiency to PDAC organoids.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHigh-throughput RNA-sequencing studies showed that the pre-mRNAs from 90%-95% of human genes undergo alternative splicing.
“High-throughput RNAsequencing studies showed that the pre-mRNAs from 90%-95% of human genes undergo alternative splicing, prominently contributing to transcriptomic and proteomic diversity.1,2”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [1]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [2]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
PremisecitationTargeting individual splicing factors involved in spliceosome assembly will affect the transcriptome globally, with likely toxicity in normal tissues.
“i) targeting individual splicing factors involved in spliceosome assembly will affect the transcriptome globally, with likely toxicity in normal tissues;”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [2]
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- cites [8]
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- cites [9]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
PremisecitationPatient-derived organoids better recapitulate the architecture and physiology of human healthy or diseased organs, thus helping to overcome some of the limitations of animal models in addressing specific aspects of human biology and disease.
“Patientderived organoids, a stem-cell-derived 3D culture system, better recapitulate the architecture and physiology of human healthy or diseased organs, thus helping to overcome some of the limitations of animal models in addressing specific aspects of human biology and disease.10”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
PremisecitationCancer cells often exhibit aberrant alternative-splicing profiles, leading to the production of isoforms that increase cell proliferation, cell migration, or resistance to apoptosis, or to the loss of isoforms that block these processes.
“Cancer cells often exhibit aberrant alternative-splicing profiles, leading to the production of isoforms that increase cell proliferation, cell migration, or resistance to apoptosis, or to the loss of isoforms that block these processes.2,5”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [2]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [5]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningIn combination with advances in chemical modifications of oligonucleotides and ASO-delivery strategies, this method has the potential to accelerate the discovery of antitumor ASO drugs that target pathological alternative splicing.
“In combination with advances in chemical modifications of oligonucleotides and ASO-delivery strategies, this method has the potential to accelerate the discovery of antitumor ASO drugs that target pathological alternative splicing.”
- Also stated in: § Abstract · hedged
“In combination with advances in oligonucleotide chemical modifications, conjugation, and other in vivo ASO-delivery strategies, we anticipate that our method will help accelerate the discovery of antitumor ASO drugs more broadly, beyond targeting pathological alternative splicing.”
Quote in the paperNot a substantial claim- Also stated in: § Abstract · hedged
Probably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningThe platform should facilitate the identification of critical therapeutic targets for clinical development.
“This in turn should facilitate the identification of critical therapeutic targets for clinical development.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).
InterpretationreasoningOur method for PDAC organoids can be adapted to other organoids to explore ASO therapeutic potential in other disease contexts.
“we expect that our method for PDAC organoids can be adapted to other organoids to explore ASO therapeutic potential in other disease contexts.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningThe pipeline can readily be extended to evaluate other oligonucleotide modalities.
“This pipeline can readily be extended to evaluate other oligonucleotide modalities.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationASOs have been developed to manipulate gene expression through multiple mechanisms in addition to alternative splicing, including RNase-H mediated knockdown, inhibition of nonsense-mediated mRNA decay, polyadenylation modification, and translation regulation.
“ASOs have been developed to manipulate gene expression through multiple mechanisms, in addition to alternative splicing, such as activating RNase-H mediated knockdown, inhibiting nonsense-mediated mRNA decay, influencing polyadenylation to modify mRNA stability, and regulating the translation of target mRNAs.15,44,45”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [15]
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- cites [44]
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- cites [45]
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationOrganoids are broadly used for studying cancer, infectious diseases, and genetic disorders.
“given the broad use of organoids for studying cancer, infectious diseases, and genetic disorders, 10,48,49”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [10]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [48]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [49]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S2 (checkable), S4 (based).
InterpretationreasoningThe method should be broadly applicable to other alternative splicing targets.
“This method should be broadly applicable to other alternative splicing targets”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationcitationOur protocol has the potential to be integrated into the development of decoy oligonucleotides for modulating RNA-binding protein activity and CpG motif-containing oligodeoxynucleotides for vaccine adjuvants to immunotherapies through TLR9 activation.
“Furthermore, our protocol has the potential to be integrated into the development of decoy oligonucleotides designed for modulating RNA-binding protein activity, as well as CpG motif-containing oligodeoxynucleotides for applications ranging from vaccine adjuvants to immunotherapies through TLR9 activation.46,47”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [46]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [47]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Interpretationown dataThe described lipofection method is highly efficient and reproducibly elicits ASO-mediated splice-switching in target pre-mRNAs.
“In summary, we described a highly efficient lipofection method to reproducibly elicit ASO-mediated splice-switching in target pre-mRNAs.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductown dataSingle-cell dissociation did not significantly change the expression of ductal lineage markers or the morphology of hF23 and hT60 organoids.
“we found no significant changes in the expression of ductal lineage markers and the organoid morphology of both hF23 (cystic organoids) and hT60 (filled organoids) with and without dissociation (Supplementary Fig. S4A, B, C, D)”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThese results highlight the specificity and therapeutic potential of splice-switching ASOs targeting PKM.
“These results highlight the specificity and therapeutic potential of splice-switching ASOs targeting PKM.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationPKM1 is more catalytically active than PKM2.
“In accordance with the fact that PKM1 is more catalytically active than PKM2, 29,41”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [29]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [41]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Classified as probably not a substantial claim.
PremisecitationHigh-throughput drug screening is an important application of PDAC organoids, owing to their ability to better recapitulate the drug sensitivity of individual patients.
“High-throughput drug screening is an important application of PDAC organoids, owing to their ability to better recapitulate the drug sensitivity of individual patients.43”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [43]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
The paper relies on this without support.
HEK293T cells are a valid baseline for comparing ASO delivery efficiency to PDAC organoids.
“Exon 7 inclusion increased by *25% at 5 lM ASO in hF23 organoids, whereas it increased by >80% in HEK293T cells (Fig. 1C, D, and Fig. 2C, D).”
“These results establish the baseline efficiency of these ASOs in 2D cell culture, which is not affected by variables associated with the use of Matrigel and the 3D architecture of organoids.”
The paper relies on this without support.
The ASO concentrations used in the splicing experiments (up to 5 µM) do not cause general toxicity that could affect splicing.
“We incubated the cells with varying ASO concentrations, ranging from 0 to 5 mM, for 3 days.”
“Exon 7 inclusion increased by *25% at 5 lM ASO in hF23 organoids, whereas it increased by >80% in HEK293T cells (Fig. 1C, D, and Fig. 2C, D).”
The paper relies on this without support.
ASO delivery by lipofection is highly efficient.
“Given the high efficiency of ASO delivery by lipofection, we sought to apply it in the PDAC organoid cultures.”
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The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth
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Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Splicing dysregulation: hallmark and therapeutic opportunity in pancreatic cancer
Naro, C., Ruta, V., & Sette, C. (2024) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2024.11.007 · Cited by 12 · see citing works
Tipping the balance of cell death: alternative splicing as a source of MCL-1S in cancer
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Fial, I., Farrier, S. A., Chimento, D. P., Ascoli, C. A., Wan, X., & Oliver, P. L. (2025) · Nucleic Acid Therapeutics · doi:10.1177/21593337251361396 · Cited by 6 · see citing works
“23,24 Therefore, we wanted to assess the functionality of the anti-PS reagents in 3D cellular systems associated with ASO uptake and penetration.”
Yang, S., He, B., He, C., et al. (2025) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.5c00412 · Cited by 5 · see citing works
Splice modulation of COL4A5 reinstates collagen IV assembly in an organoid model of Alport syndrome
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“ASO treatment improved α5(IV) chain deposition in vitro but after transplanting organoids at different induction stages, efficient restoration of collagen expression was not achieved, despite evidence of vascularization (48).”
Organoids in translation: a bench-to-bedside framework for pancreatic cancer precision medicine
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“PDO platforms have been successfully expanded to ascites and pleural fluid [13], fine-needle biopsies [14– 16], and even metastatic lesions [17, 18].”
Epigenetic Regulation and Therapeutic Targeting of Alternative Splicing Dysregulation in Cancer
Yan, L., & Lai, M. (2025) · Pharmaceuticals · doi:10.3390/ph18050713 · Cited by 5 · see citing works
Kral, A. J., Jia, L., Sim, G., Wan, L., Ishigami, Y., & Krainer, A. R. (2025) · Molecular Cell · doi:10.1016/j.molcel.2025.12.004 · Cited by 3 · see citing works
Self-citationBuijsen, R. A. M., van der Graaf, L. M., Kuijper, E. C., Pepers, B. A., Daoutsali, E., Weel, L., Raz, V., Parfitt, D. A., & van Roon‐Mom, W. (2024) · Biomedicines · doi:10.3390/biomedicines12091933 · Cited by 3 · see citing works
Organoids in the research of pancreatic neoplasms: cultivation, applications, and limitations
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Alternative Splicing in Lung Adenocarcinoma: From Bench to Bedside
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“Moreover, PKM-ASOs inhibit PDAC patient-derived organoid proliferation 25 , supporting the potential of PKM-ASO for PDAC therapy.”
Self-citationAnwar, S., & Yokota, T. (2026) · Genes · doi:10.3390/genes17070780 · Cited by 1 · see citing works
“Human-derived systems can then be used upstream in the translational pathway to test whether that therapeutic hypothesis remains biologically plausible in a disease-relevant context, before broader nonclinical evaluation is pursued [31,45,50].”
Kral, A. J., Jia, L., Sim, G., Wan, L., & Krainer, A. R. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.04.14.648775
Self-citationPotiri, M., Moschou, C., Erpapazoglou, Z., Rouni, G., Kotsoni, A., Andreadou, M., Klavdianos, A., Dragolia, M., Ntafis, V., Schrader, J., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116022 · Cited by 1 · see citing works
Heneberg, P. (2026) · Clinical Kidney Journal · doi:10.1093/ckj/sfag185
“Preclinical work already demonstrated successful ASO screening in pancreatic cancer organoids [ 61 ].”
Transcriptomic regulation of pancreatic acinar cell homeostasis and plasticity
Zhang, X., Luo, C., Coughlin, K., Li, F.-Q., Takemaru, K., & Wan, L.-D. (2026) · Biochemical Society Transactions · doi:10.1042/bst20253124
“…that therapeutic strategies modulating RNA splicing may offer a promising approach to restore correct transcript processing and gene function [142–144]. miRNAnetworks constitute an additional layer of post-transcriptional regulation that cooperates with transcriptional and epigenetic…”
Self-citation
- Authors
- Wan, L., Kral, A. J., Voss, D., Schäfer, B., Sudheendran, K., Danielsen, M., Caruthers, M. H., & Krainer, A. R.
- Affiliations
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
- University of Colorado Boulder (US)
- Venue
- Nucleic Acid Therapeutics
- Publisher
- SAGE Publications
- Published
- 2024-08-01
- Volume
- 34
- Issue
- 4
- Pages
- 188-198
- ISSN
- 2159-3337 (ISSN-L)
- 2159-3345
- PMC
- PMC11387002
- OpenAlex
- W4396736550
- Semantic Scholar
- 666b758c05ace2f8bdba269d4c30b3165c22cc52
- Cited by
- 17
- References
- 51
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 3
- FWCI
- 1.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nucleic Acid Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- Funders
- Cold Spring Harbor Laboratory
- National Institutes of Health (5t32gm008444-33, 5p30ca045508-35)
- University of Colorado Boulder
- National Cancer Institute (P30-CA045508, P01 CA013106, F30CA271804)
- National Institute of General Medical Sciences (T32‐GM008444)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- antisense oligonucleotides, alternative splicing, pancreatic ductal adenocarcinoma, patient-derived organoids, lipofection, splicing-targeted therapy, drug screening, oligonucleotide delivery, splicing factors
- MeSH terms
- Humans, Organoids, Pancreatic Neoplasms, Oligonucleotides, Antisense, Alternative Splicing, Carcinoma, Pancreatic Ductal
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-23.
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