Systemic AAV Micro-dystrophin Gene Therapy for Duchenne Muscular Dystrophy

Dongsheng Duan, Dongsheng Duan

Abstract

Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by dystrophin gene mutation. Conceptually, replacing the mutated gene with a normal one would cure the disease. However, this task has encountered significant challenges due to the enormous size of the gene and the distribution of muscle throughout the body. The former creates a hurdle for viral vector packaging and the latter begs for whole-body therapy. To address these obstacles, investigators have invented the highly abbreviated micro-dystrophin gene and developed body-wide systemic gene transfer with adeno-associated virus (AAV). Numerous microgene configurations and various AAV serotypes have been explored in animal models in many laboratories. Preclinical data suggests that intravascular AAV micro-dystrophin delivery can significantly ameliorate muscle pathology, enhance muscle force, and attenuate dystrophic cardiomyopathy in animals. Against this backdrop, several clinical trials have been initiated to test the safety and tolerability of this promising therapy in DMD patients. While these trials are not powered to reach a conclusion on clinical efficacy, findings will inform the field on the prospects of body-wide DMD therapy with a synthetic micro-dystrophin AAV vector. This review discusses the history, current status, and future directions of systemic AAV micro-dystrophin therapy.

Keywords: AAV; BMD; Becker muscular dystrophy; DMD; Duchenne muscular dystrophy; adeno-associated virus; clinical trial; dystrophin; micro-dystrophin; systemic gene therapy.

Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Figures

Figure 1
Figure 1
Historical Milestones in the Development of Systemic AAV Micro-dystrophin Gene Therapy
Figure 2
Figure 2
Adeno-associated Viral Vector (A) A representative electron microscopic image of the AAV vector. Arrowhead, a fully packaged AAV particle. Arrow, an empty AAV particle. (B) Examination of AAV purity with SDS-PAGE silver staining. Lanes 1, 2, and 3 show a gradual increase of the purity after one, two, and three rounds of purification. The highly pure AAV stock has three viral proteins (VPs) at the ratio of VP1:VP2:VP2 ≈ 1:1:10.
Figure 3
Figure 3
Full-Length Dystrophin and Representative Micro-dystrophins Full-length dystrophin contains an N-terminal domain (N), 24 spectrin-like repeats (R1 to R24), four hinges (H1 to H4), a cysteine-rich domain (CR), and a C-terminal domain (CT). ΔDysM3 is the first synthetic micro-dystrophin. Δ3990, ΔR4–23/ΔC and μDys5R are three micro-dystrophins currently in use in clinical trials. H2 is marked in orange to indicate that it compromises micro-dystrophin function in the mouse DMD model (see Banks et al. for details). R16 and R17 are marked in red to indicate that they are the nNOS-binding domain (see Lai et al., for details).
Figure 4
Figure 4
AAV Micro-dystrophin Gene Therapy Ameliorated Muscle Disease in the Murine and Canine DMD Models (A) Systemic AAV micro-dystrophin injection improved skeletal muscle function in mdx mice. Treatment significantly improved specific tetanic force and resistance to eccentric contraction-induced force drop in the extensor digitorum longus muscle (see Shin et al. for details). Error bar, mean ± SEM. (B) Systemic AAV micro-dystrophin injection improved cardiac hemodynamics in mdx mice (see Bostick et al. for details). (C) AAV micro-dystrophin therapy improved histology (left) and reduced pathological muscle calcification (right) in the extensor carp ulnaris muscle in affected dogs (see Shin et al. for details).
Figure 5
Figure 5
First AAV Micro-dystrophin Clinical Trial Direct injection of the AAV vector to the biceps of a patient by Dr. Jerry Mendell (asterisk). The injection was assisted by an interventional radiologist (triangle) and a neurologist (square). The radiologist and the neurologist guided and monitored the injection process with ultrasound and electromyography, respectively, to make sure AAV was delivered into viable muscle (see Mendell et al. for details).
Figure 6
Figure 6
Sarcolemmal nNOS Delocalization Contributes to DMD Pathogenesis In normal muscle, nNOS is localized at the sarcolemma. This allows immediate diffusion of nitric oxide (NO) to the vasculature and vasodilation in contracting muscle. In DMD, the loss of sarcolemmal nNOS compromises this process and leads to functional ischemia. The H&E-stained image illustrates focal ischemic lesions (arrow) as the first observable histological change in a 3-week-old affected dog. Despite the absence of dystrophin, histologically, the majority of myofibers appeared normal at this age.

References

    1. Kunkel L.M. 2004 William Allan award address. cloning of the DMD gene. Am. J. Hum. Genet. 2005;76:205–214.
    1. Drouin E., Péréon Y. Duchenne or Meryon muscular dystrophy? Mol. Genet. Metab. 2014;113:241–242.
    1. Mendell J.R., Lloyd-Puryear M. Report of MDA muscle disease symposium on newborn screening for Duchenne muscular dystrophy. Muscle Nerve. 2013;48:21–26.
    1. Bushby K., Finkel R., Birnkrant D.J., Case L.E., Clemens P.R., Cripe L., Kaul A., Kinnett K., McDonald C., Pandya S., DMD Care Considerations Working Group Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol. 2010;9:77–93.
    1. Mendell J.R., Province M.A., Moxley R.T., 3rd, Griggs R.C., Brooke M.H., Fenichel G.M., Miller J.P., Kaiser K.K., King W., Robison J. Clinical investigation of Duchenne muscular dystrophy. A methodology for therapeutic trials based on natural history controls. Arch. Neurol. 1987;44:808–811.
    1. Hyde S.A., Steffensen B.F., Fløytrup I., Glent S., Kroksmark A.K., Salling B., Werlauff U., Erlandsen M. Longitudinal data analysis: an application to construction of a natural history profile of Duchenne muscular dystrophy. Neuromuscul. Disord. 2001;11:165–170.
    1. Mercuri E., Signorovitch J.E., Swallow E., Song J., Ward S.J., DMD Italian Group; Trajectory Analysis Project (cTAP) Categorizing natural history trajectories of ambulatory function measured by the 6-minute walk distance in patients with Duchenne muscular dystrophy. Neuromuscul. Disord. 2016;26:576–583.
    1. Koeks Z., Bladen C.L., Salgado D., van Zwet E., Pogoryelova O., McMacken G., Monges S., Foncuberta M.E., Kekou K., Kosma K. Clinical Outcomes in Duchenne Muscular Dystrophy: A Study of 5345 Patients from the TREAT-NMD DMD Global Database. J. Neuromuscul. Dis. 2017;4:293–306.
    1. News FDA approves hereditary blindness gene therapy. Nat. Biotechnol. 2018;36:6.
    1. Russell S., Bennett J., Wellman J.A., Chung D.C., Yu Z.F., Tillman A., Wittes J., Pappas J., Elci O., McCague S. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017;390:849–860.
    1. Duan D. Dystrophin Gene Replacement and Gene Repair Therapy for Duchenne Muscular Dystrophy in 2016: An Interview. Hum. Gene Ther. Clin. Dev. 2016;27:9–18.
    1. Chamberlain J.R., Chamberlain J.S. Progress toward gene therapy for Duchenne muscular dystrophy. Mol. Ther. 2017;25:1125–1131.
    1. Muzyczka N., Berns K.I. AAV’s Golden Jubilee. Mol. Ther. 2015;23:807–808.
    1. Rondot P. G. B. A. Duchenne de Boulogne (1806-1875) J. Neurol. 2005;252:866–867.
    1. Hoffman E.P., Brown R.H., Jr., Kunkel L.M. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell. 1987;51:919–928.
    1. Koenig M., Hoffman E.P., Bertelson C.J., Monaco A.P., Feener C., Kunkel L.M. Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell. 1987;50:509–517.
    1. Kunkel L.M. The Wellcome lecture, 1988. Muscular dystrophy: a time of hope. Proc. R. Soc. Lond. B Biol. Sci. 1989;237:1–9.
    1. Duan D. Myodys, a full-length dystrophin plasmid vector for Duchenne and Becker muscular dystrophy gene therapy. Curr. Opin. Mol. Ther. 2008;10:86–94.
    1. England S.B., Nicholson L.V., Johnson M.A., Forrest S.M., Love D.R., Zubrzycka-Gaarn E.E., Bulman D.E., Harris J.B., Davies K.E. Very mild muscular dystrophy associated with the deletion of 46% of dystrophin. Nature. 1990;343:180–182.
    1. Love D.R., England S.B., Speer A., Marsden R.F., Bloomfield J.F., Roche A.L., Cross G.S., Mountford R.C., Smith T.J., Davies K.E. Sequences of junction fragments in the deletion-prone region of the dystrophin gene. Genomics. 1991;10:57–67.
    1. Ikeya K., Saito K., Hayashi K., Tanaka H., Hagiwara Y., Yoshida M., Yamauchi A., Fukuyama Y., Ishiguro T., Eguchi C. Molecular genetic and immunological analysis of dystrophin of a young patient with X-linked muscular dystrophy. Am. J. Med. Genet. 1992;43:580–587.
    1. Beggs A.H., Hoffman E.P., Snyder J.R., Arahata K., Specht L., Shapiro F., Angelini C., Sugita H., Kunkel L.M. Exploring the molecular basis for variability among patients with Becker muscular dystrophy: dystrophin gene and protein studies. Am. J. Hum. Genet. 1991;49:54–67.
    1. Nicholson L.V., Bushby K.M., Johnson M.A., Gardner-Medwin D., Ginjaar I.B. Dystrophin expression in Duchenne patients with “in-frame” gene deletions. Neuropediatrics. 1993;24:93–97.
    1. Matsumura K., Burghes A.H., Mora M., Tomé F.M., Morandi L., Cornello F., Leturcq F., Jeanpierre M., Kaplan J.C., Reinert P. Immunohistochemical analysis of dystrophin-associated proteins in Becker/Duchenne muscular dystrophy with huge in-frame deletions in the NH2-terminal and rod domains of dystrophin. J. Clin. Invest. 1994;93:99–105.
    1. Koenig M., Beggs A.H., Moyer M., Scherpf S., Heindrich K., Bettecken T., Meng G., Müller C.R., Lindlöf M., Kaariainen H. The molecular basis for Duchenne versus Becker muscular dystrophy: correlation of severity with type of deletion. Am. J. Hum. Genet. 1989;45:498–506.
    1. Winnard A.V., Klein C.J., Coovert D.D., Prior T., Papp A., Snyder P., Bulman D.E., Ray P.N., McAndrew P., King W. Characterization of translational frame exception patients in Duchenne/Becker muscular dystrophy. Hum. Mol. Genet. 1993;2:737–744.
    1. Passos-Bueno M.R., Vainzof M., Marie S.K., Zatz M. Half the dystrophin gene is apparently enough for a mild clinical course: confirmation of its potential use for gene therapy. Hum. Mol. Genet. 1994;3:919–922.
    1. Flanigan K.M., Dunn D.M., von Niederhausern A., Soltanzadeh P., Gappmaier E., Howard M.T., Sampson J.B., Mendell J.R., Wall C., King W.M., United Dystrophinopathy Project Consortium Mutational spectrum of DMD mutations in dystrophinopathy patients: application of modern diagnostic techniques to a large cohort. Hum. Mutat. 2009;30:1657–1666.
    1. Aartsma-Rus A., Van Deutekom J.C., Fokkema I.F., Van Ommen G.J., Den Dunnen J.T. Entries in the Leiden Duchenne muscular dystrophy mutation database: an overview of mutation types and paradoxical cases that confirm the reading-frame rule. Muscle Nerve. 2006;34:135–144.
    1. Chamberlain J.S. Gene therapy of muscular dystrophy. Hum. Mol. Genet. 2002;11:2355–2362.
    1. Atchison R.W., Casto B.C., Hammon W.M. Adenovirus-associated defective virus particles. Science. 1965;149:754–756.
    1. Hermonat P.L., 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;81:6466–6470.
    1. Wagner J.A., Reynolds T., Moran M.L., Moss R.B., Wine J.J., Flotte T.R., Gardner P. Efficient and persistent gene transfer of AAV-CFTR in maxillary sinus. Lancet. 1998;351:1702–1703.
    1. Xiao X., Li J., Samulski R.J. Efficient long-term gene transfer into muscle tissue of immunocompetent mice by adeno-associated virus vector. J. Virol. 1996;70:8098–8108.
    1. Kessler P.D., Podsakoff G.M., Chen X., McQuiston S.A., Colosi P.C., Matelis L.A., Kurtzman G.J., Byrne B.J. Gene delivery to skeletal muscle results in sustained expression and systemic delivery of a therapeutic protein. Proc. Natl. Acad. Sci. USA. 1996;93:14082–14087.
    1. Gregorevic P., Blankinship M.J., Allen J.M., Crawford R.W., Meuse L., Miller D.G., Russell D.W., Chamberlain J.S. Systemic delivery of genes to striated muscles using adeno-associated viral vectors. Nat. Med. 2004;10:828–834.
    1. Wang Z., Zhu T., Qiao C., Zhou L., Wang B., Zhang J., Chen C., Li J., Xiao X. Adeno-associated virus serotype 8 efficiently delivers genes to muscle and heart. Nat. Biotechnol. 2005;23:321–328.
    1. Yue Y., Ghosh A., Long C., Bostick B., Smith B.F., Kornegay J.N., Duan D. A single intravenous injection of adeno-associated virus serotype-9 leads to whole body skeletal muscle transduction in dogs. Mol. Ther. 2008;16:1944–1952.
    1. Wang D., Zhong L., Nahid M.A., Gao G. The potential of adeno-associated viral vectors for gene delivery to muscle tissue. Expert Opin. Drug Deliv. 2014;11:345–364.
    1. Duan D. Systemic delivery of adeno-associated viral vectors. Curr. Opin. Virol. 2016;21:16–25.
    1. Yuasa K., Ishii A., Miyagoe Y., Takeda S. [Introduction of rod-deleted dystrophin cDNA, delta DysM3, into mdx skeletal muscle using adenovirus vector] Nihon Rinsho. 1997;55:3148–3153.
    1. Takeda S. [Development of new therapy on muscular dystrophy] Rinsho Shinkeigaku. 2001;41:1154–1156.
    1. Wang B., Li J., Xiao X. Adeno-associated virus vector carrying human minidystrophin genes effectively ameliorates muscular dystrophy in mdx mouse model. Proc. Natl. Acad. Sci. USA. 2000;97:13714–13719.
    1. Harper S.Q., Hauser M.A., DelloRusso C., Duan D., Crawford R.W., Phelps S.F., Harper H.A., Robinson A.S., Engelhardt J.F., Brooks S.V., Chamberlain J.S. Modular flexibility of dystrophin: implications for gene therapy of Duchenne muscular dystrophy. Nat. Med. 2002;8:253–261.
    1. Foster H., Sharp P.S., Athanasopoulos T., Trollet C., Graham I.R., Foster K., Wells D.J., Dickson G. Codon and mRNA sequence optimization of microdystrophin transgenes improves expression and physiological outcome in dystrophic mdx mice following AAV2/8 gene transfer. Mol. Ther. 2008;16:1825–1832.
    1. Lai Y., Thomas G.D., Yue Y., Yang H.T., Li D., Long C., Judge L., Bostick B., Chamberlain J.S., Terjung R.L., Duan D. 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;119:624–635.
    1. Yuasa K., Miyagoe Y., Yamamoto K., Nabeshima Y., Dickson G., Takeda S. Effective restoration of dystrophin-associated proteins in vivo by adenovirus-mediated transfer of truncated dystrophin cDNAs. FEBS Lett. 1998;425:329–336.
    1. Fabb S.A., Wells D.J., Serpente P., Dickson G. Adeno-associated virus vector gene transfer and sarcolemmal expression of a 144 kDa micro-dystrophin effectively restores the dystrophin-associated protein complex and inhibits myofibre degeneration in nude/mdx mice. Hum. Mol. Genet. 2002;11:733–741.
    1. Sakamoto M., Yuasa K., Yoshimura M., Yokota T., Ikemoto T., Suzuki M., Dickson G., Miyagoe-Suzuki Y., Takeda S. Micro-dystrophin cDNA ameliorates dystrophic phenotypes when introduced into mdx mice as a transgene. Biochem. Biophys. Res. Commun. 2002;293:1265–1272.
    1. Yoshimura M., Sakamoto M., Ikemoto M., Mochizuki Y., Yuasa K., Miyagoe-Suzuki Y., Takeda S. AAV vector-mediated microdystrophin expression in a relatively small percentage of mdx myofibers improved the mdx phenotype. Mol. Ther. 2004;10:821–828.
    1. Banks G.B., Gregorevic P., Allen J.M., Finn E.E., Chamberlain J.S. Functional capacity of dystrophins carrying deletions in the N-terminal actin-binding domain. Hum. Mol. Genet. 2007;16:2105–2113.
    1. Jørgensen L.H., Larochelle N., Orlopp K., Dunant P., Dudley R.W., Stucka R., Thirion C., Walter M.C., Laval S.H., Lochmüller H. Efficient and fast functional screening of microdystrophin constructs in vivo and in vitro for therapy of duchenne muscular dystrophy. Hum. Gene Ther. 2009;20:641–650.
    1. Banks G.B., Judge L.M., Allen J.M., Chamberlain J.S. The polyproline site in hinge 2 influences the functional capacity of truncated dystrophins. PLoS Genet. 2010;6:e1000958.
    1. Koo T., Malerba A., Athanasopoulos T., Trollet C., Boldrin L., Ferry A., Popplewell L., Foster H., Foster K., Dickson G. 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 α1-syntrophin and α-dystrobrevin in skeletal muscles of mdx mice. Hum. Gene Ther. 2011;22:1379–1388.
    1. Shin J.-H., Nitahara-Kasahara Y., Hayashita-Kinoh H., Ohshima-Hosoyama S., Kinoshita K., Chiyo T., Okada H., Okada T., Takeda S. Improvement of cardiac fibrosis in dystrophic mice by rAAV9-mediated microdystrophin transduction. Gene Ther. 2011;18:910–919.
    1. Shin J.-H., Yue Y., Srivastava A., Smith B., Lai Y., Duan D. A simplified immune suppression scheme leads to persistent micro-dystrophin expression in Duchenne muscular dystrophy dogs. Hum. Gene Ther. 2012;23:202–209.
    1. Hakim C.H., Wasala N.B., Pan X., Kodippili K., Yue Y., Zhang K., Yao G., Haffner B., Duan S.X., Ramos J. A five-repeat micro-dystrophin gene ameliorated dystrophic phenotype in the severe DBA/2J-mdx model of Duchenne muscular dystrophy. Mol. Ther. Methods Clin. Dev. 2017;6:216–230.
    1. Shin J.-H., Pan X., Hakim C.H., Yang H.T., Yue Y., Zhang K., Terjung R.L., Duan D. Microdystrophin ameliorates muscular dystrophy in the canine model of duchenne muscular dystrophy. Mol. Ther. 2013;21:750–757.
    1. Bostick B., Shin J.-H., Yue Y., Duan D. AAV-microdystrophin therapy improves cardiac performance in aged female mdx mice. Mol. Ther. 2011;19:1826–1832.
    1. Duan D. Duchenne muscular dystrophy gene therapy in the canine model. Hum. Gene Ther. Clin. Dev. 2015;26:57–69.
    1. Kotterman M.A., Schaffer D.V. Engineering adeno-associated viruses for clinical gene therapy. Nat. Rev. Genet. 2014;15:445–451.
    1. McGreevy J.W., Hakim C.H., McIntosh M.A., Duan D. Animal models of Duchenne muscular dystrophy: from basic mechanisms to gene therapy. Dis. Model. Mech. 2015;8:195–213.
    1. Gregorevic P., Allen J.M., Minami E., Blankinship M.J., Haraguchi M., Meuse L., Finn E., Adams M.E., Froehner S.C., Murry C.E., Chamberlain J.S. rAAV6-microdystrophin preserves muscle function and extends lifespan in severely dystrophic mice. Nat. Med. 2006;12:787–789.
    1. Gregorevic P., Blankinship M.J., Allen J.M., Chamberlain J.S. Systemic microdystrophin gene delivery improves skeletal muscle structure and function in old dystrophic mdx mice. Mol. Ther. 2008;16:657–664.
    1. Bostick B., Shin J.-H., Yue Y., Wasala N.B., Lai Y., Duan D. AAV micro-dystrophin gene therapy alleviates stress-induced cardiac death but not myocardial fibrosis in >21-m-old mdx mice, an end-stage model of Duchenne muscular dystrophy cardiomyopathy. J. Mol. Cell. Cardiol. 2012;53:217–222.
    1. Wang B., Li J., Fu F.H., Xiao X. Systemic human minidystrophin gene transfer improves functions and life span of dystrophin and dystrophin/utrophin-deficient mice. J. Orthop. Res. 2009;27:421–426.
    1. Kornegay J.N., Li J., Bogan J.R., Bogan D.J., Chen C., Zheng H., Wang B., Qiao C., Howard J.F., Jr., Xiao X. Widespread muscle expression of an AAV9 human mini-dystrophin vector after intravenous injection in neonatal dystrophin-deficient dogs. Mol. Ther. 2010;18:1501–1508.
    1. Yue Y., Pan X., Hakim C.H., Kodippili K., Zhang K., Shin J.-H., Yang H.T., McDonald T., Duan D. Safe and bodywide muscle transduction in young adult Duchenne muscular dystrophy dogs with adeno-associated virus. Hum. Mol. Genet. 2015;24:5880–5890.
    1. Le Guiner C., Servais L., Montus M., Larcher T., Fraysse B., Moullec S., Allais M., François V., Dutilleul M., Malerba A. Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy. Nat. Commun. 2017;8:16105.
    1. Birch S.M., Lawlor M.W., Guo L.-J., Crudele J.M., Hawkins E.C., Nghiem P.P., Styner M.A., Struharik M.J., Brown K.J., Golebiowski D. A blinded placebo-controlled systemic gene therapy efficacy study in the GRMD model of Duchenne muscular dystrophy. Mol. Ther. 2017;25(Suppl 1):193.
    1. Hakim C.H., Kodippili K., Jenkins G., Yang H.T., Pan X., Lessa T.B., Leach S.B., Emter C., Yue Y., Zhang K. Single systemic AAV micro-dystrophin therapy ameliorates muscular dystrophy in young adult Duchenne muscular dystrophy dogs for up to two years. Mol. Ther. 2017;25(Suppl 1):192–193.
    1. Hakim C.H., Kodippili K., Jenkins G., Yang H.T., Pan X., Lessa T.B., Leach S., Emter C., Yue Y., Zhang K. AAV micro-dystrophin therapy ameliorates muscular dystrophy in young adult Duchenne muscular dystrophy dogs for up to 30 months following injection. Mol. Ther. 2018;26(Suppl 1):5.
    1. Crudele J.M., Birch S.M., Hakim C.H., Golebiowski D., Shanks C., Morris C., Schneider J.S., Hauschka S.D., Duan D., Kornegay J.N., Chamberlain J.S. Assessing anti-dystrophin T-cell responses by ELISPOT following AAV-9 micro-dystrophin gene therapy in dogs. Mol. Ther. 2018;26(Suppl 1):104.
    1. Mendell J.R., Campbell K., Rodino-Klapac L., Sahenk Z., Shilling C., Lewis S., Bowles D., Gray S., Li C., Galloway G. Dystrophin immunity in Duchenne’s muscular dystrophy. N. Engl. J. Med. 2010;363:1429–1437.
    1. Bowles D.E., McPhee S.W., Li C., Gray S.J., Samulski J.J., Camp A.S., Li J., Wang B., Monahan P.E., Rabinowitz J.E. Phase 1 gene therapy for Duchenne muscular dystrophy using a translational optimized AAV vector. Mol. Ther. 2012;20:443–455.
    1. Mendell J.R., Al-Zaidy S., Shell R., Arnold W.D., Rodino-Klapac L.R., Prior T.W., Lowes L., Alfano L., Berry K., Church K. Single-dose gene-replacement therapy for spinal muscular atrophy. N. Engl. J. Med. 2017;377:1713–1722.
    1. Audentes Therapeutics (2018). Audentes Announces Positive Interim Data from First Dose Cohort of ASPIRO, a Phase 1/2 Clinical Trial of AT132 in Patients With X-Linked Myotubular Myopathy. Audentes, .
    1. Kuntz N., Shieh P.B., Smith B., Bonnemann C.G., Dowling J.J., Lawlor M.W., Müller-Felber W., Noursalehi M., Rico S., Servais L., Prasad S. ASPIRO phase 1/2 gene therapy trail in X-linked myotubular myopathy (XLMTM): preliminary safety and efficacy findings. Mol. Ther. 2018;26(Suppl 1):4.
    1. Rangarajan S., Walsh L., Lester W., Perry D., Madan B., Laffan M., Yu H., Vettermann C., Pierce G.F., Wong W.Y., Pasi K.J. AAV5-Factor VIII Gene Transfer in Severe Hemophilia A. N. Engl. J. Med. 2017;377:2519–2530.
    1. Beggs A.H., Byrne B.J., De Chastonay S., Haselkorn T., Hughes I., James E.S., Kuntz N.L., Simon J., Swanson L.C., Yang M.L. A multicenter, retrospective medical record review of X-linked myotubular myopathy: The recensus study. Muscle Nerve. 2018;57:550–560.
    1. Sarepta Therapeutics (2017). Sarepta Therapeutics and Genethon Announce a Gene Therapy Research Collaboration for the Treatment of Duchenne Muscular Dystrophy. Sarepta Therapeutics, .
    1. Clément N., Knop D.R., Byrne B.J. Large-scale adeno-associated viral vector production using a herpesvirus-based system enables manufacturing for clinical studies. Hum. Gene Ther. 2009;20:796–806.
    1. Grieger J.C., Soltys S.M., Samulski R.J. Production of Recombinant Adeno-associated Virus Vectors Using Suspension HEK293 Cells and Continuous Harvest of Vector From the Culture Media for GMP FIX and FLT1 Clinical Vector. Mol. Ther. 2016;24:287–297.
    1. Salva M.Z., Himeda C.L., Tai P.W., Nishiuchi E., Gregorevic P., Allen J.M., Finn E.E., Nguyen Q.G., Blankinship M.J., Meuse L. Design of tissue-specific regulatory cassettes for high-level rAAV-mediated expression in skeletal and cardiac muscle. Mol. Ther. 2007;15:320–329.
    1. Wang B., Li J., Fu F.H., Chen C., Zhu X., Zhou L., Jiang X., Xiao X. Construction and analysis of compact muscle-specific promoters for AAV vectors. Gene Ther. 2008;15:1489–1499.
    1. Brenman J.E., Chao D.S., Xia H., Aldape K., Bredt D.S. Nitric oxide synthase complexed with dystrophin and absent from skeletal muscle sarcolemma in Duchenne muscular dystrophy. Cell. 1995;82:743–752.
    1. Chang W.J., Iannaccone S.T., Lau K.S., Masters B.S., McCabe T.J., McMillan K., Padre R.C., Spencer M.J., Tidball J.G., Stull J.T. Neuronal nitric oxide synthase and dystrophin-deficient muscular dystrophy. Proc. Natl. Acad. Sci. USA. 1996;93:9142–9147.
    1. Stamler J.S., Meissner G. Physiology of nitric oxide in skeletal muscle. Physiol. Rev. 2001;81:209–237.
    1. Thomas G.D., Sander M., Lau K.S., Huang P.L., Stull J.T., Victor R.G. Impaired metabolic modulation of alpha-adrenergic vasoconstriction in dystrophin-deficient skeletal muscle. Proc. Natl. Acad. Sci. USA. 1998;95:15090–15095.
    1. Sander M., Chavoshan B., Harris S.A., Iannaccone S.T., Stull J.T., Thomas G.D., Victor R.G. Functional muscle ischemia in neuronal nitric oxide synthase-deficient skeletal muscle of children with Duchenne muscular dystrophy. Proc. Natl. Acad. Sci. USA. 2000;97:13818–13823.
    1. Thomas G.D. Functional muscle ischemia in Duchenne and Becker muscular dystrophy. Front. Physiol. 2013;4:381.
    1. Mendell J.R., Engel W.K., Derrer E.C. Duchenne muscular dystrophy: functional ischemia reproduces its characteristic lesions. Science. 1971;172:1143–1145.
    1. Li D., Yue Y., Lai Y., Hakim C.H., Duan D. Nitrosative stress elicited by nNOSμ delocalization inhibits muscle force in dystrophin-null mice. J. Pathol. 2011;223:88–98.
    1. Gentil C., Leturcq F., Ben Yaou R., Kaplan J.C., Laforet P., Pénisson-Besnier I., Espil-Taris C., Voit T., Garcia L., Piétri-Rouxel F. Variable phenotype of del45-55 Becker patients correlated with nNOSμ mislocalization and RYR1 hypernitrosylation. Hum. Mol. Genet. 2012;21:3449–3460.
    1. Harper S.Q. Molecular dissection of dystrophin identifies the docking site for nNOS. Proc. Natl. Acad. Sci. USA. 2013;110:387–388.
    1. Hillier B.J., Christopherson K.S., Prehoda K.E., Bredt D.S., Lim W.A. Unexpected modes of PDZ domain scaffolding revealed by structure of nNOS-syntrophin complex. Science. 1999;284:812–815.
    1. Yue Y., Liu M., Duan D. C-terminal-truncated microdystrophin recruits dystrobrevin and syntrophin to the dystrophin-associated glycoprotein complex and reduces muscular dystrophy in symptomatic utrophin/dystrophin double-knockout mice. Mol. Ther. 2006;14:79–87.
    1. Lai Y., Zhao J., Yue Y., Duan D. α2 and α3 helices of dystrophin R16 and R17 frame a microdomain in the α1 helix of dystrophin R17 for neuronal NOS binding. Proc. Natl. Acad. Sci. USA. 2013;110:525–530.
    1. Zhang Y., Duan D. Novel mini-dystrophin gene dual adeno-associated virus vectors restore neuronal nitric oxide synthase expression at the sarcolemma. Hum. Gene Ther. 2012;23:98–103.
    1. Zhang Y., Yue Y., Li L., Hakim C.H., Zhang K., Thomas G.D., Duan D. Dual AAV therapy ameliorates exercise-induced muscle injury and functional ischemia in murine models of Duchenne muscular dystrophy. Hum. Mol. Genet. 2013;22:3720–3729.
    1. Hinderer C., Katz N., Buza E.L., Dyer C., Goode T., Bell P., Richman L.K., Wilson J.M. Severe Toxicity in Nonhuman Primates and Piglets Following High-Dose Intravenous Administration of an Adeno-Associated Virus Vector Expressing Human SMN. Hum. Gene Ther. 2018;29:285–298.
    1. Hordeaux J., Wang Q., Katz N., Buza E.L., Bell P., Wilson J.M. The Neurotropic Properties of AAV-PHP.B Are Limited to C57BL/6J Mice. Mol. Ther. 2018;26:664–668.
    1. Rogers G.L., Martino A.T., Aslanidi G.V., Jayandharan G.R., Srivastava A., Herzog R.W. Innate immune responses to AAV vectors. Front. Microbiol. 2011;2:194.
    1. Shayakhmetov D.M., Di Paolo N.C., Mossman K.L. Recognition of virus infection and innate host responses to viral gene therapy vectors. Mol. Ther. 2010;18:1422–1429.
    1. Mingozzi F., High K.A. Immune responses to AAV vectors: overcoming barriers to successful gene therapy. Blood. 2013;122:23–36.
    1. Raper S.E., Chirmule N., Lee F.S., Wivel N.A., Bagg A., Gao G.P., Wilson J.M., Batshaw M.L. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol. Genet. Metab. 2003;80:148–158.
    1. Hendrickx R., Stichling N., Koelen J., Kuryk L., Lipiec A., Greber U.F. Innate immunity to adenovirus. Hum. Gene Ther. 2014;25:265–284.
    1. Zaiss A.K., Liu Q., Bowen G.P., Wong N.C., Bartlett J.S., Muruve D.A. Differential activation of innate immune responses by adenovirus and adeno-associated virus vectors. J. Virol. 2002;76:4580–4590.
    1. McCaffrey A.P., Fawcett P., Nakai H., McCaffrey R.L., Ehrhardt A., Pham T.T., Pandey K., Xu H., Feuss S., Storm T.A., Kay M.A. The host response to adenovirus, helper-dependent adenovirus, and adeno-associated virus in mouse liver. Mol. Ther. 2008;16:931–941.
    1. Shayakhmetov D.M. Virus infection recognition and early innate responses to non-enveloped viral vectors. Viruses. 2010;2:244–261.
    1. Zaiss A.K., Muruve D.A. Immunity to adeno-associated virus vectors in animals and humans: a continued challenge. Gene Ther. 2008;15:808–816.
    1. Hösel M., Broxtermann M., Janicki H., Esser K., Arzberger S., Hartmann P., Gillen S., Kleeff J., Stabenow D., Odenthal M. Toll-like receptor 2-mediated innate immune response in human nonparenchymal liver cells toward adeno-associated viral vectors. Hepatology. 2012;55:287–297.
    1. Zhu J., Huang X., Yang Y. The TLR9-MyD88 pathway is critical for adaptive immune responses to adeno-associated virus gene therapy vectors in mice. J. Clin. Invest. 2009;119:2388–2398.
    1. Martino A.T., Suzuki M., Markusic D.M., Zolotukhin I., Ryals R.C., Moghimi B., Ertl H.C., Muruve D.A., Lee B., Herzog R.W. The genome of self-complementary adeno-associated viral vectors increases Toll-like receptor 9-dependent innate immune responses in the liver. Blood. 2011;117:6459–6468.
    1. Solid Biosciences (2018). Solid Biosciences announces clinical hold on SGT-001 phase I/II clinical trial for Duchenne muscualr dystrophy. Solid Biosciences, .
    1. Solid Biosciences (2018). Solid Biosciences announces FDA removes clinical hold on SGT-001. Solid Biosciences, .
    1. Zaiss A.K., Cotter M.J., White L.R., Clark S.A., Wong N.C., Holers V.M., Bartlett J.S., Muruve D.A. Complement is an essential component of the immune response to adeno-associated virus vectors. J. Virol. 2008;82:2727–2740.
    1. Noris M., Remuzzi G. Overview of complement activation and regulation. Semin. Nephrol. 2013;33:479–492.
    1. Ricklin D., Reis E.S., Lambris J.D. Complement in disease: a defence system turning offensive. Nat. Rev. Nephrol. 2016;12:383–401.
    1. Huber-Lang M., Ignatius A., Brenner R.E. Role of Complement on Broken Surfaces After Trauma. Adv. Exp. Med. Biol. 2015;865:43–55.
    1. Del Conde I., Crúz M.A., Zhang H., López J.A., Afshar-Kharghan V. Platelet activation leads to activation and propagation of the complement system. J. Exp. Med. 2005;201:871–879.
    1. Wilson W.A., Thomas E.J. Activation of the alternative pathway of human complement by haemoglobin. Clin. Exp. Immunol. 1979;36:140–144.
    1. Kaca W., Roth R. Activation of complement by human hemoglobin and by mixtures of hemoglobin and bacterial endotoxin. Biochim. Biophys. Acta. 1995;1245:49–56.
    1. Furlong, P. (2018). First Duchenne Patient Dosed in Microdystrophin Gene Therapy! Parent Project Muscular Dystrophy, .
    1. Furlong, P. (2018). Positive preliminary results from the first three children dosed in phase 1/2A gene therapy micro-dystrophin trial. Parent Project Muscular Dystrophy,().
    1. News & Media (2018). Pfizer doses first patient using investigational mini-dystrophin gene therapy for the treatment of Duchenne muscular dystrophy. Pfizer, .
    1. Mingozzi F., High K.A. Overcoming the Host Immune Response to Adeno-Associated Virus Gene Delivery Vectors: The Race Between Clearance, Tolerance, Neutralization, and Escape. Annu. Rev. Virol. 2017;4:511–534.
    1. Basner-Tschakarjan E., Bijjiga E., Martino A.T. Pre-clinical assessment of immune responses to adeno-associated virus (AAV) vectors. Front. Immunol. 2014;5:28.
    1. Masat E., Pavani G., Mingozzi F. Humoral immunity to AAV vectors in gene therapy: challenges and potential solutions. Discov. Med. 2013;15:379–389.
    1. Mays L.E., Wilson J.M. The complex and evolving story of T cell activation to AAV vector-encoded transgene products. Mol. Ther. 2011;19:16–27.
    1. Vandamme C., Adjali O., Mingozzi F. Unraveling the Complex Story of Immune Responses to AAV Vectors Trial After Trial. Hum. Gene Ther. 2017;28:1061–1074.
    1. Calcedo R., Wilson J.M. Humoral Immune Response to AAV. Front. Immunol. 2013;4:341.
    1. Manno C.S., Pierce G.F., Arruda V.R., Glader B., Ragni M., Rasko J.J., Ozelo M.C., Hoots K., Blatt P., Konkle B. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat. Med. 2006;12:342–347.
    1. Nathwani A.C., Reiss U.M., Tuddenham E.G., Rosales C., Chowdary P., McIntosh J., Della Peruta M., Lheriteau E., Patel N., Raj D. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N. Engl. J. Med. 2014;371:1994–2004.
    1. George L.A., Sullivan S.K., Giermasz A., Rasko J.E.J., Samelson-Jones B.J., Ducore J., Cuker A., Sullivan L.M., Majumdar S., Teitel J. Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant. N. Engl. J. Med. 2017;377:2215–2227.
    1. Flanigan K.M., Campbell K., Viollet L., Wang W., Gomez A.M., Walker C.M., Mendell J.R. Anti-dystrophin T cell responses in Duchenne muscular dystrophy: prevalence and a glucocorticoid treatment effect. Hum. Gene Ther. 2013;24:797–806.
    1. Louis Jeune V., Joergensen J.A., Hajjar R.J., Weber T. Pre-existing anti-adeno-associated virus antibodies as a challenge in AAV gene therapy. Hum. Gene Ther. Methods. 2013;24:59–67.
    1. Tse L.V., Moller-Tank S., Asokan A. Strategies to circumvent humoral immunity to adeno-associated viral vectors. Expert Opin. Biol. Ther. 2015;15:845–855.
    1. Arikawa-Hirasawa E., Koga R., Tsukahara T., Nonaka I., Mitsudome A., Goto K., Beggs A.H., Arahata K. A severe muscular dystrophy patient with an internally deleted very short (110 kD) dystrophin: presence of the binding site for dystrophin-associated glycoprotein (DAG) may not be enough for physiological function of dystrophin. Neuromuscul. Disord. 1995;5:429–438.
    1. Den Dunnen J.T., Grootscholten P.M., Bakker E., Blonden L.A., Ginjaar H.B., Wapenaar M.C., van Paassen H.M., van Broeckhoven C., Pearson P.L., van Ommen G.J. Topography of the Duchenne muscular dystrophy (DMD) gene: FIGE and cDNA analysis of 194 cases reveals 115 deletions and 13 duplications. Am. J. Hum. Genet. 1989;45:835–847.
    1. Fanin M., Freda M.P., Vitiello L., Danieli G.A., Pegoraro E., Angelini C. Duchenne phenotype with in-frame deletion removing major portion of dystrophin rod: threshold effect for deletion size? Muscle Nerve. 1996;19:1154–1160.
    1. Carsana A., Frisso G., Tremolaterra M.R., Lanzillo R., Vitale D.F., Santoro L., Salvatore F. Analysis of dystrophin gene deletions indicates that the hinge III region of the protein correlates with disease severity. Ann. Hum. Genet. 2005;69:253–259.
    1. Nevo Y., Muntoni F., Sewry C., Legum C., Kutai M., Harel S., Dubowitz V. Large in-frame deletions of the rod-shaped domain of the dystrophin gene resulting in severe phenotype. Isr. Med. Assoc. J. 2003;5:94–97.
    1. Takeshima Y., Nishio H., Narita N., Wada H., Ishikawa Y., Ishikawa Y., Minami R., Nakamura H., Matsuo M. Amino-terminal deletion of 53% of dystrophin results in an intermediate Duchenne-Becker muscular dystrophy phenotype. Neurology. 1994;44:1648–1651.
    1. Vainzof M., Takata R.I., Passos-Bueno M.R., Pavanello R.C., Zatz M. Is the maintainance of the C-terminus domain of dystrophin enough to ensure a milder Becker muscular dystrophy phenotype? Hum. Mol. Genet. 1993;2:39–42.
    1. Pascual J., Castresana J., Saraste M. Evolution of the spectrin repeat. BioEssays. 1997;19:811–817.
    1. Broderick M.J., Winder S.J. Spectrin, alpha-actinin, and dystrophin. Adv. Protein Chem. 2005;70:203–246.
    1. Zhao J., Kodippili K., Yue Y., Hakim C.H., Wasala L., Pan X., Zhang K., Yang N.N., Duan D., Lai Y. Dystrophin contains multiple independent membrane-binding domains. Hum. Mol. Genet. 2016;25:3647–3653.
    1. Nelson D.M., Lindsay A., Judge L.M., Duan D., Chamberlain J.S., Lowe D.A., Ervasti J.M. Variable rescue of microtubule and physiological phenotypes in mdx muscle expressing different miniaturized dystrophins. Hum. Mol. Genet. 2018;27:2090–2100.
    1. Crawford G.E., Faulkner J.A., Crosbie R.H., Campbell K.P., Froehner S.C., Chamberlain J.S. Assembly of the dystrophin-associated protein complex does not require the dystrophin COOH-terminal domain. J. Cell Biol. 2000;150:1399–1410.
    1. Tandon A., Jefferies J.L., Villa C.R., Hor K.N., Wong B.L., Ware S.M., Gao Z., Towbin J.A., Mazur W., Fleck R.J. Dystrophin genotype-cardiac phenotype correlations in Duchenne and Becker muscular dystrophies using cardiac magnetic resonance imaging. Am. J. Cardiol. 2015;115:967–971.
    1. Ricotti V., Mandy W.P., Scoto M., Pane M., Deconinck N., Messina S., Mercuri E., Skuse D.H., Muntoni F. Neurodevelopmental, emotional, and behavioural problems in Duchenne muscular dystrophy in relation to underlying dystrophin gene mutations. Dev. Med. Child Neurol. 2016;58:77–84.
    1. Daoud F., Candelario-Martínez A., Billard J.M., Avital A., Khelfaoui M., Rozenvald Y., Guegan M., Mornet D., Jaillard D., Nudel U. Role of mental retardation-associated dystrophin-gene product Dp71 in excitatory synapse organization, synaptic plasticity and behavioral functions. PLoS ONE. 2008;4:e6574.
    1. McNally E.M., Kaltman J.R., Benson D.W., Canter C.E., Cripe L.H., Duan D., Finder J.D., Groh W.J., Hoffman E.P., Judge D.P., Working Group of the National Heart, Lung, and Blood Institute. Parent Project Muscular Dystrophy Contemporary cardiac issues in Duchenne muscular dystrophy. Working Group of the National Heart, Lung, and Blood Institute in collaboration with Parent Project Muscular Dystrophy. Circulation. 2015;131:1590–1598.
    1. Johnson E.K., Zhang L., Adams M.E., Phillips A., Freitas M.A., Froehner S.C., Green-Church K.B., Montanaro F. Proteomic analysis reveals new cardiac-specific dystrophin-associated proteins. PLoS ONE. 2012;7:e43515.
    1. Bostick B., Yue Y., Long C., Marschalk N., Fine D.M., Chen J., Duan D. Cardiac expression of a mini-dystrophin that normalizes skeletal muscle force only partially restores heart function in aged Mdx mice. Mol. Ther. 2009;17:253–261.
    1. Wasala L., Shin J.-H., Lai Y., Yue Y., Montanaro F., Duan D. Cardiac specific expression of ΔH2-R15 mini-dystrophin normalized all ECG abnormalities and the end-diastolic volume in a 23-m-old mouse model of Duchenne dilated cardiomyopathy. Hum. Gene Ther. 2018;29:737–748.
    1. Yue Y., Li Z., Harper S.Q., Davisson R.L., Chamberlain J.S., Duan D. Microdystrophin gene therapy of cardiomyopathy restores dystrophin-glycoprotein complex and improves sarcolemma integrity in the mdx mouse heart. Circulation. 2003;108:1626–1632.
    1. Bostick B., Yue Y., Lai Y., Long C., Li D., Duan D. Adeno-associated virus serotype-9 microdystrophin gene therapy ameliorates electrocardiographic abnormalities in mdx mice. Hum. Gene Ther. 2008;19:851–856.
    1. Townsend D., Blankinship M.J., Allen J.M., Gregorevic P., Chamberlain J.S., Metzger J.M. Systemic administration of micro-dystrophin restores cardiac geometry and prevents dobutamine-induced cardiac pump failure. Mol. Ther. 2007;15:1086–1092.
    1. Duan D. Challenges and opportunities in dystrophin-deficient cardiomyopathy gene therapy. Hum. Mol. Genet. 2006;15:R253–R261.
    1. Lai Y., Duan D. Progress in gene therapy of dystrophic heart disease. Gene Ther. 2012;19:678–685.
    1. Yue Y., Binalsheikh I.M., Leach S.B., Domeier T.L., Duan D. Prospect of gene therapy for cardiomyopathy in hereditary muscular dystrophy. Expert Opin. Orphan Drugs. 2016;4:169–183.
    1. Himeda C.L., Chen X., Hauschka S.D. Design and testing of regulatory cassettes for optimal activity in skeletal and cardiac muscles. Methods Mol. Biol. 2011;709:3–19.
    1. Li X., Eastman E.M., Schwartz R.J., Draghia-Akli R. Synthetic muscle promoters: activities exceeding naturally occurring regulatory sequences. Nat. Biotechnol. 1999;17:241–245.
    1. Shield M.A., Haugen H.S., Clegg C.H., Hauschka S.D. E-box sites and a proximal regulatory region of the muscle creatine kinase gene differentially regulate expression in diverse skeletal muscles and cardiac muscle of transgenic mice. Mol. Cell. Biol. 1996;16:5058–5068.
    1. Boisgerault F., Gross D.A., Ferrand M., Poupiot J., Darocha S., Richard I., Galy A. Prolonged gene expression in muscle is achieved without active immune tolerance using microrRNA 142.3p-regulated rAAV gene transfer. Hum. Gene Ther. 2013;24:393–405.
    1. Wang L., Dobrzynski E., Schlachterman A., Cao O., Herzog R.W. Systemic protein delivery by muscle-gene transfer is limited by a local immune response. Blood. 2005;105:4226–4234.
    1. Brown B.D., Venneri M.A., Zingale A., Sergi Sergi L., Naldini L. Endogenous microRNA regulation suppresses transgene expression in hematopoietic lineages and enables stable gene transfer. Nat. Med. 2006;12:585–591.
    1. Majowicz A., Maczuga P., Kwikkers K.L., van der Marel S., van Logtenstein R., Petry H., van Deventer S.J., Konstantinova P., Ferreira V. Mir-142-3p target sequences reduce transgene-directed immunogenicity following intramuscular adeno-associated virus 1 vector-mediated gene delivery. J. Gene Med. 2013;15:219–232.
    1. Shao W., Chen X., Samulski R.J., Hirsch M.L., Li C. Inhibition of antigen presentation during AAV gene therapy using virus peptides. Hum. Mol. Genet. 2017;27:601–613.
    1. Clément N., Grieger J.C. Manufacturing of recombinant adeno-associated viral vectors for clinical trials. Mol. Ther. Methods Clin. Dev. 2016;3:16002.
    1. Kotin R.M., Snyder R.O. Manufacturing clinical grade recombinant adeno-associated virus using invertebrate cell lines. Hum. Gene Ther. 2017;28:350–360.
    1. Brennan T.A., Wilson J.M. The special case of gene therapy pricing. Nat. Biotechnol. 2014;32:874–876.
    1. Wilson J.M. Lessons learned from the gene therapy trial for ornithine transcarbamylase deficiency. Mol. Genet. Metab. 2009;96:151–157.
    1. Nance M.E., Duan D. Perspective on Adeno-Associated Virus Capsid Modification for Duchenne Muscular Dystrophy Gene Therapy. Hum. Gene Ther. 2015;26:786–800.
    1. Qiao C., Zhang W., Yuan Z., Shin J.H., Li J., Jayandharan G.R., Zhong L., Srivastava A., Xiao X., Duan D. Adeno-associated virus serotype 6 capsid tyrosine-to-phenylalanine mutations improve gene transfer to skeletal muscle. Hum. Gene Ther. 2010;21:1343–1348.
    1. Choudhury S.R., Fitzpatrick Z., Harris A.F., Maitland S.A., Ferreira J.S., Zhang Y., Ma S., Sharma R.B., Gray-Edwards H.L., Johnson J.A. In vivo selection yields AAV-B1 capsid for central nervous system and muscle gene therapy. Mol. Ther. 2016;24:1247–1257.
    1. Li D., Yue Y., Duan D. Preservation of muscle force in Mdx3cv mice correlates with low-level expression of a near full-length dystrophin protein. Am. J. Pathol. 2008;172:1332–1341.
    1. Li D., Yue Y., Duan D. Marginal level dystrophin expression improves clinical outcome in a strain of dystrophin/utrophin double knockout mice. PLoS ONE. 2010;5:e15286.
    1. Wasala N.B., Yue Y., Vance J., Duan D. Uniform low-level dystrophin expression in the heart partially preserved cardiac function in an aged mouse model of Duchenne cardiomyopathy. J. Mol. Cell. Cardiol. 2017;102:45–52.
    1. van Putten M., Hulsker M., Young C., Nadarajah V.D., Heemskerk H., van der Weerd L., ’t Hoen P.A., van Ommen G.J., Aartsma-Rus A.M. Low dystrophin levels increase survival and improve muscle pathology and function in dystrophin/utrophin double-knockout mice. FASEB J. 2013;27:2484–2495.
    1. van Putten M., van der Pijl E.M., Hulsker M., Verhaart I.E., Nadarajah V.D., van der Weerd L., Aartsma-Rus A. Low dystrophin levels in heart can delay heart failure in mdx mice. J. Mol. Cell. Cardiol. 2014;69:17–23.
    1. van Putten M., Hulsker M., Nadarajah V.D., van Heiningen S.H., van Huizen E., van Iterson M., Admiraal P., Messemaker T., den Dunnen J.T., ’t Hoen P.A., Aartsma-Rus A. The effects of low levels of dystrophin on mouse muscle function and pathology. PLoS ONE. 2012;7:e31937.
    1. Nicholson L.V., Johnson M.A., Bushby K.M., Gardner-Medwin D. Functional significance of dystrophin positive fibres in Duchenne muscular dystrophy. Arch. Dis. Child. 1993;68:632–636.
    1. Waldrop M.A., Gumienny F., El Husayni S., Frank D.E., Weiss R.B., Flanigan K.M. Low-level dystrophin expression attenuating the dystrophinopathy phenotype. Neuromuscul. Disord. 2018;28:116–121.
    1. Phelps S.F., Hauser M.A., Cole N.M., Rafael J.A., Hinkle R.T., Faulkner J.A., Chamberlain J.S. Expression of full-length and truncated dystrophin mini-genes in transgenic mdx mice. Hum. Mol. Genet. 1995;4:1251–1258.
    1. Wells D.J., Wells K.E., Asante E.A., Turner G., Sunada Y., Campbell K.P., Walsh F.S., Dickson G. Expression of human full-length and minidystrophin in transgenic mdx mice: implications for gene therapy of Duchenne muscular dystrophy. Hum. Mol. Genet. 1995;4:1245–1250.
    1. Godfrey C., Muses S., McClorey G., Wells K.E., Coursindel T., Terry R.L., Betts C., Hammond S., O’Donovan L., Hildyard J. How much dystrophin is enough: the physiological consequences of different levels of dystrophin in the mdx mouse. Hum. Mol. Genet. 2015;24:4225–4237.
    1. Sharp P.S., Bye-a-Jee H., Wells D.J. Physiological characterization of muscle strength with variable levels of dystrophin restoration in mdx mice following local antisense therapy. Mol. Ther. 2011;19:165–171.
    1. Neri M., Torelli S., Brown S., Ugo I., Sabatelli P., Merlini L., Spitali P., Rimessi P., Gualandi F., Sewry C. Dystrophin levels as low as 30% are sufficient to avoid muscular dystrophy in the human. Neuromuscul. Disord. 2007;17:913–918.
    1. Chamberlain J.S. Dystrophin levels required for correction of Duchenne muscular dystrophy. Basic Appl. Myol. 1997;7:251–255.
    1. Hoffman E.P., Arahata K., Minetti C., Bonilla E., Rowland L.P. Dystrophinopathy in isolated cases of myopathy in females. Neurology. 1992;42:967–975.
    1. Arpke R.W., Darabi R., Mader T.L., Zhang Y., Toyama A., Lonetree C.L., Nash N., Lowe D.A., Perlingeiro R.C., Kyba M. A new immuno-, dystrophin-deficient model, the NSG-mdx(4Cv) mouse, provides evidence for functional improvement following allogeneic satellite cell transplantation. Stem Cells. 2013;31:1611–1620.
    1. Yue Y., Skimming J.W., Liu M., Strawn T., Duan D. Full-length dystrophin expression in half of the heart cells ameliorates beta-isoproterenol-induced cardiomyopathy in mdx mice. Hum. Mol. Genet. 2004;13:1669–1675.
    1. Bostick B., Yue Y., Long C., Duan D. Prevention of dystrophin-deficient cardiomyopathy in twenty-one-month-old carrier mice by mosaic dystrophin expression or complementary dystrophin/utrophin expression. Circ. Res. 2008;102:121–130.
    1. Wasala N.B., Lai Y., Shin J.-H., Zhao J., Yue Y., Duan D. Genomic removal of a therapeutic mini-dystrophin gene from adult mice elicits a Duchenne muscular dystrophy-like phenotype. Hum. Mol. Genet. 2016;25:2633–2644.
    1. Mount J.D., Herzog R.W., Tillson D.M., Goodman S.A., Robinson N., McCleland M.L., Bellinger D., Nichols T.C., Arruda V.R., Lothrop C.D., Jr., High K.A. Sustained phenotypic correction of hemophilia B dogs with a factor IX null mutation by liver-directed gene therapy. Blood. 2002;99:2670–2676.
    1. Wang L., Nichols T.C., Read M.S., Bellinger D.A., Verma I.M. Sustained expression of therapeutic level of factor IX in hemophilia B dogs by AAV-mediated gene therapy in liver. Mol. Ther. 2000;1:154–158.
    1. Snyder R.O., Miao C., Meuse L., Tubb J., Donahue B.A., Lin H.F., Stafford D.W., Patel S., Thompson A.R., Nichols T. Correction of hemophilia B in canine and murine models using recombinant adeno-associated viral vectors. Nat. Med. 1999;5:64–70.
    1. Le Hir M., Goyenvalle A., Peccate C., Précigout G., Davies K.E., Voit T., Garcia L., Lorain S. AAV genome loss from dystrophic mouse muscles during AAV-U7 snRNA-mediated exon-skipping therapy. Mol. Ther. 2013;21:1551–1558.
    1. Peccate C., Mollard A., Le Hir M., Julien L., McClorey G., Jarmin S., Le Heron A., Dickson G., Benkhelifa-Ziyyat S., Piétri-Rouxel F. Antisense pre-treatment increases gene therapy efficacy in dystrophic muscles. Hum. Mol. Genet. 2016;25:3555–3563.
    1. Dupont J.B., Tournaire B., Georger C., Marolleau B., Jeanson-Leh L., Ledevin M., Lindenbaum P., Lecomte E., Cogné B., Dubreil L. Short-lived recombinant adeno-associated virus transgene expression in dystrophic muscle is associated with oxidative damage to transgene mRNA. Mol. Ther. Methods Clin. Dev. 2015;2:15010.
    1. Ferrand M., Galy A., Boisgerault F. A dystrophic muscle broadens the contribution and activation of immune cells reacting to rAAV gene transfer. Gene Ther. 2014;21:828–839.
    1. Cordier L., Gao G.P., Hack A.A., McNally E.M., Wilson J.M., Chirmule N., Sweeney H.L. Muscle-specific promoters may be necessary for adeno-associated virus-mediated gene transfer in the treatment of muscular dystrophies. Hum. Gene Ther. 2001;12:205–215.
    1. Velazquez V.M., Meadows A.S., Pineda R.J., Camboni M., McCarty D.M., Fu H. Effective depletion of pre-existing anti-AAV antibodies requires broad immune targeting. Mol. Ther. Methods Clin. Dev. 2017;4:159–168.
    1. Chicoine L.G., Montgomery C.L., Bremer W.G., Shontz K.M., Griffin D.A., Heller K.N., Lewis S., Malik V., Grose W.E., Shilling C.J. Plasmapheresis eliminates the negative impact of AAV antibodies on microdystrophin gene expression following vascular delivery. Mol. Ther. 2014;22:338–347.
    1. Corti M., Liberati C., Smith B.K., Lawson L.A., Tuna I.S., Conlon T.J., Coleman K.E., Islam S., Herzog R.W., Fuller D.D. 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;28:208–218.
    1. Corti M., Elder M., Falk D., Lawson L., Smith B., Nayak S., Conlon T., Clément N., Erger K., Lavassani E. B-Cell Depletion is Protective Against Anti-AAV Capsid Immune Response: A Human Subject Case Study. Mol. Ther. Methods Clin. Dev. 2014;1:14033.
    1. Maguire A.M., Simonelli F., Pierce E.A., Pugh E.N., Jr., Mingozzi F., Bennicelli J., Banfi S., Marshall K.A., Testa F., Surace E.M. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N. Engl. J. Med. 2008;358:2240–2248.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅