Distinct Classes of Proteasome-Modulating Agents Cooperatively Augment Recombinant Adeno-Associated Virus Type 2 and Type 5-Mediated Transduction from the Apical Surfaces of Human Airway Epithelia
Open accessAbstract
Tripeptidyl aldehyde proteasome inhibitors have been shown to effectively increase viral capsid ubiquitination and transduction of recombinant adeno-associated virus type 2 (rAAV-2) and rAAV-5 serotypes. In the present study we have characterized a second class of proteasome-modulating agents (anthracycline derivatives) for their ability to induce rAAV transduction. The anthracycline derivatives doxorubicin and aclarubicin were chosen for analysis because they have been shown to interact with the proteasome through a mechanism distinct from that of tripeptidyl aldehydes. Our studies demonstrated that doxorubicin and aclarubicin also significantly augmented rAAV transduction in airway cell lines, polarized human airway epithelia, and mouse lungs. Both tripeptidyl aldehyde and anthracycline proteasome-modulating agents similarly augmented nuclear accumulation of rAAV in A549 and IB3 airway cell lines. However, these two cell types demonstrated cell specificity in the ability of N -acetyl- l -leucyl- l -leucyl- l -norleucine (LLnL) or doxorubicin to augment rAAV transduction. Interestingly, the combined administration of LLnL and doxorubicin resulted in substantially increased transduction (>2,000-fold) following apical infection of human polarized epithelia with either rAAV-2 or rAAV-5. In summary, the cell type specificity of LLnL and doxorubicin to induce rAAV transduction, together with the ability of these compounds to synergistically enhance rAAV transduction in polarized airway epithelial induction, suggests that these two classes of compounds likely modulate different proteasome functions that affect rAAV transduction. Findings from this study provide new insights into how modulation of proteasome function can be effectively used to augment rAAV transduction in airway epithelia for gene therapy of cystic fibrosis.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Use of proteasome inhibitors such as MG-132 and LLnL increases transduction, providing evidence that after endosome escape, AAV must elude proteasomes in the cytoplasm while traversing to the nucleus.
“Use of proteasome inhibitors such as MG-132 and LLnL have been shown to increase transduction, providing evidence that after endosome escape, AAV must elude proteasomes in the cytoplasm while traversing to the nucleus (Fig. 8IV and V) (11, 51).”
From Packaging Capacity of Adeno-Associated Virus Serotypes: Impact of Larger Genomes on Infectivity and Postentry Steps (2005) · cites this paper as [51]
The introductory passage identifies Z-LLL as MG132 and reports that it and LLnL enhance rAAV transduction; the Results also show that LLnL increases transduction and nuclear accumulation of viral DNA. But the Discussion says how these agents alter rAAV interactions with the proteasome remains unclear. The paper does not establish that, after escaping endosomes, AAV must elude cytoplasmic proteasomes on its way to the nucleus. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDrugs/chemicals such as bafilomycin A, brefeldin A, and MG-132 augment rAAV transduction by acting on the level of endosome acidification, early-to-late endosome transition, and proteasome activity, respectively.
“Studies have been carried out by a number of groups (11, 22, 50, 51) illustrating that drugs/chemicals such as bafilomycin A, brefeldin A, and MG-132 augment rAAV transduction by acting on the level of endosome acidification, early-to-late endosome transition, and proteasome activity, respectively.”
From Packaging Capacity of Adeno-Associated Virus Serotypes: Impact of Larger Genomes on Infectivity and Postentry Steps (2005) · cites this paper as [51]
The paper identifies MG132 (Z-LLL) as a proteasome inhibitor that can enhance rAAV transduction (introductory passage; Results). It does not address the claimed effects of bafilomycin A on endosome acidification or brefeldin A on early-to-late endosome transition. No page numbers are available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredProteasomes are a barrier for intracellular trafficking.
“Proteasome inhibitors have been described in numerous studies to increase the transduction of rAAV postentry of the cell, suggesting that proteasomes are a barrier for intracellular trafficking (11, 51).”
From Packaging Capacity of Adeno-Associated Virus Serotypes: Impact of Larger Genomes on Infectivity and Postentry Steps (2005) · cites this paper as [51]
Proteasome inhibitors increase the transduction of recombinant AAV postentry of the cell.
“Proteasome inhibitors have been described in numerous studies to increase the transduction of rAAV postentry of the cell, suggesting that proteasomes are a barrier for intracellular trafficking (11, 51).”
From Packaging Capacity of Adeno-Associated Virus Serotypes: Impact of Larger Genomes on Infectivity and Postentry Steps (2005) · cites this paper as [51]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Infectious entry pathway of adeno-associated virus and adeno-associated virus vectors
Bartlett, J. S., Wilcher, R., & Samulski, R. J. (2000) · Journal of Virology · doi:10.1128/jvi.74.6.2777-2785.2000 · Cited by 532 · cited 1× · see citing works
“Studies evaluating rAAV trafficking with the fluorescent and radiolabeled virus have demonstrated that once endocytosed, the virus moves relatively slowly to the nucleus and accumulates in a perinuclear compartment (4, 14, 19, 20, 37).”
BackgroundYan, Z., Zak, R., Luxton, G. W. G., Ritchie, T. C., Bantel-Schaal, U., & Engelhardt, J. F. (2002) · Journal of Virology · doi:10.1128/jvi.76.5.2043-2053.2002 · Cited by 222 · see citing works
Self-citationHansen, J., Qing, K., & Srivastava, A. (2001) · Journal of Virology · doi:10.1128/jvi.75.9.4080-4090.2001 · Cited by 129 · cited 1× · see citing works
“Studies evaluating rAAV trafficking with the fluorescent and radiolabeled virus have demonstrated that once endocytosed, the virus moves relatively slowly to the nucleus and accumulates in a perinuclear compartment (4, 14, 19, 20, 37).”
Background
Flagged first, then by citations
Research works printed but not linked: 7
- [5]5. Berns, K. I., and C. Giraud. 1996. Adeno-associated virus (AAV) vectors in gene therapy. Springer, Berlin, Germany.
- [7]7. Carter, B. J., H. B. Burnstein, and R. W. Peluso. AAV vectors for gene therapy, in press. Marcel Dekker, Inc., New York, N.Y.
- [9]9. Davidson, B. L., C. S. Stein, J. A. Heth, I. Martins, R. M. Kotin, T. A. Derksen, J. Zabner, A. Ghodsi, and J. A. Chiorini. 2000. Recombinant adeno-associated virus type 2, 4, and 5 vectors: transduction of variant cell types and regions in the mammalian central nervous system. Proc. Natl. Acad. Sci. USA 97: 3428-3432.
- [15]15. Duan, D., Y. Zhang, and J. F. Engelhardt. 1998. Gene delivery to the airway, p. 13.9.1-13.9.34. In N. C. Dracopoli, J. L. Haines, B. R. Korf, D. T. Moir, C. C. Morton, C. E. Seidman, J. G. Seidman, and D. R. Smith (ed.), Current protocols in human genetics. John Wiley & Sons, Inc., New York, N.Y.
- [17]17. Gabizon, A., H. Shmeeda, and Y. Barenholz. 2003. Pharmacokinetics of pegylated liposomal Doxorubicin: review of animal and human studies. Clin. Pharmacokinet. 42: 419-436.
- [18]18. Gao, G. P., M. R. Alvira, L. Wang, R. Calcedo, J. Johnston, and J. M. Wilson. 2002. Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc. Natl. Acad. Sci. USA 99: 11854-11859.
- [22]22. Keizer, H. G., H. M. Pinedo, G. J. Schuurhuis, and H. Joenje. 1990. Doxorubicin (adriamycin): a critical review of free radical-dependent mechanisms of cytotoxicity. Pharmacol. Ther. 47: 219-231.
Cited by
Sorted by citations
Zhong, L., Li, B., Mah, C. S., Govindasamy, L., Agbandje-McKenna, M., Cooper, M., Herzog, R. W., Zolotukhin, I., Warrington, K. H., Weigel-Van Aken, K. A., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0802866105 · Cited by 558 · see citing works
“In addition, it is also possible that the proteasome effect may be cell type-specific (31, 39, 40).”
BackgroundGrieger, J. C., & Samulski, R. J. (2005) · Journal of Virology · doi:10.1128/jvi.79.15.9933-9944.2005 · Cited by 419 · see citing works
“Studies have been carried out by a number of groups (11, 22, 50, 51) illustrating that drugs/chemicals such as bafilomycin A, brefeldin A, and MG-132 augment rAAV transduction by acting on the level of endosome acidification, early-to-late endosome transition, and proteasome activity, respectively.”
BackgroundSonntag, F., Bleker, S., Leuchs, B., Fischer, R., & Kleinschmidt, J. A. (2006) · Journal of Virology · doi:10.1128/jvi.01056-06 · Cited by 277 · see citing works
“Proteasome inhibitors significantly increase gene transduction with AAV2 (12, 14, 16, 23, 34, 75, 76); however, the mechanism of inhibitor action remains unclear,”
BackgroundIntracellular transport of recombinant adeno-associated virus vectors
Nonnenmacher, M., & Weber, T. (2012) · Gene Therapy · doi:10.1038/gt.2012.6 · Cited by 258 · see citing works
Intracellular trafficking of adeno-associated viral vectors
Ding, W., Zhang, L., Yan, Z., & Engelhardt, J. F. (2005) · Gene Therapy · doi:10.1038/sj.gt.3302527 · Cited by 251 · see citing works
Self-citationRecombinant Adeno-associated Virus Transduction and Integration
Schultz, B. R., & Chamberlain, J. S. (2008) · Molecular Therapy · doi:10.1038/mt.2008.103 · Cited by 216 · see citing works
AAV Capsid Structure and Cell Interactions
Agbandje-McKenna, M., & Kleinschmidt, J. (2012) · Methods in Molecular Biology · doi:10.1007/978-1-61779-370-7_3 · Cited by 215 · see citing works
Recent developments in adeno‐associated virus vector technology
Büning, H., Perabò, L., Coutelle, O., Quadt‐Humme, S., & Hallek, M. J. (2008) · The Journal of Gene Medicine · doi:10.1002/jgm.1205 · Cited by 189 · see citing works
Directed evolution of adeno-associated virus to an infectious respiratory virus
Excoffon, K., Koerber, J. T., Dickey, D. D., Murtha, M., Keshavjee, S., Kaspar, B., Zabner, J., & Schaffer, D. (2009) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0813365106 · Cited by 190 · see citing works
“studies that used proteasomal inhibitors to augment AAV transduction (32).”
Qiu, J.-M., Söderlund-Venermo, M., & Young, N. (2016) · Clinical Microbiology Reviews · doi:10.1128/cmr.00040-16 · Cited by 188 · see citing works
Enhancement of Adeno-Associated Virus Infection by Mobilizing Capsids into and Out of the Nucleolus
Johnson, J. S., & Samulski, R. J. (2008) · Journal of Virology · doi:10.1128/jvi.02309-08 · Cited by 158 · see citing works
“Studies in addition to ours have demonstrated prolonged genome persistence following administration of proteasome inhibitors (18), and several reports provide evidence that interfering with proteasomal degradation increases AAV transduction primarily by improving nuclear uptake of genomes (16, 71).”
BackgroundGrieger, J. C., Snowdy, S., & Samulski, R. J. (2006) · Journal of Virology · doi:10.1128/jvi.02723-05 · Cited by 172 · see citing works
“7, steps 4 and 5) (7, 67) or facilitating down-”
BackgroundEstablishment of a Reverse Genetics System for Studying Human Bocavirus in Human Airway Epithelia
Huang, Q.-F., Deng, X., Yan, Z.-Y., Cheng, F., Luo, Y., Shen, W., Lei-Butters, D. C. M., Chen, A., Li, Y., Tang, L., et al. (2012) · PLoS Pathogens · doi:10.1371/journal.ppat.1002899 · Cited by 165 · see citing works
Self-citationGene transfer to the lung: lessons learned from more than 2 decades of CF gene therapy.
Griesenbach, U., & Alton, E. (2009) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2008.09.010 · Cited by 163 · see citing works
“Proteasome inhibitors, for example, have been shown to increase AAV2 and AAV2/5 transfection in vitro [53] probably via increasing their chances of transit to the nucleus.”
BackgroundLi, Z., Zhao, W., Wu, J., Li, B., Zolotukhin, S., Lakshmanan Govindasamy, A., Agbandje‐McKenna, M., & Srivastava, A. (2007) · Molecular Therapy · doi:10.1038/sj.mt.6300170 · Cited by 146 · see citing works
Monahan, P. E., Lothrop, C. D., Sun, J., Hirsch, M. L., Kafri, T., Kantor, B., Sarkar, R., Tillson, D. M., Elia, J. R., & Samulski, R. J. (2010) · Molecular Therapy · doi:10.1038/mt.2010.170 · Cited by 125 · see citing works
Journey to the Center of the Cell: Tracing the Path of AAV Transduction
Dhungel, B. P., Bailey, C. G., & Rasko, J. E. J. (2021) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2020.09.010 · Cited by 122 · see citing works
Cystic Fibrosis Gene Therapy: Looking Back, Looking Forward
Cooney, A. L., McCray, P., & Sinn, P. (2018) · Genes · doi:10.3390/genes9110538 · Cited by 118 · see citing works
“Co-delivery of AAV with proteasome inhibitors such as doxorubicin and LLnL increased expression in airway cells by preventing proteasomal degradation of the vector [168, 169] .”
BackgroundFinn, J. D., Hui, D., Downey, H. D., Dunn, D., Pien, G. C., Mingozzi, F., Zhou, S., & High, K. A. (2010) · Molecular Therapy · doi:10.1038/mt.2009.257 · Cited by 115 · see citing works
Yan, Z., Zak, R., Zhang, Y., & Engelhardt, J. F. (2005) · Journal of Virology · doi:10.1128/jvi.79.1.364-379.2005 · Cited by 107 · see citing works
“Understanding the mechanisms of AAV intracellular trafficking and the involvement of the ubiquitin/proteasome system has led to methods to improve rAAV transduction by enhancing intracellular processing of the virus with proteasome inhibitors (6, 13, 42).”
MethodSelf-citationrAAV2 traffics through both the late and the recycling endosomes in a dose-dependent fashion
Ding, W., Zhang, L. N., Yeaman, C. A., & Engelhardt, J. F. (2006) · Molecular Therapy · doi:10.1016/j.ymthe.2005.12.002 · Cited by 99 · see citing works
“To understand better how m.o.i.-dependent changes in rAAV2 trafficking affect transgene expression, we performed a simple dose titration of AV2Luc on HeLa cells and assessed luciferase transgene expression at increasing m.o.i. of vector.”
MethodInfluentialSelf-citationAkache, B., Grimm, D., Shen, X., Fuess, S., Yant, S. R., Glazer, D. S., Park, J., & Kay, M. A. (2007) · Molecular Therapy · doi:10.1038/sj.mt.6300053 · Cited by 85 · see citing works
“[20] [21] [22] Inside the nucleus, AAV eventually uncoats to release its genome and allow its subsequent transcription and replication.”
BackgroundCFTR gene transfer with AAV improves early cystic fibrosis pig phenotypes
Steines, B. R., Dickey, D. D., Bergen, J., Excoffon, K. J. D. A., Weinstein, J. R., Li, X., Yan, Z., Alaiwa, M. H. A., Shah, V. S., Bouzek, D. C., et al. (2016) · JCI Insight · doi:10.1172/jci.insight.88728 · Cited by 92 · see citing works
Self-citationLi, W.-P., Zhang, L., Johnson, J. S., Wu, Z.-J., Grieger, J., Xiao, P.-J., Drouin, L., Agbandje-McKenna, M., Pickles, R., & Samulski, R. (2009) · Molecular Therapy · doi:10.1038/mt.2009.155 · Cited by 94 · see citing works
Long-Term Modeling of SARS-CoV-2 Infection of In Vitro Cultured Polarized Human Airway Epithelium
Hao, S., Ning, K., Küz, Ç. A., Vorhies, K., Yan, Z., & Qiu, J. (2020) · mBio · doi:10.1128/mbio.02852-20 · Cited by 98 · see citing works
Self-citationStieger, K., Schroeder, J., Provost, N., Mendes-Madeira, A., Belbellaa, B., Meur, G. L., Weber, M., Deschamps, J.-Y., Lorenz, B., Moullier, P., et al. (2009) · Molecular Therapy · doi:10.1038/mt.2008.283 · Cited by 88 · see citing works
Enhanced Real-Time Monitoring of Adeno-Associated Virus Trafficking by Virus–Quantum Dot Conjugates
Joo, K., Fang, Y. H., Liu, Y., Liang, X., Gu, Z., Tai, A., Lee, C.-L., Tang, Y., & Wang, P. (2011) · ACS Nano · doi:10.1021/nn102651p · Cited by 88 · see citing works
“org H the second-strand genome synthesis caused by the proteasome inhibitor.(53,55) Instead, our confocal images showed that particle numbers accumulated in the nucleus were remarkably increased in MG132-treated cells (Figure 6D and E).”
BackgroundGene therapy progress and prospects: cystic fibrosis
Uta Griesenbach, D., Geddes, D. M., & Alton, E. W. F. W. (2006) · Gene Therapy · doi:10.1038/sj.gt.3302809 · Cited by 173 · see citing works
Grieger, J. C., Johnson, J. S., Gurda-Whitaker, B., Agbandje-McKenna, M., & Samulski, R. J. (2007) · Journal of Virology · doi:10.1128/jvi.00580-07 · Cited by 83 · see citing works
“Based on a number of studies, it has been proposed that AAV requires endosomal acidification to escape from the late endosome and traffic to the nucleus (16, 20, 50, 51).”
BackgroundCellular transduction mechanisms of adeno-associated viral vectors
Berry, G. E., & Asokan, A. (2016) · Current Opinion in Virology · doi:10.1016/j.coviro.2016.08.001 · Cited by 78 · see citing works
Ferret and Pig Models of Cystic Fibrosis: Prospects and Promise for Gene Therapy
Yan, Z.-Y., Stewart, Z., Sinn, P., Olsen, J., Hu, J., McCray, P., & Engelhardt, J. (2014) · Human Gene Therapy Clinical Development · doi:10.1089/humc.2014.154 · Cited by 75 · see citing works
“Subsequent studies demonstrated that rAAV2 has low tropism for transduction from the apical surface of the human airway epithelium(40) and has impaired proteasome-dependent intracellular processing and trafficking to the nucleus for productive transduction.(41,55,56) A major limitation of firstgeneration rAD vectors i…”
Self-citationYan, Z., Keiser, N. W., Song, Y., Deng, X., Cheng, F., Qiu, J., & Engelhardt, J. F. (2013) · Molecular Therapy · doi:10.1038/mt.2013.92 · Cited by 76 · see citing works
Self-citationViral vector-mediated and cell-based therapies for treatment of cystic fibrosis.
Flotte, T., Ng, P., Dylla, D., McCray, P., Wang, G.-S., Kolls, J., & Hu, J. (2007) · Molecular Therapy · doi:10.1038/sj.mt.6300002 · Cited by 70 · see citing works
Liu, X., Luo, M., Zhang, L. N., Yan, Z., Žák, R., Ding, W., Mansfield, S. G., Mitchell, L. G., & Engelhardt, J. F. (2005) · Human Gene Therapy · doi:10.1089/hum.2005.16.1116 · Cited by 66 · see citing works
“Physical titers of rAAV were determined by slot-blot hybridization, and peak fractions were combined for analysis (Duan et al., 1998b; Yan et al., 2004).”
BackgroundMethodResultInfluentialSelf-citationDenby, L., Nicklin, S., & Baker, A. H. (2005) · Gene Therapy · doi:10.1038/sj.gt.3302564 · Cited by 69 · see citing works
Mitchell, A. M., & Samulski, R. J. (2013) · Journal of Virology · doi:10.1128/jvi.01826-13 · Cited by 63 · see citing works
In Vitro Modeling of Human Bocavirus 1 Infection of Polarized Primary Human Airway Epithelia
Deng, X., Yan, Z.-Y., Luo, Y., Xu, J., Cheng, F., Li, Y., Engelhardt, J., & Qiu, J.-M. (2013) · Journal of Virology · doi:10.1128/jvi.03132-12 · Cited by 61
Self-citationYan, Z., Sun, X., Feng, Z., Li, G., Fisher, J. T., Stewart, Z. A., & Engelhardt, J. F. (2015) · Human Gene Therapy · doi:10.1089/hum.2015.001 · Cited by 64 · see citing works
“system, and purified by two rounds of CsCl ultracentrifugation as reported previously.(42) All the rAAV cis transfer plasmids and enhancer-containing plasmid vectors were propagated in the E.”
MethodSelf-citationAn Adeno-Associated Viral Vector Capable of Penetrating the Mucus Barrier to Inhaled Gene Therapy
Duncan, G. A., Kim, N., Colon-Cortes, Y., Rodriguez, J., Mazur, M., Birket, S. E., Rowe, S. M., West, N. E., Livraghi-Butrico, A., Boucher, R. C., et al. (2018) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2018.03.006 · Cited by 60 · see citing works
Wang, L.-N., Wang, Y., Lu, Y., Yin, Z.-F., Zhang, Y.-H., Aslanidi, G., Srivastava, A., Ling, C., & Ling, C. (2014) · Journal of Chinese Integrative Medicine · doi:10.1016/s2095-4964(14)60003-0 · Cited by 54 · see citing works
Self-citationEfficient Whole-body Transduction with Trans-splicing Adeno-associated Viral Vectors.
Ghosh, A., Yue, Y., Long, C., Bostick, B., & Duan, D. (2007) · Molecular Therapy · doi:10.1038/sj.mt.6300153 · Cited by 53 · see citing works
Liu, X., Yan, Z., Luo, M., & Engelhardt, J. F. (2005) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2005-0189oc · Cited by 46 · see citing works
“However, in terms of polarized human airway epithelia, there is disagreement as to whether rAAV5 has a greater (12) or similar capacity (11, 17, 18) to transduce the apical membrane of human polarized airway epithelia.”
BackgroundMethodInfluentialSelf-citationFakhiri, J., Schneider, M. A., Puschhof, J., Stanifer, M. L., Schildgen, V., Holderbach, S., Voß, Y., Andari, J. E., Schildgen, O., Boulant, S., et al. (2019) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2019.01.003 · Cited by 57 · see citing works
“The same inhibitor agents are also commonly used to facilitate transduction with genuine AAV vectors, especially in the airway epithelia.(34) We note that we have routinely used these inhibitors for all AAV2 controls in this work to remain consistent with the BoV samples and that AAV2 transduction in the absence of th…”
BackgroundSelf-citationNicolson, S. C., Li, C., Hirsch, M. L., Setola, V., & Samulski, R. J. (2016) · Journal of Virology · doi:10.1128/jvi.02953-15 · Cited by 48 · see citing works
“Generalizing from the entire collection of our identified hits, it seems that rAAV can be enhanced by two mechanisms: (i) inhibition of the proteasome and (ii) induction of DNA damage, which corroborates previously published results (38, 39, 69, 77, 78).”
BackgroundResultWatson-Levings, R. S., Broome, T. A., Smith, A. D., Rice, B. L., Gibbs, E. P., Myara, D. A., Hyddmark, E. V., Nasri, E., Zarezadeh, A., Levings, P., et al. (2018) · Human Gene Therapy Clinical Development · doi:10.1089/humc.2017.142 · Cited by 48 · see citing works
Unique Biologic Properties of Recombinant AAV1 Transduction in Polarized Human Airway Epithelia
Yan, Z., Lei-Butters, D. C. M., Liu, X., Zhang, Y., Zhang, L. N., Luo, M., Žák, R., & Engelhardt, J. F. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m604099200 · Cited by 47 · see citing works
Self-citationAdeno-Associated Virus-Based Gene Therapy for Inherited Disorders
Flotte, T. (2005) · Pediatric Research · doi:10.1203/01.pdr.0000189226.03684.fe · Cited by 47 · see citing works
“Both of these were relative limitations, however, as indicated by recent data from a tracheal xenograft model in which an alternative receptor pathway that is more susceptible to proteasome-mediated degradation has been defined (33).”
Analysis of Adeno-associated Virus Progenitor Cell Transduction in Mouse Lung
Liu, X., Luo, M., Guo, C., Yan, Z., Wang, Y., Lei-Butters, D. C. M., & Engelhardt, J. F. (2008) · Molecular Therapy · doi:10.1038/mt.2008.248 · Cited by 39 · see citing works
Self-citationFlotte, T., Schwiebert, E., Zeitlin, P., Carter, B., & Guggino, W. (2005) · Human Gene Therapy · doi:10.1089/hum.2005.16.921 · Cited by 42 · see citing works
“It has been reported that vector DNA administered at the apical surface of airway epithelial cells may be trafficked to an extranuclear compartment, but enter the nucleus later if appropriate stimuli are provided (Duan et al., 2000; Yan et al., 2004).”
BackgroundYan, Z., Lei-Butters, D. C. M., Zhang, Y., Zak, R., & Engelhardt, J. F. (2007) · Human Gene Therapy · doi:10.1089/hum.2006.128 · Cited by 41 · see citing works
Self-citationEfficient whole-body transduction with trans-splicing adeno-associated viral vectors.
Ghosh, A., Yue, Y., Long, C., Bostick, B., & Duan, D. (2007) · Molecular Therapy · doi:10.1038/sj.mt.6300081 · Cited by 41 · see citing works
Bacteriophages as vehicles for gene delivery into mammalian cells: prospects and problems
Bakhshinejad, B., & Sadeghizadeh, M. (2014) · Expert Opinion on Drug Delivery · doi:10.1517/17425247.2014.927437 · Cited by 40 · see citing works
“In contrast, in HIV type-1 and adeno-associated virus, ubiquitination and proteasomal degradation fulfill a negative role and act as inhibitory factors for viral infection process [81-87].”
BackgroundYan, Z., Feng, Z., Sun, X., Zhang, Y., Zou, W., Wang, Z., Jensen-Cody, C. W., Liang, B., Park, S.-Y., Qiu, J., et al. (2017) · Human Gene Therapy · doi:10.1089/hum.2017.060 · Cited by 40 · see citing works
Self-citationSantangeloyz, K. S., & Bertoneyz, A. L. (2011) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2011.09.004 · Cited by 39
Materials promoting viral gene delivery
Kaygisiz, K., & Synatschke, C. V. (2020) · Biomaterials Science · doi:10.1039/d0bm01367f · Cited by 56 · see citing works
Present and Future of Adeno Associated Virus Based Gene Therapy Approaches
Ortolano, S., Spuch, C., & Fernández-Balbuena, C. N. (2012) · Recent Patents on Endocrine Metabolic & Immune Drug Discovery · doi:10.2174/187221412799015245 · Cited by 34 · see citing works
Gene therapy for cystic fibrosis: Challenges and prospects
Sui, H., Xu, X., Su, Y., Gong, Z., Yao, M., Liu, X., Zhang, T., Jiang, Z., Bai, T., Wang, J., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1015926 · Cited by 51 · see citing works
“This post-entry block is responsive to the inhibition of proteasome activity, and it can be overcome by transient pharmacological intervention during or post transduction (Yan et al., 2002; Yan et al., 2004; Ding et al., 2005; Jennings et al., 2005; Monahan et al., 2010).”
BackgroundJiang, M.-H., Liu, Z., Xiang, Y., Ma, H., Liu, S.-L., Liu, Y.-X., & Zheng, D. (2011) · BMC Cancer · doi:10.1186/1471-2407-11-54 · Cited by 37 · see citing works
“Previous studies reported that DNAdamaging agents, such as UV light, gamma irradiation, cis-platinum, and tritiated thymidine can significantly increase the efficiency of AAV transduction in various cells, including nondividing cells [15], airway cells [16], neuronal cells [17] and cancer cells [12,18,19].”
BackgroundNegishi, A., Chen, J.-H., Mccarty, D., Samulski, R., Liu, J., & Superfine, R. (2004) · Glycobiology · doi:10.1093/glycob/cwh118 · Cited by 37 · see citing works
“…because they determine the specific tissues that can be treated with these gene delivery vectors, and second, because they appear to influence the intracellular trafficking of the virus, thus effecting the efficiency of its translocation to the nucleus and subsequent expression (Yan et al., 2004).”
Keiser, N. W., Yan, Z., Zhang, Y., Lei-Butters, D. C. M., & Engelhardt, J. F. (2011) · Human Gene Therapy · doi:10.1089/hum.2011.044 · Cited by 40 · see citing works
“The intracellular trafficking of rAAV2/2 has been shown to be quite slow (Duan et al. , 2000; Hansen et al. , 2000), and enhancement of this process with proteasome inhibitors can facilitate viral movement to the nucleus and enhance transduction (Duan et al. , 2000; Yan et al. , 2002, 2004).”
Self-citationNovel AAV-mediated gene delivery system corrects CFTR function in pigs.
Cooney, A. L., Thornell, I., Singh, B., Shah, V. S., Stoltz, D., McCray, P., Zabner, J., & Sinn, P. (2019) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2019-0006oc · Cited by 35 · see citing works
“Delivery of AAV in the presence of doxorubicin increases AAV expression through proteasome inhibition (20, 21).”
BackgroundAalbers, C., Bevaart, L., Loiler, S., de Cortie, K., Wright, J. F., Mingozzi, F., Tak, P., & Vervoordeldonk, M. (2015) · PLoS ONE · doi:10.1371/journal.pone.0130612 · Cited by 35 · see citing works
“Doxorubicin, an anthracycline derivative, has been shown to increase transduction efficiency for several AAV serotypes in different cell lines, through a proteasome modulating mechanism [22–24].”
BackgroundLiu, X.-M., Luo, M., Trygg, C., Yan, Z.-Y., Lei-Butters, D. C. M., Smith, C. I., Fischer, A., Munson, K., Guggino, W., Bunnell, B., et al. (2007) · Molecular Therapy · doi:10.1038/sj.mt.6300277 · Cited by 35 · see citing works
Self-citationCorrection of Airway Stem Cells: Genome Editing Approaches for the Treatment of Cystic Fibrosis
King, N. E., Suzuki, S., Barillà, C., Hawkins, F. J., Randell, S. H., Reynolds, S. D., Stripp, B. R., & Davis, B. R. (2020) · Human Gene Therapy · doi:10.1089/hum.2020.160 · Cited by 40 · see citing works
Celastrol enhances AAV1-mediated gene expression in mice adipose tissues
Zhang, F.-L., Jia, S.-Q., Zheng, S.-P., & Ding, W. (2011) · Gene Therapy · doi:10.1038/gt.2010.120 · Cited by 33 · see citing works
Self-citationSox17 modulates Wnt3A/beta-catenin-mediated transcriptional activation of the Lef-1 promoter.
Liu, X.-M., Luo, M., Xie, W.-L., Wells, J. M., Goodheart, M., & Engelhardt, J. (2010) · American Journal of Physiology - Lung cellular and Molecular Physiology · doi:10.1152/ajplung.00140.2010 · Cited by 32 · see citing works
Self-citationAdvances in cystic fibrosis gene therapy
Griesenbach, U., Geddes, D., & Alton, E. (2004) · Current opinion in pulmonary medicine · doi:10.1097/01.mcp.0000142102.91202.04 · Cited by 32 · see citing works
White, A. F., Mazur, M., Sorscher, E., Zinn, K., & Ponnazhagan, S. (2008) · Human Gene Therapy · doi:10.1089/hum.2008.117 · Cited by 31 · see citing works
“Additional strategies to increase the permeability of the apical surface of the airway epithelium to AAV, using chemicals and a combination of transduction-enhancing compounds after vector transduction, have resulted in significant augmentation of gene expression in airway epithelium (Duan et al., 2000; Ding et al., 2…”
BackgroundViral Vectors, Animal Models, and Cellular Targets for Gene Therapy of Cystic Fibrosis Lung Disease
Tang, Y., Yan, Z., & Engelhardt, J. F. (2020) · Human Gene Therapy · doi:10.1089/hum.2020.013 · Cited by 34 · see citing works
“that can be overcome by co-administration of proteasome inhibitors.(23,130) Directed evolution with an AAV2/AAV5 capsid library after multiple rounds of apical infection of ALI cultures has generated a novel AAV capsid variant (AAV2.”
BackgroundSelf-citationInput Virion Proteins: Cryptic Targets of Antivector Immune Responses in Preimmunized Subjects
Lowenstein, P. R. (2004) · Molecular Therapy · doi:10.1016/j.ymthe.2004.05.019 · Cited by 22 · see citing works
Rapamycin control of transgene expression from a single AAV vector in mouse salivary glands
Wang, J.-H., Voutetakis, A., Papa, M., Rivera, V. M., Clackson, T., Lodde, B. M., Mineshiba, F., & Baum, B. (2006) · Gene Therapy · doi:10.1038/sj.gt.3302647 · Cited by 27
Progress in Respiratory Gene Therapy
McLachlan, G., Alton, E., Boyd, A., Clarke, N. K., Davies, J., Gill, D., Griesenbach, U., Hickmott, J., Hyde, S., Miah, K., et al. (2022) · Human Gene Therapy · doi:10.1089/hum.2022.172 · Cited by 26 · see citing works
“71 Despite this encouraging clinical proof of concept, the magnitude of the effect was deemed insufficient to justify proceeding immediately to Phase III studies as a stand-alone therapy, particularly in the context of the lung function improvements observed with modulator therapies.”
Doxorubicin augments rAAV-2 transduction in rat neuronal cells
Zhang, T., Hu, J., Ding, W., & Wang, X. (2009) · Neurochemistry International · doi:10.1016/j.neuint.2009.05.005 · Cited by 23 · see citing works
“As a potent proteasome inhibitor, doxorubicin was previously reported to significantly enhance rAAV-2 transduction in airway epithelia cells both in vitro and in vivo (Yan et al., 2004).”
BackgroundResultInfluentialSelf-citationTang, S.-C., Sambanis, A., & Sibley, E. (2005) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2005.03.245 · Cited by 25 · see citing works
Gene therapy for cystic fibrosis airway disease- is clinical success imminent?
Anson, D., Smith, G. J., & Parsons, D. (2006) · Current Gene Therapy · doi:10.2174/156652306776359496 · Cited by 24 · see citing works
AAV-6 mediated efficient transduction of mouse lower airways
Li, W.-P., Zhang, L., Wu, Z.-J., Pickles, R., & Samulski, R. (2011) · Virology · doi:10.1016/j.virol.2011.06.009 · Cited by 23 · see citing works
“…has a unique ability at escaping the ubiquitin/proteasome degradation pathway in mouse airway epithelia The ubiquitin/proteasome pathway plays a role in AAV transduction of non-polarized cell lines and differentiated human airway epithelia (Douar et al., 2001; Duan et al., 2000; Yan et al., 2004).”
BackgroundMethodCurrent landscape of cystic fibrosis gene therapy
Plasschaert, L. W., MacDonald, K. D., & Moffit, J. S. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1476331 · Cited by 27 · see citing works
Kim, N., Kwak, G., Rodriguez, J., Livraghi-Butrico, A., Zuo, X., Simon, V., Han, E., Shenoy, S., Pandey, N., Mazur, M., et al. (2021) · Thorax · doi:10.1136/thoraxjnl-2020-215185 · Cited by 22 · see citing works
Doxorubicin Improves Cancer Cell Targeting by Filamentous Phage Gene Delivery Vectors
Tsafa, E., Bentayebi, K., Topanurak, S., Yata, T., Przystal, J., Fongmoon, D., Hajji, N., Waramit, S., Suwan, K., & Hajitou, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21217867 · Cited by 19 · see citing works
“Nevertheless, these data are consistent with previous studies reporting that doxorubicin augments the transduction efficiency of airway cell lines by the recombinant rAAV vector [41].”
BackgroundResultKeswani, S., Balaji, S., Le, L., Leung, A., Katz, A. B., Lim, F., Habli, M., Jones, H., Wilson, J. M., & Crombleholme, T. (2012) · PLoS ONE · doi:10.1371/journal.pone.0043633 · Cited by 19 · see citing works
Proteasome inhibitors enhance bacteriophage lambda (λ) mediated gene transfer in mammalian cells
Volcy, K., & Dewhurst, S. (2008) · Virology · doi:10.1016/j.virol.2008.11.019 · Cited by 18 · see citing works
Bower, J., Song, L.-J., Bastola, P., & Hirsch, M. L. (2021) · Viruses · doi:10.3390/v13071205 · Cited by 15 · see citing works
The role of doxorubicin in non-viral gene transfer in the lung.
Griesenbach, U., Meng, C., Farley, R., Gardner, A., Brake, M., Frankel, G., Gruenert, D., Cheng, S. H., Scheule, R., & Alton, E. (2009) · Biomaterials · doi:10.1016/j.biomaterials.2008.12.037 · Cited by 15 · see citing works
Gong, H., Yuan, N., Shen, Z., Tang, C., Shipp, S. D., Liling, Q., Lu, Y., Andolina, I. M., Zhang, S., Wu, J., et al. (2021) · iScience · doi:10.1016/j.isci.2021.102685 · Cited by 14 · see citing works
“Furthermore, doxorubicin may also promote viral nuclear entry through modulation of proteasome function (Yan et al., 2004).”
BackgroundInfluentialYan, Z., Sun, X., Evans, I. A., Tyler, S. R., Song, Y., Liu, X., Sui, H., & Engelhardt, J. F. (2013) · Human Gene Therapy · doi:10.1089/hum.2013.137 · Cited by 18 · see citing works
“Various rAAV serotypes have differences in their susceptibility to proteasome-dependent blocks in apical transduction of HAE, with rAAV1 being the least sensitive, and rAAV2 and rAAV5 being the most sensitive (Yan et al., 2004, 2006).”
BackgroundSelf-citationBinny, C., & Nathwani, A. C. (2012) · Humana Press eBooks · doi:10.1007/978-1-61779-873-3_6 · Cited by 12 · see citing works
Excoffon, K., Lin, S., Narayan, P. K. L., Sitaraman, S., Jimah, A. M., Fallon, T. T., James, M. L., Glatfelter, M., Limberis, M., Smith, M. D., et al. (2024) · Human Gene Therapy · doi:10.1089/hum.2024.063 · Cited by 12 · see citing works
“…that indicates that doxorubicin HCl enhances the translocation of AAV vg from the cell cytoplasm into the cell nucleus after AAV cell entry, 15,24,25 VCN (vg/cell) did not change with increasing concentrations of doxorubicin HCl for any given SP-101 MOI except for the highest MOI (1E5…”
Chen, C.-Y., Lo, C.-K., Lin, B.-L., Sibley, E., & Tang, S.-C. (2008) · Cancer Biology & Therapy · doi:10.4161/cbt.7.2.5333 · Cited by 11 · see citing works
Najafi, S., Rahimpour, A., Ahmadieh, H., Tehrani, M. M., Khalilzad, M. A., Suri, F., & Ranjbari, J. (2024) · Electronic Journal of Biotechnology · doi:10.1016/j.ejbt.2024.07.005 · Cited by 10 · see citing works
Excoffon, K., Smith, M. D., Falese, L., Schulingkamp, R., Lin, S., Mahankali, M., Narayan, P. K. L., Glatfelter, M., Limberis, M., Yuen, E., et al. (2024) · Human Gene Therapy · doi:10.1089/hum.2024.064 · Cited by 10 · see citing works
Hao, S., Zhang, X., Ning, K., Feng, Z., Park, S. Y., Küz, Ç. A., McFarlin, S., Richart, D., Cheng, F., Zhang, E. Y., et al. (2023) · Journal of Virology · doi:10.1128/jvi.01330-23 · Cited by 15 · see citing works
“5T in HAE-ALI from either the apical or basal side, consistent with previous observations in the transduction of other AAV serotypes in HAE-ALI, with less efficiencies (23).”
BackgroundResultSelf-citationAktaş, Z., Rao, H., Slauson, S. R., Gabelt, B., Larsen, I., Sheridan, R. T. C., Herrnberger, L., Tamm, E., Kaufman, P., & Brandt, C. (2018) · Investigative Ophthalmology and Visual Science · doi:10.1167/iovs.17-22074 · Cited by 10 · see citing works
“, doxorubicin and aclarubicin) in human airway epithelial cells.(67) Tang et al.”
BackgroundParvovirus particles and movement in the cellular cytoplasm and effects of the cytoskeleton
Lyi, S. M., Tan, M. J. A., & Parrish, C. R. (2014) · Virology · doi:10.1016/j.virol.2014.04.003 · Cited by 10 · see citing works
“However, the effects reported vary for different viruses, and while proteosomal inhibitors such as MG138 enhance transduction by AAV type-2 or type-5 (Ding et al., 2003; Yan et al., 2004), they inhibit infection by autonomous parvoviruses (Ros and Kempf, 2004), and it may be difficult to distinguish direct and indirec…”
Ma, H., Zhang, Y., Wang, H.-L., Han, C.-H., Lei, R.-H., Zhang, L., Yang, Z., Rao, L., Qing, H., Xiang, J., et al. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms15010001 · Cited by 10 · see citing works
“efficiency of rAAV transduction in various cells [18,19].”
BackgroundSelf-citationAdeno-Associated Virus-Mediated Gene Transfer for Lung Diseases
Flotte, T. R. (2005) · Human Gene Therapy · doi:10.1089/hum.2005.16.643 · Cited by 13 · see citing works
Adeno-associated virus vectors: versatile tools for in vivo gene transfer.
Zentilin, L., & Giacca, M. (2008) · Contributions to Nephrology · doi:10.1159/000125584 · Cited by 10 · see citing works
Effect of Proteasome Inhibitors on the AAV-Mediated Transduction Efficiency in Retinal Bipolar Cells
Cui, S., Ganjawala, T. H., Abrams, G. W., & Pan, Z. (2020) · Current Gene Therapy · doi:10.2174/1566523220666200211111326 · Cited by 7 · see citing works
Molecular chaperones: from proteostasis to pathogenesis
Ravindran, M. S. (2018) · FEBS Journal · doi:10.1111/febs.14576 · Cited by 8 · see citing works
“Parvoviridae Non-enveloped DNA Adeno-associated virus 2/8 Ubiquitin-proteasome pathways is involved in uncoating [54, 55]”
BackgroundComparative Efficacy of Intratracheal Adeno-Associated Virus Administration to Newborn Rats
Fleurence, E., Rivière, C., Lacaze-Masmonteil, T., Franco-Motoya, M.-L., Waszak, P., Bourbon, J., Danos, O., Douar, A., & Delacourt, C. (2005) · Human Gene Therapy · doi:10.1089/hum.2005.16.1298 · Cited by 8 · see citing works
Porter, J. M., Oswald, M. S., Sharma, A., Emmanuel, S., Kansol, A., Bennett, A., McKenna, R., & Smith, J. G. (2023) · Journal of Virology · doi:10.1128/jvi.00060-23 · Cited by 7 · see citing works
“All viruses and defensins were diluted in serum-free DMEM (SFM) supplemented with 1 mM doxorubicin (Dox), which has been shown to increase AAV transduction (60).”
Method
- Authors
- Yan, Z., Zak, R., Zhang, Y., Ding, W., Godwin, S., Munson, K., Peluso, R., & Engelhardt, J. F.
- Affiliations
- University of Iowa (US)
- Department of Anatomy and Cell Biology
- Targeted Genetics Corporation, Seattle, Washington 98101
- Corresponding author
- Engelhardt, John F.
- Venue
- Journal of Virology
- Publisher
- American Society for Microbiology
- Published
- 2004-03-15
- Volume
- 78
- Issue
- 6
- Pages
- 2863-2874
- ISSN
- 0022-538X (ISSN-L)
- 1098-5514
- PMC
- PMC353734
- OpenAlex
- W1982346550
- Cited by
- 138
- References
- 0
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 7 · 2023: 7 · 2022: 4 · 2021: 3 · 2020: 8 · 2019: 7 · 2018: 6 · 2017: 1 · 2016: 5 · 2015: 3 · 2014: 4 · 2013: 5 · 2012: 6
- FWCI
- 6.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Virology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL058340, R01 HL58340)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK54759, P30DK054759)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- proteasome inhibitors, adeno-associated virus type 2, doxorubicin, aclarubicin, Lawrence Livermore National Laboratory
- MeSH terms
- Dependovirus, Animals, Cell Line, Cysteine Endopeptidases, Cystic Fibrosis, Doxorubicin, Epithelial Cells, Humans, Leupeptins, Lung, Mice, Inbred C57BL, Multienzyme Complexes, Parvoviridae Infections, Recombination, Genetic, Transduction, Genetic, Aclarubicin, Genetic Therapy, Cysteine Proteinase Inhibitors, Cell Polarity, Proteasome Endopeptidase Complex, Mice
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
