General Research Article

Effect of Proteasome Inhibitors on the AAV-Mediated Transduction Efficiency in Retinal Bipolar Cells

Author(s): Shengjie Cui*, Tushar H. Ganjawala, Gary W. Abrams and Zhuo-Hua Pan*

Volume 19, Issue 6, 2019

Page: [404 - 412] Pages: 9

DOI: 10.2174/1566523220666200211111326

Price: $65


Background: Adeno-associated Virus (AAV) vectors are the most promising vehicles for therapeutic gene delivery to the retina. To develop a practical gene delivery tool, achieving high AAV transduction efficiency in specific cell types is often required. AAV-mediated targeted expression in retinal bipolar cells is needed in certain applications such as optogenetic therapy, however, the transduction efficiency driven by endogenous cell-specific promoters is usually low. Methods that can improve AAV transduction efficiency in bipolar cells need to be developed.

Objective: The study aimed to examine the effect of proteasome inhibitors on AAV-mediated transduction efficiency in retinal bipolar cells.

Methods: Quantitative analysis of fluorescent reporter protein expression was performed to assess the effect of two proteasome inhibitors, doxorubicin and MG132, on AAV-mediated transduction efficiency in retinal bipolar cells in mice.

Results: Our results showed that doxorubicin can increase the AAV transduction efficiency in retinal bipolar cells in a dose-dependent manner. We also observed doxorubicin-mediated cytotoxicity in retinal neurons, but the cytotoxicity could be mitigated by the coapplication of dexrazoxane. Three months after the coapplication of doxorubicin (300 μM) and dexrazoxane, the AAV transduction efficiency in retinal bipolar cells increased by 33.8% and no cytotoxicity was observed in all the layers of the retina.

Conclusion: Doxorubicin could enhance the AAV transduction efficiency in retinal bipolar cells in vivo. The potential long-term cytotoxicity caused by doxorubicin to retinal neurons could be partially mitigated by dexrazoxane. The coapplication of doxorubicin and dexrazoxane may serve as a potential adjuvant regimen for improving AAV transduction efficiency in retinal bipolar cells.

Keywords: Adeno-associated virus, retinal gene therapy, doxorubicin, dexrazoxane, retina, bipolar cells.

Graphical Abstract
Vandenberghe LH, Auricchio A. Novel adeno-associated viral vectors for retinal gene therapy. Gene Ther 2012; 19(2): 162-8.
[] [PMID: 21993172]
Dalkara D, Sahel JA. Gene therapy for inherited retinal degenerations. C R Biol 2014; 337(3): 185-92.
[] [PMID: 24702845]
Buch PK, Bainbridge JW, Ali RR. AAV-mediated gene therapy for retinal disorders: from mouse to man. Gene Ther 2008; 15(11): 849-57.
[] [PMID: 18418417]
Wang D, Tai PWL, Gao G. Adeno-associated virus vector as a platform for gene therapy delivery. Nat Rev Drug Discov 2019; 18(5): 358-78.
[] [PMID: 30710128]
Naso MF, Tomkowicz B, Perry WL, Strohl WR. Adeno-Associated Virus (AAV) as a vector for gene therapy. BioDrugs 2017; 31(4): 317-34.
[] [PMID: 28669112]
Surace EM, Auricchio A. Versatility of AAV vectors for retinal gene transfer. Vision Res 2008; 48(3): 353-9.
[] [PMID: 17923143]
McClements ME, MacLaren RE. Gene therapy for retinal disease. Transl Res 2013; 161(4): 241-54.
[] [PMID: 23305707]
Boyd RF, Sledge DG, Boye SL, et al. Photoreceptor-targeted gene delivery using intravitreally administered AAV vectors in dogs. Gene Ther 2016; 23(2): 223-30.
[] [PMID: 26467396]
Macé E, Caplette R, Marre O, et al. Targeting channelrhodopsin-2 to ON-bipolar cells with vitreally administered AAV Restores on and off visual responses in blind mice. Mol Ther 2015; 23(1): 7-16.
Lu Q, Ganjawala TH, Ivanova E, Cheng JG, Troilo D, Pan ZH. AAV-mediated transduction and targeting of retinal bipolar cells with improved mGluR6 promoters in rodents and primates. Gene Ther 2016; 23(8-9): 680-9.
[] [PMID: 27115727]
Hanlon KS, Chadderton N, Palfi A, et al. A novel retinal ganglion cell promoter for utility in AAV vectors. Front Neurosci 2017; 11: 521.
[] [PMID: 28983234]
Chaffiol A, Caplette R, Jaillard C, et al. A new promoter allows optogenetic vision restoration with enhanced sensitivity in macaque retina. Mol Ther 2017; 25(11): 2546-60.
Sun X, Pawlyk B, Xu X, et al. Gene therapy with a promoter targeting both rods and cones rescues retinal degeneration caused by AIPL1 mutations. Gene Ther 2010; 17(1): 117-31.
[] [PMID: 19710705]
Khani SC, Pawlyk BS, Bulgakov OV, et al. AAV-mediated expression targeting of rod and cone photoreceptors with a human rhodopsin kinase promoter. Invest Ophthalmol Vis Sci 2007; 48(9): 3954-61.
[] [PMID: 17724172]
Jüttner J, Szabo A, Gross-Scherf B, et al. Targeting neuronal and glial cell types with synthetic promoter AAVs in mice, non-human primates and humans. Nat Neurosci 2019; 22(8): 1345-56.
[] [PMID: 31285614]
Lagali PS, Balya D, Awatramani GB, et al. Light-activated channels targeted to ON bipolar cells restore visual function in retinal degeneration. Nat Neurosci 2008; 11(6): 667-75.
[] [PMID: 18432197]
Doroudchi MM, Greenberg KP, Liu J, et al. Virally delivered channelrhodopsin-2 safely and effectively restores visual function in multiple mouse models of blindness. Mol Ther 2011; 19(7): 1220-9.
Cronin T, Vandenberghe LH, Hantz P, et al. Efficient transduction and optogenetic stimulation of retinal bipolar cells by a synthetic adeno-associated virus capsid and promoter. EMBO Mol Med 2014; 6(9): 1175-90.
[] [PMID: 25092770]
van Wyk M, Pielecka-Fortuna J, Löwel S, Kleinlogel S. Restoring the ON switch in blind retinas: Opto-mGluR6, a next-generation, cell-tailored optogenetic tool. PLoS Biol 2015; 13(5)e1002143
[] [PMID: 25950461]
Klapper SD, Swiersy A, Bamberg E, Busskamp V. Biophysical properties of optogenetic tools and their application for vision restoration approaches. Front Syst Neurosci 2016; 10: 74.
[] [PMID: 27642278]
Busskamp V, Picaud S, Sahel JA, Roska B. Optogenetic therapy for retinitis pigmentosa. Gene Ther 2012; 19(2): 169-75.
[] [PMID: 21993174]
Pan ZH, Lu Q, Bi A, Dizhoor AM, Abrams GW. Optogenetic Approaches to restoring vision. Annu Rev Vis Sci 2015; 1: 185-210.
[] [PMID: 28532375]
Kim DS, Matsuda T, Cepko CL. A core paired-type and POU homeodomain-containing transcription factor program drives retinal bipolar cell gene expression. J Neurosci 2008; 28(31): 7748-64.
[] [PMID: 18667607]
Powell SK, Rivera-Soto R, Gray SJ. Viral expression cassette elements to enhance transgene target specificity and expression in gene therapy. Discov Med 2015; 19(102): 49-57.
[PMID: 25636961]
Nonnenmacher M, Weber T. Intracellular transport of recombinant adeno-associated virus vectors. Gene Ther 2012; 19(6): 649-58.
[] [PMID: 22357511]
Dalkara D, Kolstad KD, Caporale N, et al. Inner limiting membrane barriers to AAV-mediated retinal transduction from the vitreous. Mol Ther 2009; 17(12): 2096-102.
[] [PMID: 19672248]
Ding W, Zhang L, Yan Z, Engelhardt JF. Intracellular trafficking of adeno-associated viral vectors. Gene Ther 2005; 12(11): 873-80.
[] [PMID: 15829993]
Douar AM, Poulard K, Stockholm D, Danos O. Intracellular trafficking of adeno-associated virus vectors: routing to the late endosomal compartment and proteasome degradation. J Virol 2001; 75(4): 1824-33.
[] [PMID: 11160681]
Petrs-Silva H, Dinculescu A, Li Q, et al. High-efficiency transduction of the mouse retina by tyrosine-mutant AAV serotype vectors. Mol Ther 2009; 17(3): 463-71.
Kay CN, Ryals RC, Aslanidi GV, et al. Targeting photoreceptors via intravitreal delivery using novel, capsid-mutated AAV vectors. PLoS One 2013; 8(4)e62097
[] [PMID: 23637972]
Petrs-Silva H, Dinculescu A, Li Q, et al. Novel properties of tyrosine-mutant AAV2 vectors in the mouse retina. Mol Ther 2011; 19(2): 293-301.
Han YH, Moon HJ, You BR, Park WH. The effect of MG132, a proteasome inhibitor on HeLa cells in relation to cell growth, reactive oxygen species and GSH. Oncol Rep 2009; 22(1): 215-21.
[PMID: 19513526]
Guo N, Peng Z. MG132, a proteasome inhibitor, induces apoptosis in tumor cells. Asia Pac J Clin Oncol 2013; 9(1): 6-11.
[] [PMID: 22897979]
Kisselev AF, Goldberg AL. Proteasome inhibitors: from research tools to drug candidates. Chem Biol 2001; 8(8): 739-58.
[] [PMID: 11514224]
Liu J, Zheng H, Tang M, Ryu YC, Wang X. A therapeutic dose of doxorubicin activates ubiquitin-proteasome system-mediated proteolysis by acting on both the ubiquitination apparatus and proteasome. Am J Physiol Heart Circ Physiol 2008; 295(6): H2541-50.
[] [PMID: 18978187]
Ortiz-Lazareno PC, Bravo-Cuellar A, Lerma-Díaz JM, et al. Sensitization of U937 leukemia cells to doxorubicin by the MG132 proteasome inhibitor induces an increase in apoptosis by suppressing NF-kappa B and mitochondrial membrane potential loss. Cancer Cell Int 2014; 14(1): 13.
[] [PMID: 24495648]
Yan Z, Zak R, Luxton GW, Ritchie TC, Bantel-Schaal U, Engelhardt JF. Ubiquitination of both adeno-associated virus type 2 and 5 capsid proteins affects the transduction efficiency of recombinant vectors. J Virol 2002; 76(5): 2043-53.
[] [PMID: 11836382]
Yan Z, Zak R, Zhang Y, et al. 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. J Virol 2004; 78(6): 2863-74.
[] [PMID: 14990705]
Zhang T, Hu J, Ding W, Wang X. Doxorubicin augments rAAV-2 transduction in rat neuronal cells. Neurochem Int 2009; 55(7): 521-8.
[] [PMID: 19450628]
Gammella E, Maccarinelli F, Buratti P, Recalcati S, Cairo G. The role of iron in anthracycline cardiotoxicity. Front Pharmacol 2014; 5: 25.
[] [PMID: 24616701]
Kwok JC, Richardson DR. The cardioprotective effect of the iron chelator dexrazoxane (ICRF-187) on anthracycline-mediated cardiotoxicity. Redox Rep 2000; 5(6): 317-24.
[] [PMID: 11140743]
Ichikawa Y, Ghanefar M, Bayeva M, et al. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J Clin Invest 2014; 124(2): 617-30.
[] [PMID: 24382354]
Zhao L, Dai J, Wu Q. Autophagy-like processes are involved in lipid droplet degradation in Auxenochlorella protothecoides during the heterotrophy-autotrophy transition. Front Plant Sci 2014; 5: 400.
[] [PMID: 25177326]
Jeon CJ, Strettoi E, Masland RH. The major cell populations of the mouse retina. J Neurosci 1998; 18(21): 8936-46.
[] [PMID: 9786999]
Kumar S, Marfatia R, Tannenbaum S, Yang C, Avelar E. Doxorubicin-induced cardiomyopathy 17 years after chemotherapy. Tex Heart Inst J 2012; 39(3): 424-7.
[PMID: 22719160]
Steinherz LJ, Steinherz PG, Tan CT, Heller G, Murphy ML. Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA 1991; 266(12): 1672-7.
[] [PMID: 1886191]
Longhi A, Ferrari S, Bacci G, Specchia S. Long-term follow-up of patients with doxorubicin-induced cardiac toxicity after chemotherapy for osteosarcoma. Anticancer Drugs 2007; 18(6): 737-44.
[] [PMID: 17762406]
Lopes MA, Meisel A, Dirnagl U, Carvalho FD, Bastos MdeL. Doxorubicin induces biphasic neurotoxicity to rat cortical neurons. Neurotoxicology 2008; 29(2): 286-93.
[] [PMID: 18258305]
Muindi JR, Sinha BK, Gianni L, Myers CE. Hydroxyl radical production and DNA damage induced by anthracycline-iron complex. FEBS Lett 1984; 172(2): 226-30.
[] [PMID: 6086388]
Buss JL, Hasinoff BB. The one-ring open hydrolysis product intermediates of the cardioprotective agent ICRF-187 (dexrazoxane) displace iron from iron-anthracycline complexes. Agents Actions 1993; 40(1-2): 86-95.
[] [PMID: 8147274]
Imondi AR, Della Torre P, Mazué G, et al. Dose-response relationship of dexrazoxane for prevention of doxorubicin-induced cardiotoxicity in mice, rats, and dogs. Cancer Res 1996; 56(18): 4200-4.
[PMID: 8797592]
Octavia Y, Tocchetti CG, Gabrielson KL, Janssens S, Crijns HJ, Moens AL. Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies. J Mol Cell Cardiol 2012; 52(6): 1213-25.
[] [PMID: 22465037]
Kim SY, Kim SJ, Kim BJ, et al. Doxorubicin-induced reactive oxygen species generation and intracellular Ca2+ increase are reciprocally modulated in rat cardiomyocytes. Exp Mol Med 2006; 38(5): 535-45.
[] [PMID: 17079870]
Singal PK, Iliskovic N. Doxorubicin-induced cardiomyopathy. N Engl J Med 1998; 339(13): 900-5.
[] [PMID: 9744975]
Sanlioglu S, Engelhardt JF. Cellular redox state alters recombinant adeno-associated virus transduction through tyrosine phosphatase pathways. Gene Ther 1999; 6(8): 1427-37.
[] [PMID: 10467367]
Hasinoff BB, Kuschak TI, Yalowich JC, Creighton AM. A QSAR study comparing the cytotoxicity and DNA topoisomerase II inhibitory effects of bisdioxopiperazine analogs of ICRF-187 (dexrazoxane). Biochem Pharmacol 1995; 50(7): 953-8.
[] [PMID: 7575679]
Deng S, Yan T, Nikolova T, et al. The catalytic topoisomerase II inhibitor dexrazoxane induces DNA breaks, ATF3 and the DNA damage response in cancer cells. Br J Pharmacol 2015; 172(9): 2246-57.
[] [PMID: 25521189]
Hasinoff BB, Abram ME, Chee GL, et al. The catalytic DNA topoisomerase II inhibitor dexrazoxane (ICRF-187) induces endopolyploidy in Chinese hamster ovary cells. J Pharmacol Exp Ther 2000; 295(2): 474-83.
[PMID: 11046078]
Hensley ML, Hagerty KL, Kewalramani T, et al. American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants. J Clin Oncol 2009; 27(1): 127-45.
[] [PMID: 19018081]
Reichardt P, Tabone MD, Mora J, Morland B, Jones RL. Risk-benefit of dexrazoxane for preventing anthracycline-related cardiotoxicity: re-evaluating the European labeling. Future Oncol 2018; 14(25): 2663-76.
[] [PMID: 29747541]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy