Advertisement

Gene Therapy for Muscular Dystrophy: Moving the Field Forward

      Abstract

      Gene therapy for the muscular dystrophies has evolved as a promising treatment for this progressive group of disorders. Although corticosteroids and/or supportive treatments remain the standard of care for Duchenne muscular dystrophy, loss of ambulation, respiratory failure, and compromised cardiac function is the inevitable outcome. Recent developments in genetically mediated therapies have allowed for personalized treatments that strategically target individual muscular dystrophy subtypes based on disease pathomechanism and phenotype. In this review, we highlight the therapeutic progress with emphasis on evolving preclinical data and our own experience in completed clinical trials and others currently underway. We also discuss the lessons we have learned along the way and the strategies developed to overcome limitations and obstacles in this field.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Pediatric Neurology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Klein C.J.
        • Coovert D.D.
        • Bulman D.E.
        • Ray P.N.
        • Mendell J.R.
        • Burghes A.H.M.
        Somatic Reversion Suppression in Duchenne Muscular-Dystrophy (Dmd) - Evidence Supporting a Frame-Restoring Mechanism in Rare Dystrophin-Positive Fibers.
        Am J Hum Gen. 1992; 50: 950-959
        • Aartsma-Rus A.
        • Fokkema I.
        • Verschuuren J.
        • et al.
        Theoretic applicability of antisense-mediated exon skipping for Duchenne muscular dystrophy mutations.
        Hum Mutat. 2009; 30: 293-299
        • Mann C.J.
        • Honeyman K.
        • Cheng A.J.
        • et al.
        Antisense-induced exon skipping and synthesis of dystrophin in the mdx mouse.
        Proc Natl Acad Sci U S A. 2001; 98: 42-47
        • Goyenvalle A.
        • Babbs A.
        • Powell D.
        • et al.
        Prevention of dystrophic pathology in severely affected dystrophin/utrophin-deficient mice by morpholino-oligomer-mediated exon-skipping.
        Mol Ther. 2010; 18: 198-205
        • Yokota T.
        • Lu Q.L.
        • Partridge T.
        • et al.
        Efficacy of systemic morpholino exon-skipping in Duchenne dystrophy dogs.
        Ann Neurol. 2009; 65: 667-676
        • van Deutekom J.C.
        • Janson A.A.
        • Ginjaar I.B.
        • et al.
        Local dystrophin restoration with antisense oligonucleotide PRO051.
        N Engl J Med. 2007; 357: 2677-2686
        • Kinali M.
        • Arechavala-Gomeza V.
        • Feng L.
        • et al.
        Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-of-concept study.
        Lancet Neurol. 2009; 8: 918-928
        • Goemans N.M.
        • Tulinius M.
        • van den Akker J.T.
        • et al.
        Systemic administration of PRO051 in Duchenne's muscular dystrophy.
        N Engl J Med. 2011; 364: 1513-1522
        • Cirak S.
        • Arechavala-Gomeza V.
        • Guglieri M.
        • et al.
        Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study.
        Lancet. 2011; 378: 595-605
        • JR M.
        • Rodino-Klapac L.R.
        • Sahenk Z.
        • et al.
        Eteplirsen for the treatment of Duchenne muscular dystrophy.
        Ann Neurol. 2013; 74: 637-647
        • McDonald C.M.
        • Henricson E.K.
        • Abresch R.T.
        • et al.
        The 6-minute walk test and other clinical endpoints in duchenne muscular dystrophy: Reliability, concurrent validity, and minimal clinically important differences from a multicenter study.
        Muscle Nerve. 2013; 48: 357-368
        • McDonald C.M.
        • Henricson E.K.
        • Han J.J.
        • et al.
        The 6-minute walk test in Duchenne/Becker muscular dystrophy: longitudinal observations.
        Muscle Nerve. 2010; 42: 966-974
        • Strober J.B.
        Therapeutics in duchenne muscular dystrophy.
        NeuroRx. 2006; 3: 225-234
        • Mendell J.R.
        • Buzin C.H.
        • Feng J.
        • et al.
        Diagnosis of Duchenne dystrophy by enhanced detection of small mutations.
        Neurology. 2001; 57: 645-650
        • Flanigan K.M.
        • von Niederhausern A.
        • Dunn D.M.
        • Alder J.
        • Mendell J.R.
        • Weiss R.B.
        Rapid direct sequence analysis of the dystrophin gene.
        Am J Hum Gen. 2003; 72: 931-939
        • Du L.
        • Damoiseaux R.
        • Nahas S.
        • et al.
        Nonaminoglycoside compounds induce readthrough of nonsense mutations.
        J Exp Med. 2009; 206: 2285-2297
        • Du M.
        • Jones J.R.
        • Lanier J.
        • et al.
        Aminoglycoside suppression of a premature stop mutation in a Cftr-/- mouse carrying a human CFTR-G542X transgene.
        J Mol Med (Berl). 2002; 80: 595-604
        • Barton-Davis E.R.
        • Cordier L.
        • Shoturma D.I.
        • Leland S.E.
        • Sweeney H.L.
        Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice.
        J Clin Invest. 1999; 104: 375-381
        • Wagner K.R.
        • Hamed S.
        • Hadley D.W.
        • et al.
        Gentamicin treatment of Duchenne and Becker muscular dystrophy due to nonsense mutations.
        Ann Neurol. 2001; 49: 706-711
        • Politano L.
        • Nigro G.
        • Nigro V.
        • et al.
        Gentamicin administration in Duchenne patients with premature stop codon. Preliminary results.
        Acta Myol. 2003; 22: 15-21
        • Malik V.
        • Rodino-Klapac L.R.
        • Viollet L.
        • et al.
        Gentamicin-induced readthrough of stop codons in Duchenne muscular dystrophy.
        Ann Neurol. 2010; 67: 771-780
        • Ahmad A.
        • Brinson M.
        • Hodges B.L.
        • Chamberlain J.S.
        • Amalfitano A.
        Mdx mice inducibly expressing dystrophin provide insights into the potential of gene therapy for duchenne muscular dystrophy.
        Hum Mol Gen. 2000; 9: 2507-2515
        • Ghahramani Seno M.M.
        • Graham I.R.
        • Athanasopoulos T.
        • et al.
        RNAi-mediated knockdown of dystrophin expression in adult mice does not lead to overt muscular dystrophy pathology.
        Hum Mol Gen. 2008; 17: 2622-2632
        • Tang H.Y.
        • Hutcheson E.
        • Neill S.
        • Drummond-Borg M.
        • Speer M.
        • Alford R.L.
        Genetic susceptibility to aminoglycoside ototoxicity: how many are at risk?.
        Genet Med. 2002; 4: 336-345
        • Viollet L.
        • Gailey S.
        • Thornton D.J.
        • et al.
        Utility of Cystatin C to Monitor Renal Function in Duchenne Muscular Dystrophy.
        Muscle Nerve. 2009; 40: 438-442
        • Howard M.T.
        • Shirts B.H.
        • Petros L.M.
        • Flanigan K.M.
        • Gesteland R.F.
        • Atkins J.F.
        Sequence specificity of aminoglycoside-induced stop condon readthrough: potential implications for treatment of Duchenne muscular dystrophy.
        Ann Neurol. 2000; 48: 164-169
        • Welch E.M.
        • Barton E.R.
        • Zhuo J.
        • et al.
        PTC124 targets genetic disorders caused by nonsense mutations.
        Nature. 2007; 447: 87-91
        • Hirawat S.
        • Welch E.M.
        • Elfring G.L.
        • et al.
        Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers.
        J Clin Pharmacol. 2007; 47: 430-444
      1. Quinlivan R KJ, Comi G, Bushby K, the Ataluren DBMD Study Group. Safety and efficacy of ataluren 10,10,20 mg/kg TID in patients with nonsense mutation dystrophinopathy. European Paediatric Neurology Society Congress, 9th EPNS Congress [online]; 2010.

        • Mendell J.R.
        • Moxley R.T.
        • Griggs R.C.
        • et al.
        Randomized, double-blind six-month trial of prednisone in Duchenne's muscular dystrophy.
        N Engl J Med. 1989; 320: 1592-1597
        • Griggs R.C.
        • Herr B.E.
        • Reha A.
        • et al.
        Corticosteroids in Duchenne muscular dystrophy: major variations in practice.
        Muscle & Nerve. 2013; 48: 27-31
        • Mendell J.R.
        • Shilling C.
        • Leslie N.D.
        • et al.
        Evidence-based path to newborn screening for Duchenne muscular dystrophy.
        Ann Neurol. 2012; 71: 304-313
        • 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
        • England S.B.
        • Nicholson L.V.
        • Johnson M.A.
        • et al.
        Very mild muscular dystrophy associated with the deletion of 46% of dystrophin.
        Nature. 1990; 343: 180-182
        • 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 U S A. 2000; 97: 13714-13719
        • Watchko J.
        • O'Day T.
        • Wang B.
        • et al.
        Adeno-associated virus vector-mediated minidystrophin gene therapy improves dystrophic muscle contractile function in mdx mice.
        Hum Gene Ther. 2002; 13: 1451-1460
        • Mendell J.R.
        • Campbell K.
        • Rodino-Klapac L.
        • et al.
        Dystrophin immunity in Duchenne's muscular dystrophy.
        N Engl J Med. 2010; 363: 1429-1437
        • Flanigan K.M.
        • Campbell K.
        • Viollet L.
        • et al.
        Anti-Dystrophin T Cell Responses in Duchenne Muscular Dystrophy: Prevalence and a Glucocorticoid Treatment Effect.
        Hum Gene Ther Methods. 2013; 24: 797-806
        • Moore S.
        • Shilling C.
        • Mendell J.
        Limb-Girdle Muscular Dystrophy in the United States.
        J Neuropath Exp Neurol. 2006; 65: 995-1003
        • Rodino-Klapac L.R.
        • Lee J.S.
        • Mulligan R.C.
        • Clark K.R.
        • Mendell J.R.
        Lack of toxicity of alpha-sarcoglycan overexpression supports clinical gene transfer trial in LGMD2D.
        Neurology. 2008; 71: 240-247
        • Mendell J.R.
        • Rodino-Klapac L.R.
        • Rosales-Quintero X.
        • et al.
        Limb-girdle muscular dystrophy type 2D gene therapy restores alpha-sarcoglycan and associated proteins.
        Ann Neurol. 2009; 66: 290-297
        • Mendell J.R.
        • Rodino-Klapac L.R.
        • Rosales X.Q.
        • et al.
        Sustained alpha-sarcoglycan gene expression after gene transfer in limb-girdle muscular dystrophy, type 2D.
        Ann Neurol. 2010; 68: 629-638
        • Toromanoff A.
        • Cherel Y.
        • Guilbaud M.
        • et al.
        Safety and efficacy of regional intravenous (r.i.) versus intramuscular (i.m.) delivery of rAAV1 and rAAV8 to nonhuman primate skeletal muscle.
        Mol Ther. 2008; 16: 1291-1299
        • Toromanoff A.
        • Adjali O.
        • Larcher T.
        • et al.
        Lack of immunotoxicity after regional intravenous (RI) delivery of rAAV to nonhuman primate skeletal muscle.
        Mol Ther. 2010; 18: 151-160
        • Rodino-Klapac L.R.
        • Montgomery C.L.
        • Bremer W.G.
        • et al.
        Persistent expression of FLAG-tagged micro dystrophin in nonhuman primates following intramuscular and vascular delivery.
        Mol Ther. 2010; 18: 109-117
        • Hegge J.O.
        • Wooddell C.I.
        • Zhang G.
        • et al.
        Evaluation of hydrodynamic limb vein injections in nonhuman primates.
        Hum Gene Ther. 2010; 21: 829-842
        • Arruda V.R.
        • Stedman H.H.
        • Nichols T.C.
        • et al.
        Regional intravascular delivery of AAV-2-F.IX to skeletal muscle achieves long-term correction of hemophilia B in a large animal model.
        Blood. 2005; 105: 3458-3464
        • Katwal A.B.
        • Konkalmatt P.R.
        • Piras B.A.
        • et al.
        Adeno-associated virus serotype 9 efficiently targets ischemic skeletal muscle following systemic delivery.
        Gene Ther. 2013; 20: 930-938
        • Rodino-Klapac L.R.
        • Montgomery C.L.
        • Mendell J.R.
        • Chicoine L.G.
        AAV-mediated gene therapy to the isolated limb in rhesus macaques.
        Methods Mol Biol. 2011; 709: 287-298
        • Rodino-Klapac L.R.
        • Janssen P.M.
        • Montgomery C.L.
        • et al.
        A translational approach for limb vascular delivery of the micro-dystrophin gene without high volume or high pressure for treatment of Duchenne muscular dystrophy.
        J Transl Med. 2007; 5: 45
        • Liu J.
        • Aoki M.
        • Illa I.
        • et al.
        Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy.
        Nature Genetics. 1998; 20: 31-36
        • Illa I.
        • Serrano-Munuera C.
        • Gallardo E.
        • et al.
        Distal anterior compartment myopathy: a dysferlin mutation causing a new muscular dystrophy phenotype.
        Ann Neurol. 2001; 49: 130-134
        • Nagashima T.
        • Chuma T.
        • Mano Y.
        • et al.
        Dysferlinopathy associated with rigid spine syndrome.
        Neuropathology. 2004; 24: 341-346
        • Grose W.E.
        • Clark K.R.
        • Griffin D.
        • et al.
        Homologous Recombination Mediates Functional Recovery of Dysferlin Deficiency following AAV5 Gene Transfer.
        Plos One. 2012; 7
        • Krahn M.
        • Wein N.
        • Bartoli M.
        • et al.
        A naturally occurring human minidysferlin protein repairs sarcolemmal lesions in a mouse model of dysferlinopathy.
        Sci Transl Med. 2010; 2: 50ra69
        • Lostal W.
        • Bartoli M.
        • Bourg N.
        • et al.
        Efficient recovery of dysferlin deficiency by dual adeno-associated vector-mediated gene transfer.
        Hum Mol Gen. 2010; 19: 1897-1907