Skip to main content
SpringerLink
Log in

Histological and Biochemical Evaluation of Muscle Gene Therapy

  • Chapter
  • First Online:
Muscle Gene Therapy

  • 1127 Accesses

Abstract

The histological and biochemical evaluation of muscle tissue can be of critical importance for the establishment of safety and efficacy in muscle gene therapy studies. While specific pathological and biochemical endpoints vary greatly with respect to disease, most gene therapy studies encounter common challenges associated with study planning, tissue triage, and tissue preparation. This chapter discusses a number of issues related to study planning for the performance of histological and biochemical studies, highlighting our own experience and lessons learned from other studies. Additionally, we illustrate some current approaches using our own experiences in gene therapy studies of X-linked myotubular myopathy (XLMTM) and Duchenne muscular dystrophy (DMD), both of which are now in the human clinical trial stage. The evaluation of endpoints related to important histological features and the expression of key proteins by immunohistochemistry, western blot, and mass spectrometry are discussed in the context of these studies.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Meng H, Janssen PM, Grange RW, Yang L, Beggs AH, Swanson LC, Cossette SA, Frase A, Childers MK, Granzier H, Gussoni E, Lawlor MW (2014) Tissue triage and freezing for models of skeletal muscle disease. J Vis Exp (89):e51586. https://doi.org/10.3791/51586

  2. Dubowitz V, Sewry CA, Oldfors A (2013) Histological and histochemical stains and reactions. In: Dubowitz V, Sewry CA, Oldfors A (eds) Muscle biopsy: a practical approach, 4th edn. Saunders Elsevier, Philadelphia, pp 16–27

    Google Scholar 

  3. Yue Y, Pan X, Hakim CH, Kodippili K, Zhang K, Shin JH, Yang HT, McDonald T, Duan D (2015) Safe and bodywide muscle transduction in young adult Duchenne muscular dystrophy dogs with adeno-associated virus. Hum Mol Genet 24(20):5880–5890. https://doi.org/10.1093/hmg/ddv310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Duan D (2015) Duchenne muscular dystrophy gene therapy in the canine model. Hum Gene Ther Clin Dev 26(1):57–69. https://doi.org/10.1089/humc.2015.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yue Y, Ghosh A, Long C, Bostick B, Smith BF, Kornegay JN, Duan D (2008) A single intravenous injection of adeno-associated virus serotype-9 leads to whole body skeletal muscle transduction in dogs. Mol Ther 16(12):1944–1952. https://doi.org/10.1038/mt.2008.207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Shin JH, Yue Y, Srivastava A, Smith B, Lai Y, Duan D (2012) A simplified immune suppression scheme leads to persistent micro-dystrophin expression in Duchenne muscular dystrophy dogs. Hum Gene Ther 23(2):202–209. https://doi.org/10.1089/hum.2011.147

    Article  CAS  PubMed  Google Scholar 

  7. Lawlor MW, Beggs AH, Buj-Bello A, Childers MK, Dowling JJ, James ES, Meng H, Moore SA, Prasad S, Schoser B, Sewry CA (2016) Skeletal muscle pathology in X-linked myotubular myopathy: review with cross-species comparisons. J Neuropathol Exp Neurol 75(2):102–110. https://doi.org/10.1093/jnen/nlv020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Mack DL, Poulard K, Goddard MA, Latournerie V, Snyder JM, Grange RW, Elverman MR, Denard J, Veron P, Buscara L, Le Bec C, Hogrel JY, Brezovec AG, Meng H, Yang L, Liu F, O’Callaghan M, Gopal N, Kelly VE, Smith BK, Strande JL, Mavilio F, Beggs AH, Mingozzi F, Lawlor MW, Buj-Bello A, Childers MK (2017) Systemic AAV8-mediated gene therapy drives whole-body correction of Myotubular myopathy in dogs. Mol Ther 25(4):839–854. https://doi.org/10.1016/j.ymthe.2017.02.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Rosenberg AS, Puig M, Nagaraju K, Hoffman EP, Villalta SA, Rao VA, Wakefield LM, Woodcock J (2015) Immune-mediated pathology in Duchenne muscular dystrophy. Sci Transl Med 7(299):299rv294. https://doi.org/10.1126/scitranslmed.aaa7322

    Article  CAS  Google Scholar 

  10. Mendell JR, Campbell K, Rodino-Klapac L, Sahenk Z, Shilling C, Lewis S, Bowles D, Gray S, Li C, Galloway G, Malik V, Coley B, Clark KR, Li J, Xiao X, Samulski J, McPhee SW, Samulski RJ, Walker CM (2010) Dystrophin immunity in Duchenne’s muscular dystrophy. N Engl J Med 363(15):1429–1437. https://doi.org/10.1056/NEJMoa1000228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wang B, Li J, Xiao X (2000) Adeno-associated virus vector carrying human minidystrophin genes effectively ameliorates muscular dystrophy in mdx mouse model. Proc Natl Acad Sci U S A 97(25):13714–13719. https://doi.org/10.1073/pnas.240335297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Howell JM, Lochmuller H, O’Hara A, Fletcher S, Kakulas BA, Massie B, Nalbantoglu J, Karpati G (1998) High-level dystrophin expression after adenovirus-mediated dystrophin minigene transfer to skeletal muscle of dystrophic dogs: prolongation of expression with immunosuppression. Hum Gene Ther 9(5):629–634. https://doi.org/10.1089/hum.1998.9.5-629

    Article  CAS  PubMed  Google Scholar 

  13. Gregorevic P, Blankinship MJ, Allen JM, Crawford RW, Meuse L, Miller DG, Russell DW, Chamberlain JS (2004) Systemic delivery of genes to striated muscles using adeno-associated viral vectors. Nat Med 10(8):828–834. https://doi.org/10.1038/nm1085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gregorevic P, Allen JM, Minami E, Blankinship MJ, Haraguchi M, Meuse L, Finn E, Adams ME, Froehner SC, Murry CE, Chamberlain JS (2006) rAAV6-microdystrophin preserves muscle function and extends lifespan in severely dystrophic mice. Nat Med 12(7):787–789. https://doi.org/10.1038/nm1439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lai Y, Thomas GD, Yue Y, Yang HT, Li D, Long C, Judge L, Bostick B, Chamberlain JS, Terjung RL, Duan D (2009) 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 Investig 119(3):624–635. https://doi.org/10.1172/JCI36612

    Article  CAS  PubMed  Google Scholar 

  16. Foster H, Sharp PS, Athanasopoulos T, Trollet C, Graham IR, Foster K, Wells DJ, Dickson G (2008) Codon and mRNA sequence optimization of microdystrophin transgenes improves expression and physiological outcome in dystrophic mdx mice following AAV2/8 gene transfer. Mol Ther 16(11):1825–1832. https://doi.org/10.1038/mt.2008.186

    Article  CAS  PubMed  Google Scholar 

  17. Koo T, Malerba A, Athanasopoulos T, Trollet C, Boldrin L, Ferry A, Popplewell L, Foster H, Foster K, Dickson G (2011) Delivery of AAV2/9-microdystrophin genes incorporating helix 1 of the coiled-coil motif in the C-terminal domain of dystrophin improves muscle pathology and restores the level of alpha1-syntrophin and alpha-dystrobrevin in skeletal muscles of mdx mice. Hum Gene Ther 22(11):1379–1388. https://doi.org/10.1089/hum.2011.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Banks GB, Judge LM, Allen JM, Chamberlain JS (2010) The polyproline site in hinge 2 influences the functional capacity of truncated dystrophins. PLoS Genet 6(5):e1000958. https://doi.org/10.1371/journal.pgen.1000958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lai Y, Zhao J, Yue Y, Duan D (2013) alpha2 and alpha3 helices of dystrophin R16 and R17 frame a microdomain in the alpha1 helix of dystrophin R17 for neuronal NOS binding. Proc Natl Acad Sci U S A 110(2):525–530. https://doi.org/10.1073/pnas.1211431109

    Article  PubMed  Google Scholar 

  20. Shin JH, Pan X, Hakim CH, Yang HT, Yue Y, Zhang K, Terjung RL, Duan D (2013) Microdystrophin ameliorates muscular dystrophy in the canine model of duchenne muscular dystrophy. Mol Ther 21(4):750–757. https://doi.org/10.1038/mt.2012.283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kornegay JN, Li J, Bogan JR, Bogan DJ, Chen C, Zheng H, Wang B, Qiao C, Howard JF Jr, Xiao X (2010) Widespread muscle expression of an AAV9 human mini-dystrophin vector after intravenous injection in neonatal dystrophin-deficient dogs. Mol Ther 18(8):1501–1508. https://doi.org/10.1038/mt.2010.94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Rodino-Klapac LR, Lee JS, Mulligan RC, Clark KR, Mendell JR (2008) Lack of toxicity of alpha-sarcoglycan overexpression supports clinical gene transfer trial in LGMD2D. Neurology 71(4):240–247. https://doi.org/10.1212/01.wnl.0000306309.85301.e2

    Article  CAS  PubMed  Google Scholar 

  23. Mendell JR, Rodino-Klapac LR, Rosales-Quintero X, Kota J, Coley BD, Galloway G, Craenen JM, Lewis S, Malik V, Shilling C, Byrne BJ, Conlon T, Campbell KJ, Bremer WG, Viollet L, Walker CM, Sahenk Z, Clark KR (2009) Limb-girdle muscular dystrophy type 2D gene therapy restores alpha-sarcoglycan and associated proteins. Ann Neurol 66(3):290–297. https://doi.org/10.1002/ana.21732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mendell JR, Rodino-Klapac LR, Rosales XQ, Coley BD, Galloway G, Lewis S, Malik V, Shilling C, Byrne BJ, Conlon T, Campbell KJ, Bremer WG, Taylor LE, Flanigan KM, Gastier-Foster JM, Astbury C, Kota J, Sahenk Z, Walker CM, Clark KR (2010) Sustained alpha-sarcoglycan gene expression after gene transfer in limb-girdle muscular dystrophy, type 2D. Ann Neurol 68(5):629–638. https://doi.org/10.1002/ana.22251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Al-Zaidy S, Rodino-Klapac L, Mendell JR (2014) Gene therapy for muscular dystrophy: moving the field forward. Pediatr Neurol 51(5):607–618. https://doi.org/10.1016/j.pediatrneurol.2014.08.002

    Article  PubMed  PubMed Central  Google Scholar 

  26. Grose WE, Clark KR, Griffin D, Malik V, Shontz KM, Montgomery CL, Lewis S, Brown RH Jr, Janssen PM, Mendell JR, Rodino-Klapac LR (2012) Homologous recombination mediates functional recovery of dysferlin deficiency following AAV5 gene transfer. PLoS One 7(6):e39233. https://doi.org/10.1371/journal.pone.0039233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Krahn M, Wein N, Bartoli M, Lostal W, Courrier S, Bourg-Alibert N, Nguyen K, Vial C, Streichenberger N, Labelle V, DePetris D, Pecheux C, Leturcq F, Cau P, Richard I, Levy N (2010) A naturally occurring human minidysferlin protein repairs sarcolemmal lesions in a mouse model of dysferlinopathy. Sci Transl Med 2(50):50ra69. https://doi.org/10.1126/scitranslmed.3000951

    Article  CAS  PubMed  Google Scholar 

  28. Lostal W, Bartoli M, Bourg N, Roudaut C, Bentaib A, Miyake K, Guerchet N, Fougerousse F, McNeil P, Richard I (2010) Efficient recovery of dysferlin deficiency by dual adeno-associated vector-mediated gene transfer. Hum Mol Genet 19(10):1897–1907. https://doi.org/10.1093/hmg/ddq065

    Article  CAS  PubMed  Google Scholar 

  29. Bengtsson NE, Seto JT, Hall JK, Chamberlain JS, Odom GL (2016) Progress and prospects of gene therapy clinical trials for the muscular dystrophies. Hum Mol Genet 25(R1):R9–R17. https://doi.org/10.1093/hmg/ddv420

    Article  CAS  PubMed  Google Scholar 

  30. Ramos J, Chamberlain JS (2015) Gene therapy for Duchenne muscular dystrophy. Expert Opin Orphan Drugs 3(11):1255–1266. https://doi.org/10.1517/21678707.2015.1088780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bulman DE, Murphy EG, Zubrzycka-Gaarn EE, Worton RG, Ray PN (1991) Differentiation of Duchenne and Becker muscular dystrophy phenotypes with amino- and carboxy-terminal antisera specific for dystrophin. Am J Hum Genet 48(2):295–304

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Byers TJ, Neumann PE, Beggs AH, Kunkel LM (1992) ELISA quantitation of dystrophin for the diagnosis of Duchenne and Becker muscular dystrophies. Neurology 42(3 Pt 1):570–576

    CAS  PubMed  Google Scholar 

  33. Hoffman EP, Kunkel LM, Angelini C, Clarke A, Johnson M, Harris JB (1989) Improved diagnosis of Becker muscular dystrophy by dystrophin testing. Neurology 39(8):1011–1017

    Article  CAS  Google Scholar 

  34. Neri M, Torelli S, Brown S, Ugo I, Sabatelli P, Merlini L, Spitali P, Rimessi P, Gualandi F, Sewry C, Ferlini A, Muntoni F (2007) Dystrophin levels as low as 30% are sufficient to avoid muscular dystrophy in the human. Neuromuscul Disord 17(11–12):913–918. https://doi.org/10.1016/j.nmd.2007.07.005

    Article  PubMed  Google Scholar 

  35. McGreevy JW, Hakim CH, McIntosh MA, Duan D (2015) Animal models of Duchenne muscular dystrophy: from basic mechanisms to gene therapy. Dis Model Mech 8(3):195–213. https://doi.org/10.1242/dmm.018424

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mendell JR, Rodino-Klapac LR, Sahenk Z, Roush K, Bird L, Lowes LP, Alfano L, Gomez AM, Lewis S, Kota J, Malik V, Shontz K, Walker CM, Flanigan KM, Corridore M, Kean JR, Allen HD, Shilling C, Melia KR, Sazani P, Saoud JB, Kaye EM, Eteplirsen Study G (2013) Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol 74(5):637–647. https://doi.org/10.1002/ana.23982

    Article  CAS  PubMed  Google Scholar 

  37. Committee PaCNSDA (2016) FDA Briefing Document, NDA 206488 Eteplirsen

    Google Scholar 

  38. Lawlor MW, Armstrong D, Viola MG, Widrick JJ, Meng H, Grange RW, Childers MK, Hsu CP, O’Callaghan M, Pierson CR, Buj-Bello A, Beggs AH (2013) Enzyme replacement therapy rescues weakness and improves muscle pathology in mice with X-linked myotubular myopathy. Hum Mol Genet 22(8):1525–1538. https://doi.org/10.1093/hmg/ddt003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lawlor MW, Read BP, Edelstein R, Yang N, Pierson CR, Stein MJ, Wermer-Colan A, Buj-Bello A, Lachey JL, Seehra JS, Beggs AH (2011) Inhibition of activin receptor type IIb increases strength and lifespan in myotubularin-deficient mice. Am J Pathol 178(2):784–793. https://doi.org/10.1016/j.ajpath.2010.40.035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lawlor MW, Viola MG, Meng H, Edelstein RV, Liu F, Yan K, Luna EJ, Lerch-Gaggl A, Hoffmann RG, Pierson CR, Buj-Bello A, Lachey JL, Pearsall S, Yang L, Hillard CJ, Beggs AH (2014) Differential muscle hypertrophy is associated with satellite cell numbers and Akt pathway activation following Activin type IIB receptor inhibition in Mtm1 p.R69C mice. Am J Pathol 184(6):1831–1842. https://doi.org/10.1016/j.ajpath.2014.03.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Mendell JR, Sahenk Z, Malik V, Gomez AM, Flanigan KM, Lowes LP, Alfano LN, Berry K, Meadows E, Lewis S, Braun L, Shontz K, Rouhana M, Clark KR, Rosales XQ, Al-Zaidy S, Govoni A, Rodino-Klapac LR, Hogan MJ, Kaspar BK (2015) A phase 1/2a follistatin gene therapy trial for Becker muscular dystrophy. Mol Ther 23(1):192–201. https://doi.org/10.1038/mt.2014.200

    Article  CAS  PubMed  Google Scholar 

  42. Rodino-Klapac LR, Janssen PM, Shontz KM, Canan B, Montgomery CL, Griffin D, Heller K, Schmelzer L, Handy C, Clark KR, Sahenk Z, Mendell JR, Kaspar BK (2013) Micro-dystrophin and follistatin co-delivery restores muscle function in aged DMD model. Hum Mol Genet 22(24):4929–4937. https://doi.org/10.1093/hmg/ddt342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kota J, Handy CR, Haidet AM, Montgomery CL, Eagle A, Rodino-Klapac LR, Tucker D, Shilling CJ, Therlfall WR, Walker CM, Weisbrode SE, Janssen PM, Clark KR, Sahenk Z, Mendell JR, Kaspar BK (2009) Follistatin gene delivery enhances muscle growth and strength in nonhuman primates. Sci Transl Med 1(6):6ra15. https://doi.org/10.1126/scitranslmed.3000112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Thurberg BL, Lynch Maloney C, Vaccaro C, Afonso K, Tsai AC, Bossen E, Kishnani PS, O’Callaghan M (2006) Characterization of pre- and post-treatment pathology after enzyme replacement therapy for Pompe disease. Lab Investig 86(12):1208–1220. https://doi.org/10.1038/labinvest.3700484

    Article  CAS  PubMed  Google Scholar 

  45. Schanzer A, Kaiser AK, Muhlfeld C, Kulessa M, Paulus W, von Pein H, Rohrbach M, Viergutz L, Mengel E, Marquardt T, Neubauer B, Acker T, Hahn A (2017) Quantification of muscle pathology in infantile Pompe disease. Neuromuscul Disord 27(2):141–152. https://doi.org/10.1016/j.nmd.2016.10.010

    Article  PubMed  Google Scholar 

  46. Prater SN, Patel TT, Buckley AF, Mandel H, Vlodavski E, Banugaria SG, Feeney EJ, Raben N, Kishnani PS (2013) Skeletal muscle pathology of infantile Pompe disease during long-term enzyme replacement therapy. Orphanet J Rare Dis 8:90. https://doi.org/10.1186/1750-1172-8-90

    Article  PubMed  PubMed Central  Google Scholar 

  47. van der Ploeg A, Carlier PG, Carlier RY, Kissel JT, Schoser B, Wenninger S, Pestronk A, Barohn RJ, Dimachkie MM, Goker-Alpan O, Mozaffar T, Pena LD, Simmons Z, Straub V, Guglieri M, Young P, Boentert M, Baudin PY, Wens S, Shafi R, Bjartmar C, Thurberg BL (2016) Prospective exploratory muscle biopsy, imaging, and functional assessment in patients with late-onset Pompe disease treated with alglucosidase alfa: the EMBASSY study. Mol Genet Metab 119(1–2):115–123. https://doi.org/10.1016/j.ymgme.2016.05.013

    Article  CAS  PubMed  Google Scholar 

  48. Falk DJ, Todd AG, Lee S, Soustek MS, ElMallah MK, Fuller DD, Notterpek L, Byrne BJ (2015) Peripheral nerve and neuromuscular junction pathology in Pompe disease. Hum Mol Genet 24(3):625–636. https://doi.org/10.1093/hmg/ddu476

    Article  CAS  PubMed  Google Scholar 

  49. Al-Qusairi L, Weiss N, Toussaint A, Berbey C, Messaddeq N, Kretz C, Sanoudou D, Beggs AH, Allard B, Mandel JL, Laporte J, Jacquemond V, Buj-Bello A (2009) T-tubule disorganization and defective excitation-contraction coupling in muscle fibers lacking myotubularin lipid phosphatase. Proc Natl Acad Sci U S A 106(44):18763–18768. https://doi.org/10.1073/pnas.0900705106

    Article  PubMed  PubMed Central  Google Scholar 

  50. Dowling JJ, Vreede AP, Low SE, Gibbs EM, Kuwada JY, Bonnemann CG, Feldman EL (2009) Loss of myotubularin function results in T-tubule disorganization in zebrafish and human myotubular myopathy. PLoS Genet 5(2):e1000372. https://doi.org/10.1371/journal.pgen.1000372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Childers MK, Joubert R, Poulard K, Moal C, Grange RW, Doering JA, Lawlor MW, Rider BE, Jamet T, Daniele N, Martin S, Riviere C, Soker T, Hammer C, Van Wittenberghe L, Lockard M, Guan X, Goddard M, Mitchell E, Barber J, Williams JK, Mack DL, Furth ME, Vignaud A, Masurier C, Mavilio F, Moullier P, Beggs AH, Buj-Bello A (2014) Gene therapy prolongs survival and restores function in murine and canine models of myotubular myopathy. Sci Transl Med 6(220):220ra210. https://doi.org/10.1126/scitranslmed.3007523

    Article  CAS  Google Scholar 

  52. Mays LE, Wilson JM (2011) The complex and evolving story of T cell activation to AAV vector-encoded transgene products. Mol Ther 19(1):16–27. https://doi.org/10.1038/mt.2010.250

    Article  CAS  PubMed  Google Scholar 

  53. Buj-Bello A, Fougerousse F, Schwab Y, Messaddeq N, Spehner D, Pierson CR, Durand M, Kretz C, Danos O, Douar AM, Beggs AH, Schultz P, Montus M, Denefle P, Mandel JL (2008) AAV-mediated intramuscular delivery of myotubularin corrects the myotubular myopathy phenotype in targeted murine muscle and suggests a function in plasma membrane homeostasis. Hum Mol Genet 17(14):2132–2143. https://doi.org/10.1093/hmg/ddn112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Arruda VR, Schuettrumpf J, Herzog RW, Nichols TC, Robinson N, Lotfi Y, Mingozzi F, Xiao W, Couto LB, High KA (2004) Safety and efficacy of factor IX gene transfer to skeletal muscle in murine and canine hemophilia B models by adeno-associated viral vector serotype 1. Blood 103(1):85–92. https://doi.org/10.1182/blood-2003-05-1446

    Article  CAS  PubMed  Google Scholar 

  55. Niemeyer GP, Herzog RW, Mount J, Arruda VR, Tillson DM, Hathcock J, van Ginkel FW, High KA, Lothrop CD Jr (2009) Long-term correction of inhibitor-prone hemophilia B dogs treated with liver-directed AAV2-mediated factor IX gene therapy. Blood 113(4):797–806. https://doi.org/10.1182/blood-2008-10-181479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ferreira V, Twisk J, Kwikkers K, Aronica E, Brisson D, Methot J, Petry H, Gaudet D (2014) Immune responses to intramuscular administration of alipogene tiparvovec (AAV1-LPL(S447X)) in a phase II clinical trial of lipoprotein lipase deficiency gene therapy. Hum Gene Ther 25(3):180–188. https://doi.org/10.1089/hum.2013.169

    Article  CAS  PubMed  Google Scholar 

  57. Ohshima S, Shin JH, Yuasa K, Nishiyama A, Kira J, Okada T, Takeda S (2009) Transduction efficiency and immune response associated with the administration of AAV8 vector into dog skeletal muscle. Mol Ther 17(1):73–80. https://doi.org/10.1038/mt.2008.225

    Article  CAS  PubMed  Google Scholar 

  58. Wang Z, Allen JM, Riddell SR, Gregorevic P, Storb R, Tapscott SJ, Chamberlain JS, Kuhr CS (2007) Immunity to adeno-associated virus-mediated gene transfer in a random-bred canine model of Duchenne muscular dystrophy. Hum Gene Ther 18(1):18–26. https://doi.org/10.1089/hum.2006.093

    Article  CAS  PubMed  Google Scholar 

  59. Wang Z, Kuhr CS, Allen JM, Blankinship M, Gregorevic P, Chamberlain JS, Tapscott SJ, Storb R (2007) Sustained AAV-mediated dystrophin expression in a canine model of Duchenne muscular dystrophy with a brief course of immunosuppression. Mol Ther 15(6):1160–1166. https://doi.org/10.1038/sj.mt.6300161

    Article  CAS  PubMed  Google Scholar 

  60. Wang Z, Storb R, Lee D, Kushmerick MJ, Chu B, Berger C, Arnett A, Allen J, Chamberlain JS, Riddell SR, Tapscott SJ (2010) Immune responses to AAV in canine muscle monitored by cellular assays and noninvasive imaging. Mol Ther 18(3):617–624. https://doi.org/10.1038/mt.2009.294

    Article  CAS  PubMed  Google Scholar 

  61. Yuasa K, Yoshimura M, Urasawa N, Ohshima S, Howell JM, Nakamura A, Hijikata T, Miyagoe-Suzuki Y, Takeda S (2007) Injection of a recombinant AAV serotype 2 into canine skeletal muscles evokes strong immune responses against transgene products. Gene Ther 14(17):1249–1260. https://doi.org/10.1038/sj.gt.3302984

    Article  CAS  PubMed  Google Scholar 

  62. Todd AG, McElroy JA, Grange RW, Fuller DD, Walter GA, Byrne BJ, Falk DJ (2015) Correcting neuromuscular deficits with gene therapy in Pompe disease. Ann Neurol 78(2):222–234. https://doi.org/10.1002/ana.24433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Anthony K, Arechavala-Gomeza V, Taylor LE, Vulin A, Kaminoh Y, Torelli S, Feng L, Janghra N, Bonne G, Beuvin M, Barresi R, Henderson M, Laval S, Lourbakos A, Campion G, Straub V, Voit T, Sewry CA, Morgan JE, Flanigan KM, Muntoni F (2014) Dystrophin quantification: biological and translational research implications. Neurology 83(22):2062–2069. https://doi.org/10.1212/WNL.0000000000001025

    Article  PubMed  PubMed Central  Google Scholar 

  64. Taylor LE, Kaminoh YJ, Rodesch CK, Flanigan KM (2012) Quantification of dystrophin immunofluorescence in dystrophinopathy muscle specimens. Neuropathol Appl Neurobiol 38(6):591–601. https://doi.org/10.1111/j.1365-2990.2012.01250.x

    Article  CAS  PubMed  Google Scholar 

  65. Marx V (2013) Targeted proteomics. Nat Methods 10(1):19–22

    Article  CAS  Google Scholar 

  66. Vila MC, Rayavarapu S, Hogarth MW, Van der Meulen JH, Horn A, Defour A, Takeda S, Brown KJ, Hathout Y, Nagaraju K, Jaiswal JK (2017) Mitochondria mediate cell membrane repair and contribute to Duchenne muscular dystrophy. Cell Death Differ 24(2):330–342. https://doi.org/10.1038/cdd.2016.127

    Article  CAS  PubMed  Google Scholar 

  67. Brown KJ, Marathi R, Fiorillo AA, Ciccimaro EF, Sharma S, Rowlands DS, Rayavarapu S, Nagaraju K, Hoffman EP, Hathout Y (2012) Accurate quantitation of dystrophin protein in human skeletal muscle using mass spectrometry. J Bioanal Biomed s7:001. https://doi.org/10.4172/1948-593X.S7-001

    Article  Google Scholar 

  68. Punetha J, Mansoor S, Bertorini TE, Kesari A, Brown KJ, Hoffman EP (2016) Somatic mosaicism due to a reversion variant causing hemi-atrophy: a novel variant of dystrophinopathy. Eur J Hum Genet 24(10):1511–1514. https://doi.org/10.1038/ejhg.2016.22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We would like to thank Ms. Margaret Beatka for her assistance with the design and construction of figures. This work was supported in part by funding from Solid Biosciences and Audentes Therapeutics.

Author information

Authors and Affiliations

  1. Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI, USA

    Michael W. Lawlor

  2. Solid Biosciences, Inc., Cambridge, MA, USA

    Joel S. Schneider & Kristy J. Brown

  3. Department of Rehabilitation Medicine, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA

    Martin K. Childers

Authors
  1. Michael W. Lawlor
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joel S. Schneider
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Martin K. Childers
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kristy J. Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael W. Lawlor .

Editor information

Editors and Affiliations

  1. Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO, USA; Department of Neurology, School of Medicine, University of Missouri, Columbia, MO, USA, Department of Biomedical Sciences College of Veterinary Medicine, University of Missouri, Columbia, MO, USA; Department of Bioengineering, University of Missouri, Columbia, MO, USA

    Dongsheng Duan

  2. Department of Pediatrics Nationwide Children’s Hospital and Research Institute, Department of Neurology Nationwide Children’s Hospital and Research Institute, The Ohio State University, Columbus, OH, USA

    Jerry R. Mendell

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Lawlor, M.W., Schneider, J.S., Childers, M.K., Brown, K.J. (2019). Histological and Biochemical Evaluation of Muscle Gene Therapy. In: Duan, D., Mendell, J. (eds) Muscle Gene Therapy. Springer, Cham. https://doi.org/10.1007/978-3-030-03095-7_12

Download citation

Publish with us

Policies and ethics

Search

Navigation