Research Article

Reduction of Autophagic Accumulation in Pompe Disease Mouse Model Following Gene Therapy

Author(s): Angela L. McCall*, Sylvia G. Stankov, Gabrielle Cowen, Denise Cloutier, Zizhao Zhang, Lin Yang, Nathalie Clement, Darin J. Falk and Barry J. Byrne*

Volume 19, Issue 3, 2019

Page: [197 - 207] Pages: 11

DOI: 10.2174/1566523219666190621113807

Abstract

Background: Pompe disease is a fatal neuromuscular disorder caused by a deficiency in acid α-glucosidase, an enzyme responsible for glycogen degradation in the lysosome. Currently, the only approved treatment for Pompe disease is enzyme replacement therapy (ERT), which increases patient survival, but does not fully correct the skeletal muscle pathology. Skeletal muscle pathology is not corrected with ERT because low cation-independent mannose-6-phosphate receptor abundance and autophagic accumulation inhibits the enzyme from reaching the lysosome. Thus, a therapy that more efficiently targets skeletal muscle pathology, such as adeno-associated virus (AAV), is needed for Pompe disease.

Objective: The goal of this project was to deliver a rAAV9-coGAA vector driven by a tissue restrictive promoter will efficiently transduce skeletal muscle and correct autophagic accumulation.

Methods: Thus, rAAV9-coGAA was intravenously delivered at three doses to 12-week old Gaa-/- mice. 1 month after injection, skeletal muscles were biochemically and histologically analyzed for autophagy-related markers.

Results: At the highest dose, GAA enzyme activity and vacuolization scores achieved therapeutic levels. In addition, resolution of autophagosome (AP) accumulation was seen by immunofluorescence and western blot analysis of autophagy-related proteins. Finally, mice treated at birth demonstrated persistence of GAA expression and resolution of lysosomes and APs compared to those treated at 3 months.

Conclusion: In conclusion, a single systemic injection of rAAV9-coGAA ameliorates vacuolar accumulation and prevents autophagic dysregulation.

Keywords: Pompe disease, autophagy, gene therapy, rAAV, GAA, skeletal muscle.

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[1]
Engel AG, Gomez MR, Seybold ME, Lambert EH. The spectrum and diagnosis of acid maltase deficiency. Neuro 1973; 23(1): 95-106.
[http://dx.doi.org/10.1212/WNL.23.1.95] [PMID: 4510595]
[2]
Reuser AJ, Kroos M, Willemsen R, Swallow D, Tager JM, Galjaard H. Clinical diversity in glycogenosis type II. Biosynthesis and in situ localization of acid alpha-glucosidase in mutant fibroblasts. J Clin Invest 1987; 79(6): 1689-99.
[http://dx.doi.org/10.1172/JCI113008] [PMID: 3108320]
[3]
Reuser AJ, Koster JF, Hoogeveen A, Galjaard H. Biochemical, immunological, and cell genetic studies in glycogenosis type II. Am J Hum Genet 1978; 30(2): 132-43.
[PMID: 350041]
[4]
Hers HG. Alpha-Glucosidase deficiency in generalized glycogenstorage disease (Pompe’s disease). Biochem J 1963; 86: 11-6.
[http://dx.doi.org/10.1042/bj0860011] [PMID: 13954110]
[5]
Kroos M, Pomponio RJ, van Vliet L, et al. Update of the pompe disease mutation database with 107 sequence variants and a format for severity rating. Hum Mutat 2008; 29(6): E13-26.
[http://dx.doi.org/10.1002/humu.20745] [PMID: 18425781]
[6]
Klionsky DJ. Autophagy revisited: A conversation with Christian de Duve. Autophagy 2008; 4(6): 740-3.
[http://dx.doi.org/10.4161/auto.6398]
[7]
Reggiori F, Klionsky DJ. Autophagy in the eukaryotic cell. Eukaryot Cell 2002; 1(1): 11-21.
[http://dx.doi.org/10.1128/EC.01.1.11-21.2002] [PMID: 12455967]
[8]
Mijaljica D, Prescott M, Devenish RJ. V-ATPase engagement in autophagic processes. Autoph 2011; 7(6): 666-8.
[http://dx.doi.org/10.4161/auto.7.6.15812] [PMID: 21494095]
[9]
Dunn WA Jr. Studies on the mechanisms of autophagy: Formation of the autophagic vacuole. J Cell Biol 1990; 110(6): 1923-33.
[http://dx.doi.org/10.1083/jcb.110.6.1923] [PMID: 2351689]
[10]
Fukuda T, Ewan L, Bauer M, et al. Dysfunction of endocytic and autophagic pathways in a lysosomal storage disease. Ann Neurol 2006; 59(4): 700-8.
[http://dx.doi.org/10.1002/ana.20807]
[11]
Raben N, Roberts A, Plotz PH. Role of autophagy in the pathogenesis of Pompe disease. Acta Myol 2007; 26(1): 45-8.
[12]
Griffin JL. Infantile acid maltase deficiency. I. Muscle fiber destruction after lysosomal rupture. Virchows Arch B Cell Pathol Incl Mol Pathol 1984; 45(1): 23-36.
[http://dx.doi.org/10.1007/BF02889849] [PMID: 6199885]
[13]
Raben N, Ralston E, Chien Y-H, et al. Differences in the predominance of lysosomal and autophagic pathologies between infants and adults with Pompe disease: Implications for therapy. Mol Genet Metab 2010; 101(4): 324-31.
[http://dx.doi.org/10.1016/j.ymgme.2010.08.001] [PMID: 20801068]
[14]
Raben N, Takikita S, Pittis MG, et al. Deconstructing Pompe disease by analyzing single muscle fibers: To see a world in a grain of sand. Autophagy 2007; 3(6): 546-52.
[http://dx.doi.org/10.4161/auto.4591] [PMID: 17592248]
[15]
Nascimbeni AC, Fanin M, Masiero E, Angelini C, Sandri M. The role of autophagy in the pathogenesis of glycogen storage disease type II (GSDII). Cell Death Differ 2012; 19(10): 1698-708.
[http://dx.doi.org/10.1038/cdd.2012.52] [PMID: 22595755]
[16]
Kishnani PS, Corzo D, Nicolino M, et al. Recombinant human acid [alpha]-glucosidase: Major clinical benefits in infantile-onset Pompe disease. Neurology 2007; 68(2): 99-109.
[17]
Fukuda T, Ahearn M, Roberts A, et al. Autophagy and mistargeting of therapeutic enzyme in skeletal muscle in Pompe disease. Mol Ther 2006; 14(6): 831-9.
[http://dx.doi.org/10.1016/j.ymthe.2006.08.009]
[18]
Hagemans MLC, Winkel LPF, Hop WCJ, Reuser AJ, Van Doorn PA, Van der Ploeg AT. Disease severity in children and adults with Pompe disease related to age and disease duration. Neuro 2005; 64(12): 2139-41.
[http://dx.doi.org/10.1212/01.WNL.0000165979.46537.56] [PMID: 15985590]
[19]
Raben N, Schreiner C, Baum R, et al. Suppression of autophagy permits successful enzyme replacement therapy in a lysosomal storage disorder--murine Pompe disease. Autoph 2010; 6(8): 1078-89.
[http://dx.doi.org/10.4161/auto.6.8.13378] [PMID: 20861693]
[20]
Prater SN, Patel TT, Buckley AF, et al. Skeletal muscle pathology of infantile pompe disease during long-term enzyme replacement therapy. Orphanet J Rare Dis 2013; 8(1): 90.
[http://dx.doi.org/10.1186/1750-1172-8-90] [PMID: 23787031]
[21]
Hermonat PL, Muzyczka N. Use of adeno-associated virus as a mammalian DNA cloning vector: transduction of neomycin resistance into mammalian tissue culture cells. Proc Natl Acad Sci USA 1984; 81(20): 6466-70.
[http://dx.doi.org/10.1073/pnas.81.20.6466] [PMID: 6093102]
[22]
Wang D, Zhong L, Nahid MA, Gao G. The potential of adeno-associated viral vectors for gene delivery to muscle tissue. Expert Opin Drug Deliv 2014; 11(3): 345-64.
[http://dx.doi.org/10.1517/17425247.2014.871258] [PMID: 24386892]
[23]
Kessler PD, Podsakoff GM, Chen X, et al. Gene delivery to skeletal muscle results in sustained expression and systemic delivery of a therapeutic protein. Proc Natl Acad Sci USA 1996; 93(24): 14082-7.
[http://dx.doi.org/10.1073/pnas.93.24.14082] [PMID: 8943064]
[24]
Bowles DE, McPhee SWJ, Li C, et al. Phase 1 gene therapy for Duchenne muscular dystrophy using a translational optimized AAV vector. Mol Ther 2012; 20(2): 443-55.
[http://dx.doi.org/10.1038/mt.2011.237] [PMID: 22068425]
[25]
Smith BK, Collins SW, Conlon TJ, et al. Phase I/II trial of adeno-associated virus-mediated alpha-glucosidase gene therapy to the diaphragm for chronic respiratory failure in Pompe disease: Initial safety and ventilatory outcomes. Hum Gene Ther 2013; 24(6): 630-40.
[26]
Byrne BJ, Falk DJ, Pacak CA, et al. Pompe disease gene therapy. Hum Mol Genet 2011; 20(R1): R61-8.
[http://dx.doi.org/10.1093/hmg/ddr174] [PMID: 21518733]
[27]
Falk DJ, Soustek MS, Todd AG, et al. Comparative impact of AAV and enzyme replacement therapy on respiratory and cardiac function in adult Pompe mice. Mol Ther Methods Clin Dev 2015; 2: 15007.
[http://dx.doi.org/10.1038/mtm.2015.7] [PMID: 26029718]
[28]
Doerfler PA, Todd AG, Clément N, et al. Copackaged AAV9 vectors promote simultaneous immune tolerance and phenotypic correction of pompe disease. Hum Gene Ther 2016; 27(1): 43-59.
[http://dx.doi.org/10.1089/hum.2015.103] [PMID: 26603344]
[29]
Zolotukhin S, Potter M, Zolotukhin I, et al. Production and purification of serotype 1, 2, and 5 recombinant adeno-associated viral vectors. Methods 2002; 28(2): 158-67.
[http://dx.doi.org/10.1016/S1046-2023(02)00220-7] [PMID: 12413414]
[30]
Keeler AM, Zieger M, Todeasa S, et al. Systemic delivery of AAVB1-GAA clears glycogen and prolongs survival in a mouse model of Pompe disease. Hum Gene Ther 2018; 30(1): 57-68.
[31]
Pacak CA, Sakai Y, Thattaliyath BD, et al. Tissue specific promoters improve specificity of AAV9 mediated transgene expression following intra-vascular gene delivery in neonatal mice. Genet Vaccines Ther 2008; 6(1): 13.
[http://dx.doi.org/10.1186/1479-0556-6-13]
[32]
Adamson-Small L, Potter M, Falk DJ, Cleaver B, Byrne BJ, Clément N. A scalable method for the production of high-titer and high-quality adeno-associated type 9 vectors using the HSV platform. Mol Ther Methods Clin Dev 2016; 3(3): 16031.
[http://dx.doi.org/10.1038/mtm.2016.31] [PMID: 27222839]
[33]
Adamson-Small L, Potter M, Byrne BJ, Clément N. Sodium chloride enhances recombinant adeno-associated virus production in a serum-free suspension manufacturing platform using the herpes simplex virus system. Hum Gene Ther Methods 2017; 28(1): 1-14.
[http://dx.doi.org/10.1089/hgtb.2016.151] [PMID: 28117600]
[34]
Bothe GWM, Bolivar VJ, Vedder MJ, Geistfeld JG. Genetic and behavioral differences among five inbred mouse strains commonly used in the production of transgenic and knockout mice. Genes Brain Behav 2004; 3(3): 149-57.
[http://dx.doi.org/10.1111/j.1601-183x.2004.00064.x] [PMID: 15140010]
[35]
Raben N, Nagaraju K, Lee E, et al. Targeted disruption of the acid alpha-glucosidase gene in mice causes an illness with critical features of both infantile and adult human glycogen storage disease type II. J Biol Chem 1998; 273(30): 19086-92.
[http://dx.doi.org/10.1074/jbc.273.30.19086] [PMID: 9668092]
[36]
Gombash Lampe SE, Kaspar BK, Foust KD. Intravenous injections in neonatal mice. J Vis Exp 2014; (93): e52037
[PMID: 25407048]
[37]
Galjaard H, Mekes M, Josselin de Jong JEDE, Niermeijer MF. A method for rapid prenatal diagnosis of glycogenosis II (Pompe’s disease). Clin Chim Acta 1973; 49(3): 361-75.
[http://dx.doi.org/10.1016/0009-8981(73)90234-9] [PMID: 4272965]
[38]
Meng H, Janssen PML, Grange RW, et al. Tissue triage and freezing for models of skeletal muscle disease. J Vis Exp 2014; (89): e51586
[http://dx.doi.org/10.3791/51586] [PMID: 25078247]
[39]
Liu F, Mackey AL, Srikuea R, Esser KA, Yang L. Automated image segmentation of haematoxylin and eosin stained skeletal muscle cross-sections. J Microsc 2013; 252(3): 275-85.
[http://dx.doi.org/10.1111/jmi.12090] [PMID: 24118017]
[40]
Mah C, Cresawn KO, Fraites TJ Jr, et al. Sustained correction of glycogen storage disease type II using adeno-associated virus serotype 1 vectors. Gene Ther 2005; 12(18): 1405-9.
[http://dx.doi.org/10.1038/sj.gt.3302550] [PMID: 15920463]
[41]
Mah CS, Falk DJ, Germain SA, et al. Gel-mediated delivery of AAV1 vectors corrects ventilatory function in Pompe mice with established disease. Mol Ther 2010; 18(3): 502-10.
[http://dx.doi.org/10.1038/mt.2009.305] [PMID: 20104213]
[42]
Burkholder TJ, Fingado B, Baron S, Lieber RL. Relationship between muscle fiber types and sizes and muscle architectural properties in the mouse hindlimb. J Morphol 1994; 221(2): 177-90.
[http://dx.doi.org/10.1002/jmor.1052210207] [PMID: 7932768]
[43]
Augusto V, Padovani CR, Campos GER. Skeletal Muscle Fiber Types in C57BL6J Mice. Braz J Morphol Sci 2004; 21(2): 89-94.
[44]
Scott W, Stevens J, Binder-Macleod SA. Human skeletal muscle fiber type classifications. Phys Ther 2001; 81(11): 1810-6.
[PMID: 11694174]
[45]
Close RI. Dynamic mammalian properties of skeletal muscles. Physiol Rev 1972; 52(1): 129-97.
[http://dx.doi.org/10.1152/physrev.1972.52.1.129] [PMID: 4256989]
[46]
Van den Berg LEM, Drost MR, Schaart G, et al. Muscle fiber-type distribution, fiber-type-specific damage, and the Pompe disease phenotype. J Inherit Metab Dis 2013; 36(5): 787-94.
[http://dx.doi.org/10.1007/s10545-012-9541-7] [PMID: 23053471]
[47]
Maughan RJ, Watson JS, Weir J. Strength and cross-sectional area of human skeletal muscle. J Physiol 1983; 338: 37-49.
[http://dx.doi.org/10.1113/jphysiol.1983.sp014658] [PMID: 6875963]
[48]
Mendell JR, Al-Zaidy S, Shell R, et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med 2017; 377(18): 1713-22.
[http://dx.doi.org/10.1056/NEJMoa1706198] [PMID: 29091557]
[49]
Kuntz N, Shieh PB, Smith B, et al. Abstract 7. Gene therapy trial in X-linked myotubular myopathy (Xlmtm): Preliminary safety and efficacy findings. Mol Ther 2018; 26(5S1). : 4.
[50]
Fukuda T, Roberts A, Ahearn M, et al. Autophagy and lysosomes in pompe disease. Autophagy 2006; 2(4): 318-20.
[http://dx.doi.org/10.4161/auto.2984]
[51]
Takikita S, Schreiner C, Baum R, et al. Fiber type conversion by PGC-1α activates lysosomal and autophagosomal biogenesis in both unaffected and Pompe skeletal muscle. PLoS One 2010; 5(12)e15239
[http://dx.doi.org/10.1371/journal.pone.0015239] [PMID: 21179212]
[52]
Corti M, Liberati C, Smith BK, et al. Safety of intradiaphragmatic delivery of adeno-associated virus-mediated alpha-glucosidase (rAAV1-CMV-hGAA) gene therapy in children affected by pompe disease. Hum Gene Ther Clin Dev 2017; 28(4): 146.
[53]
Bostick B, Ghosh A, Yue Y, Long C, Duan D. Systemic AAV-9 transduction in mice is influenced by animal age but not by the route of administration. Gene Ther 2007; 14(22): 1605-9.
[http://dx.doi.org/10.1038/sj.gt.3303029] [PMID: 17898796]
[54]
Todd AG, McElroy JA, Grange RW, et al. Correcting neuromuscular deficits with gene therapy in pompe disease. Ann Neurol 2015; 78(2): 222-34.
[http://dx.doi.org/10.1002/ana.24433] [PMID: 25925726]
[55]
Chien YH, Chiang SC, Zhang XK, et al. Early detection of Pompe disease by newborn screening is feasible: results from the Taiwan screening program. Pediatrics 2008; 122(1): e39-45.
[http://dx.doi.org/10.1542/peds.2007-2222] [PMID: 18519449]
[56]
Chien Y-HY-H, Lee N-C, Thurberg BL, et al. Pompe disease in infants: Improving the prognosis by newborn screening and early treatment. Pediatrics 2009; 124(6): e1116-25.
[http://dx.doi.org/10.1542/peds.2008-3667] [PMID: 19948615]
[57]
Kishnani PS, Corzo D, Leslie ND, et al. Early treatment with alglucosidase alpha prolongs long-term survival of infants with Pompe disease Pediatr Res NIH Public Access 2009; 66(3): 329-5.

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