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Current Gene Therapy

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ISSN (Print): 1566-5232
ISSN (Online): 1875-5631

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Research Article

Lentiviral Micro-dystrophin Gene Treatment into Late-stage mdx Mice for Duchenne Muscular Dystrophy Disease

Author(s): Selen Abanuz Eren*, Cihan Tastan, Kevser Buse Karadeniz, Raife Dilek Turan, Didem Cakirsoy, Derya Dilek Kancagi, Sevdican Ustun Yilmaz, Mustafa Oztatlici, Hulya Oztatlici, Samed Ozer, Gamze Tumentemur, Ahmet Tarık Baykal and Ercument Ovali

Volume 23, Issue 4, 2023

Published on: 04 May, 2023

Page: [304 - 315] Pages: 12

DOI: 10.2174/1566523223666230407091317

Price: $65

Abstract

Aim: Duchenne Muscular Dystrophy (DMD) results in a deficiency of dystrophin expression in patient muscle fibers, leading to progressive muscle degeneration. Treatment of DMD has undertaken current transformation with the advancement of novel gene therapy and molecular biology techniques, which are secure, well-tolerated, and effective therapeutic approaches.

Introduction: DMD gene therapies have mainly focused on young DMD patients as in vivo animal model trials have been performed in 0–1-month DMD mice. However, it has not yet been answered how micro-dystrophin encoding lentiviral treatment affects Dystrophin expression and DMD symptoms in 10-month mdx mice.

Methods: We planned to integrate the micro-Dystrophin gene sequence into the muscle cells by viral transfer, using micro-Dystrophin-encoding lentivirus to reduce the dystrophic pathology in late-stage dmd mice. The histopathological and physiological-functional regeneration activities of the lentiviralmicro- Dystrophin gene therapy methods were compared, along with changes in temporal Dystrophin expression and their functionality, toxicity, and gene expression level.

Results: Here, we showed that the micro-dystrophin transgene transfers intramuscularly and intraperitoneally in late-stage dmd-mdx-4cv mice restored dystrophin expression in the skeletal and cardiac muscle (p <0.001). Furthermore, motor performance analysis, including hanging and tracking tests, improved statistically significantly after the treatment (p <0.05).

Conclusion: Consequently, this study suggests that patients in the late stages of muscular dystrophy can benefit from lentiviral micro-dystrophin gene therapies to present an improvement in dystrophic muscle pathology.

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Graphical Abstract

[1]
Mah JK, Korngut L, Dykeman J, Day L, Pringsheim T, Jette N. A systematic review and meta-analysis on the epidemiology of Duchenne and Becker muscular dystrophy. Neuromuscul Disord 2014; 24(6): 482-91.
[http://dx.doi.org/10.1016/j.nmd.2014.03.008] [PMID: 24780148]
[2]
Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: Diagnosis, and pharmaco-logical and psychosocial management. Lancet Neurol 2010; 9(1): 77-93.
[http://dx.doi.org/10.1016/S1474-4422(09)70271-6] [PMID: 19945913]
[3]
Hoffman EP, Brown RH Jr, Kunkel LM. Dystrophin: The protein product of the duchenne muscular dystrophy locus. Cell 1987; 51(6): 919-28.
[http://dx.doi.org/10.1016/0092-8674(87)90579-4] [PMID: 3319190]
[4]
Ervasti JM, Campbell KP. A role for the dystrophin-glycoprotein complex as a transmembrane linker between laminin and actin. J Cell Biol 1993; 122(4): 809-23.
[http://dx.doi.org/10.1083/jcb.122.4.809] [PMID: 8349731]
[5]
Mariol MC, Ségalat L. Muscular degeneration in the absence of dystrophin is a calcium-dependent process. Curr Biol 2001; 11(21): 1691-4.
[http://dx.doi.org/10.1016/S0960-9822(01)00528-0] [PMID: 11696327]
[6]
The molecular basis for Duchenne versus Becker muscular dystrophy: correlation of severity with type of deletion. Am J Hum Genet 1989; 45(4): 498-506.
[7]
Ervasti JM. Structure and function of the dystrophin-glycoprotein complex. In: Molecular Mechanisms of Muscular Dystrophies. Georgetown: Landes Biosciences 2006; pp. 1-13.
[8]
Rando TA. The dystrophin-glycoprotein complex, cellular signaling, and the regulation of cell survival in the muscular dystrophies. Muscle Nerve 2001; 24(12): 1575-94.
[http://dx.doi.org/10.1002/mus.1192] [PMID: 11745966]
[9]
Petrof BJ, Shrager JB, Stedman HH, Kelly AM, Sweeney HL. Dystrophin protects the sarcolemma from stresses developed during mus-cle contraction. Proc Natl Acad Sci USA 1993; 90(8): 3710-4.
[http://dx.doi.org/10.1073/pnas.90.8.3710] [PMID: 8475120]
[10]
Deconinck N, Dan B. Pathophysiology of duchenne muscular dystrophy: Current hypotheses. Pediatr Neurol 2007; 36(1): 1-7.
[http://dx.doi.org/10.1016/j.pediatrneurol.2006.09.016] [PMID: 17162189]
[11]
Ramos J, Chamberlain JS. Gene therapy for Duchenne muscular dystrophy. Expert Opin Orphan Drugs 2015; 3(11): 1255-66.
[http://dx.doi.org/10.1517/21678707.2015.1088780] [PMID: 26594599]
[12]
Dumont NA, Wang YX, von Maltzahn J, et al. Dystrophin expression in muscle stem cells regulates their polarity and asymmetric divi-sion. Nat Med 2015; 21(12): 1455-63.
[http://dx.doi.org/10.1038/nm.3990] [PMID: 26569381]
[13]
Counsell JR, Asgarian Z, Meng J, Ferrer V, Vink CA, Howe SJ. Lentiviral vectors can be used for full-length dystrophin gene therapy. Sci Rep 2017; 7(1): 1-10.
[14]
Annoni A, Brown BD, Cantore A, Sergi LS, Naldini L, Roncarolo MG. In vivo delivery of a microRNA-regulated transgene induces anti-gen-specific regulatory T cells and promotes immunologic tolerance. Blood 2009; 114(25): 5152-61.
[http://dx.doi.org/10.1182/blood-2009-04-214569] [PMID: 19794140]
[15]
Bostick B, Yue Y, Lai Y, Long C, Li D, Duan D. Adeno-associated virus serotype-9 microdystrophin gene therapy ameliorates electro-cardiographic abnormalities in mdx mice. Hum Gene Ther 2008; 19(8): 851-6.
[http://dx.doi.org/10.1089/hum.2008.058] [PMID: 18666839]
[16]
Lai Y, Thomas GD, Yue Y, et al. Dystrophins carrying spectrin-like repeats 16 and 17 anchor nNOS to the sarcolemma and enhance exercise performance in a mouse model of muscular dystrophy. J Clin Invest 2009; 119(3): 624-35.
[http://dx.doi.org/10.1172/JCI36612] [PMID: 19229108]
[17]
Shin JH, Hakim CH, Zhang K, Duan D. Genotyping mdx, mdx3cv, and mdx4cv mice by primer competition polymerase chain reaction. Muscle Nerve 2011; 43(2): 283-6.
[http://dx.doi.org/10.1002/mus.21873] [PMID: 21254096]
[18]
Lefaucheur JP, Pastoret C, Sebille A. Phenotype of dystrophinopathy in old mdx mice. Anat Rec 1995; 242(1): 70-6.
[19]
Pastoret C, Sebille A. mdx mice show progressive weakness and muscle deterioration with age. J Neurol Sci 1995; 129(2): 97-105.
[http://dx.doi.org/10.1016/0022-510X(94)00276-T] [PMID: 7608742]
[20]
Lynch GS, Hinkle RT, Chamberlain JS, Brooks SV, Faulkner JA. Force and power output of fast and slow skeletal muscles from mdx mice 6‐28 months old. J Physiol 2001; 535(2): 591-600.
[http://dx.doi.org/10.1111/j.1469-7793.2001.00591.x] [PMID: 11533147]
[21]
Judge LM, Arnett ALH, Banks GB, Chamberlain JS. Expression of the dystrophin isoform Dp116 preserves functional muscle mass and extends lifespan without preventing dystrophy in severely dystrophic mice. Hum Mol Genet 2011; 20(24): 4978-90.
[http://dx.doi.org/10.1093/hmg/ddr433] [PMID: 21949353]
[22]
Gaedigk R, Law DJ, Fitzgerald-Gustafson KM, et al. Improvement in survival and muscle function in an mdx/utrn−/− double mutant mouse using a human retinal dystrophin transgene. Neuromuscul Disord 2006; 16(3): 192-203.
[http://dx.doi.org/10.1016/j.nmd.2005.12.007] [PMID: 16487708]
[23]
Manning J, O’Malley D. What has the mdx mouse model of duchenne muscular dystrophy contributed to our understanding of this dis-ease? J Muscle Res Cell Motil 2015; 36(2): 155-67.
[http://dx.doi.org/10.1007/s10974-015-9406-4] [PMID: 25669899]
[24]
Cros D, Harnden P, Pellissier JF, Serratrice G. Muscle hypertrophy in Duchenne muscular dystrophy. J Neurol 1989; 236(1): 43-7.
[http://dx.doi.org/10.1007/BF00314217] [PMID: 2915226]
[25]
Marques MJ, Oggiam DS, Barbin ICC, Ferretti R, Santo Neto H. Long-term therapy with deflazacort decreases myocardial fibrosis in mdx mice. Muscle Nerve 2009; 40(3): 466-8.
[http://dx.doi.org/10.1002/mus.21341] [PMID: 19623634]
[26]
Kimura E, Han JJ, Li S, et al. Cell-lineage regulated myogenesis for dystrophin replacement: a novel therapeutic approach for treatment of muscular dystrophy. Hum Mol Genet 2008; 17(16): 2507-17.
[http://dx.doi.org/10.1093/hmg/ddn151] [PMID: 18511457]
[27]
Stewart SA, Dykxhoorn DM, Palliser D, et al. Lentivirus-delivered stable gene silencing by RNAi in primary cells. RNA 2003; 9(4): 493-501.
[http://dx.doi.org/10.1261/rna.2192803] [PMID: 12649500]
[28]
Taştan C, Kançağı DD, Turan RD, et al. Preclinical assessment of efficacy and safety analysis of car-t cells (Isikok-19) targeting cd19-expressing b-cells for the first turkish academic clinical trial with relapsed/refractory all and nhl patients. Turk J Haematol 2020; 37(4): 234-47.
[http://dx.doi.org/10.4274/tjh.galenos.2020.2020.0070] [PMID: 32755128]
[29]
Zhao Y, Stepto H, Schneider CK. Development of the first world health organization lentiviral vector standard: Toward the production control and standardization of lentivirus-based gene therapy products. Hum Gene Ther Methods 2017; 28(4): 205-14.
[http://dx.doi.org/10.1089/hgtb.2017.078] [PMID: 28747142]
[30]
Cornetta K, Yao J, Jasti A, et al. Replication-competent lentivirus analysis of clinical grade vector products. Mol Ther 2011; 19(3): 557-66.
[http://dx.doi.org/10.1038/mt.2010.278] [PMID: 21179010]
[31]
Agudo J, Ruzo A, Kitur K, Sachidanandam R, Blander JM, Brown BD. A TLR and non-TLR mediated innate response to lentiviruses restricts hepatocyte entry and can be ameliorated by pharmacological blockade. Mol Ther 2012; 20(12): 2257-67.
[http://dx.doi.org/10.1038/mt.2012.150] [PMID: 22871668]
[32]
Aartsma-Rus A, van Putten M. Assessing functional performance in the mdx mouse model. J Vis Exp 2014.
[33]
Kawano R, Ishizaki M, Maeda Y, Uchida Y, Kimura E, Uchino M. Transduction of full-length dystrophin to multiple skeletal muscles improves motor performance and life span in utrophin/dystrophin double knockout mice. Mol Ther 2008; 16(5): 825-31.
[http://dx.doi.org/10.1038/mt.2008.23] [PMID: 18334987]
[34]
Gibbs EM, Crosbie-Watson RH. A simple and low-cost assay for measuring ambulation in mouse models of muscular dystrophy. J Vis Exp 2017; 130: 56772.
[35]
Foster H, Sharp PS, Athanasopoulos T, et al. Codon and mRNA sequence optimization of microdystrophin transgenes improves expres-sion and physiological outcome in dystrophic mdx mice following AAV2/8 gene transfer. Mol Ther 2008; 16(11): 1825-32.
[http://dx.doi.org/10.1038/mt.2008.186] [PMID: 18766174]
[36]
Zatz M, Rapaport D, Vainzof M, et al. Serum creatine-kinase (CK) and pyruvate-kinase (PK) activities in duchenne (DMD) as compared with becker (BMD) muscular dystrophy. J Neurol Sci 1991; 102(2): 190-6.
[http://dx.doi.org/10.1016/0022-510X(91)90068-I] [PMID: 2072118]
[37]
Duan D. Micro-dystrophin gene therapy goes systemic in duchenne muscular dystrophy patients. Hum Gene Ther 2018; 29(7): 733-6.
[http://dx.doi.org/10.1089/hum.2018.012] [PMID: 29463117]
[38]
Dellorusso C, Crawford RW, Chamberlain JS, Brooks SV. Tibialis anterior muscles in mdx mice are highly susceptible to contraction-induced injury. J Muscle Res Cell Motil 2001; 22(5): 467-75.
[http://dx.doi.org/10.1023/A:1014587918367] [PMID: 11964072]
[39]
Chu X, Li J, Qiao C, et al. Long‐term effect of human mini‐dystrophin in transgenic mdx mice improves muscle physiological function. FASEB J 2021; 35(6): e21628.
[http://dx.doi.org/10.1096/fj.202100057RR] [PMID: 33982338]
[40]
Isaac C, Wright A, Usas A, et al. Dystrophin and utrophin “double knockout” dystrophic mice exhibit a spectrum of degenerative mus-culoskeletal abnormalities. J Orthop Res 2013; 31(3): 343-9.
[http://dx.doi.org/10.1002/jor.22236] [PMID: 23097179]
[41]
Wang JW, Song M, He YH, Gong HR. Stability, adsorption, and diffusion of hydrogen in Pd3Ag phases. J Membr Sci 2016; 503: 124-31.
[http://dx.doi.org/10.1016/j.memsci.2015.11.021]
[42]
Long C, Amoasii L, Mireault AA, McAnally JR, Li H, Sanchez-Ortiz E. Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy. Science 2016; 351(6271): 400-3.
[43]
Crawford GE, Faulkner JA, Crosbie RH, Campbell KP, Froehner SC, Chamberlain JS. Assembly of the dystrophin-associated protein complex does not require the dystrophin COOH-terminal domain. J Cell Biol 2000; 150(6): 1399-410.
[http://dx.doi.org/10.1083/jcb.150.6.1399] [PMID: 10995444]

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