After years of relentless efforts, gene therapy has now begun to deliver its therapeutic promise in several diseases. A number of gene therapy products have received regulatory approval in Europe and Asia. Duchenne muscular dystrophy (DMD) is an X-linked inherited lethal muscle disease. It is caused by mutations in the dystrophin gene. Replacing and/or repairing the mutated dystrophin gene holds great promises to treated DMD at the genetic level. Last several years have evidenced significant developments in preclinical experimentations in murine and canine models of DMD. There has been a strong interest in moving these promising findings to clinical trials. In light of rapid progress in this field, the Parent Project Muscular Dystrophy (PPMD) recently interviewed me on the current status of DMD gene therapy and readiness for clinical trials. Here I summarized the interview with PPMD.
Get full access to this article
View all access options for this article.
References
1.
BernsKI, ByrneBJ, FlotteTR, et al.Adeno-associated virus type 2 and hepatocellular carcinoma?. Hum Gene Ther, 2015; 26:779–781.
2.
WilsonJM. Adverse events in gene transfer trials and an agenda for the new year. Hum Gene Ther, 2008; 19:1–2.
3.
Board of the European Society of Gene and Cell Therapy. Case of leukaemia associated with X-linked severe combined immunodeficiency gene therapy trial in London. Hum Gene Ther, 2008; 19:3–4.
4.
NaldiniL. Gene therapy returns to centre stage. Nature, 2015; 526:351–360.
BrimbleMA, ReissUM, NathwaniAC, DavidoffAM. New and improved AAVenues: Current status of hemophilia B gene therapy. Expert Opin Biol Ther, 2016; 16:79–92.
7.
HighKA, AnguelaXM. Adeno-associated viral vectors for the treatment of hemophilia. Hum Mol Genet, 2015. [Epub ahead of print]
8.
WilsonJM. Gendicine: The first commercial gene therapy product. Hum Gene Ther, 2005; 16:1014–1015.
9.
MaG, ShimadaH, HiroshimaK, et al.Gene medicine for cancer treatment: Commercially available medicine and accumulated clinical data in China. Drug Des Dev Ther, 2009; 2:115–122.
10.
GordonEM, HallFL. Rexin-G, a targeted genetic medicine for cancer. Expert Opin Biol Ther, 2010; 10:819–832.
DeevRV, BozoIY, MzhavanadzeND, et al.pCMV-vegf165 intramuscular gene transfer is an effective method of treatment for patients with chronic lower limb ischemia. J Cardiovasc Pharmacol Ther, 2015; 20:473–482.
13.
BryantLM, ChristopherDM, GilesAR, et al.Lessons learned from the clinical development and market authorization of Glybera. Hum Gene Ther Clin Dev, 2013; 24:55–64.
14.
MelchiorriD, PaniL, GaspariniP, et al.Regulatory evaluation of Glybera in Europe—two committees, one mission. Nat Rev Drug Discov, 2013; 12:719.
GreigSL. Talimogene laherparepvec: First global approval. Drugs, 2016; 76:147–154.
17.
KunkelLM. 2004 William Allan award address. Cloning of the DMD gene. Am J Hum Genet, 2005; 76:205–214.
18.
BladenCL, SalgadoD, MongesS, et al.The TREAT-NMD DMD global database: Analysis of more than 7000 Duchenne muscular dystrophy mutations. Hum Mutat, 2015; 36:395–402.
19.
EnglandSB, NicholsonLV, JohnsonMA, et al.Very mild muscular dystrophy associated with the deletion of 46% of dystrophin. Nature, 1990; 343:180–182.
20.
WilsonJM. Lessons learned from the gene therapy trial for ornithine transcarbamylase deficiency. Mol Genet Metab, 2009; 96:151–157.
21.
DuanD. Myodys, a full-length dystrophin plasmid vector for Duchenne and Becker muscular dystrophy gene therapy. Curr Opin Mol Ther, 2008; 10:86–94.
22.
RomeroNB, BraunS, BenvenisteO, et al.Phase I study of dystrophin plasmid-based gene therapy in Duchenne/Becker muscular dystrophy. Hum Gene Ther, 2004; 15:1065–1076.
23.
StedmanH, WilsonJM, FinkeR, et al.Phase I clinical trial utilizing gene therapy for limb girdle muscular dystrophy: Alpha-, beta-, gamma-, or delta-sarcoglycan gene delivered with intramuscular instillations of adeno-associated vectors. Hum Gene Ther, 2000; 11:777–790.
24.
MendellJR, Rodino-KlapacLR, Rosales-QuinteroX, et al.Limb-girdle muscular dystrophy type 2D gene therapy restores alpha-sarcoglycan and associated proteins. Ann Neurol, 2009; 66:290–297.
25.
MendellJR, CampbellK, Rodino-KlapacL, et al.Dystrophin immunity in Duchenne's muscular dystrophy. N Engl J Med, 2010; 363:1429–1437.
26.
MannoCS, ArrudaVR, PierceGF, et al.Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med, 2006; 12:342–347.
27.
SpitaliP, Aartsma-RusA. Splice modulating therapies for human disease. Cell, 2012; 148:1085–1088.
28.
van DeutekomJC, JansonAA, GinjaarIB, et al.Local dystrophin restoration with antisense oligonucleotide PRO051. N Engl J Med, 2007; 357:2677–2686.
GoyenvalleA, GriffithG, BabbsA, et al.Functional correction in mouse models of muscular dystrophy using exon-skipping tricyclo-DNA oligomers. Nat Med, 2015; 21:270–275.
31.
NanceME, DuanD. Perspective on adeno-associated virus (AAV) capsid modification for Duchenne muscular dystrophy gene therapy. Hum Gene Ther, 2015; 26:786–800.
32.
KoenigM, HoffmanEP, BertelsonCJ, et al.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.
33.
KoenigM, MonacoAP, KunkelLM. The complete sequence of dystrophin predicts a rod-shaped cytoskeletal protein. Cell, 1988; 53:219–226.
34.
HoffmanEP, BrownRHJr., KunkelLM. Dystrophin: The protein product of the Duchenne muscular dystrophy locus. Cell, 1987; 51:919–928.
DelloRussoC, ScottJM, Hartigan-O'ConnorD, et al.Functional correction of adult mdx mouse muscle using gutted adenoviral vectors expressing full-length dystrophin. Proc Natl Acad Sci U S A, 2002; 99:12979–12984.
37.
ScottJ, LiS, HarperS, et al.Viral vectors for gene transfer of micro-, mini-, or full-length dystrophin. Neuromuscul Disord, 2002; 12Suppl:S23.
38.
WinnardAV, KleinCJ, CoovertDD, et al.Characterization of translational frame exception patients in Duchenne/Becker muscular dystrophy. Hum Mol Genet, 1993; 2:737–744.
39.
MatsumuraK, BurghesAH, MoraM, et al.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.
40.
MirabellaM, GalluzziG, ManfrediG, et al.Giant dystrophin deletion associated with congenital cataract and mild muscular dystrophy. Neurology, 1998; 51:592–595.
41.
NicholsonLV, JohnsonMA, BushbyKM, et al.Integrated study of 100 patients with Xp21 linked muscular dystrophy using clinical, genetic, immunochemical, and histopathological data. Part 3. Differential diagnosis and prognosis. J Med Genet, 1993; 30:745–751.
DuanD. Duchenne muscular dystrophy gene therapy in the canine model. Hum Gene Ther Clin Dev, 2015; 26:57–69.
44.
DuanD. From the smallest virus to the biggest gene: Marching towards gene therapy for Duchenne muscular dystrophy. Discov Med, 2006; 6:103–108.
45.
OusteroutDG, KabadiAM, ThakorePI, et al.Multiplex CRISPR/Cas9-based genome editing for correction of dystrophin mutations that cause Duchenne muscular dystrophy. Nat Commun, 2015; 6:6244.
46.
WojtalD, KemaladewiDU, MalamZ, et al.Spell checking nature: Versatility of CRISPR/Cas9 for developing treatments for inherited disorders. Am J Hum Genet, 2016; 98:1–12.
47.
NelsonCE, HakimCH, OusteroutDG, et al.In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy. Science, 2016; 351:493–407.
48.
TabebordbarM, ZhuK, ChengJK, et al.In vivo gene editing in dystrophic mouse muscle and muscle stem cells. Science, 2016; 351:407–411.
49.
LongC, AmoasiiL, MireaultAA, et al.Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy. Science, 2016; 351:400–403.
50.
GregorevicP, BlankinshipMJ, AllenJM, et al.Systemic delivery of genes to striated muscles using adeno-associated viral vectors. Nat Med, 2004; 10:828–834.
51.
WangZ, ZhuT, QiaoC, et al.Adeno-associated virus serotype 8 efficiently delivers genes to muscle and heart. Nat Biotechnol, 2005; 23:321–328.
52.
YueY, GhoshA, LongC, et al.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.
53.
PanX, YueY, ZhangK, et al.Long-term robust myocardial transduction of the dog heart from a peripheral vein by adeno-associated virus serotype-8. Hum Gene Ther, 2013; 24:584–594.
54.
HakimCH, YueY, ShinJH, et al.Systemic gene transfer reveals distinctive muscle transduction profile of tyrosine mutant AAV-1, -6, and -9 in neonatal dogs. Mol Ther Methods Clin Dev, 2014; 1:14002.
55.
KornegayJN, LiJ, BoganJR, et al.Widespread muscle expression of an AAV9 human mini-dystrophin vector after intravenous injection in neonatal dystrophin-deficient dogs. Mol Ther, 2010; 18:1501–1508.
56.
YueY, PanX, HakimCH, et al.Safe and bodywide muscle transduction in young adult Duchenne muscular dystrophy dogs with adeno-associated virus. Hum Mol Genet, 2015; 24:5880–5890.
57.
GregorevicP, BlankinshipMJ, AllenJMet al. Systemic microdystrophin gene delivery improves skeletal muscle structure and function in old dystrophic mdx mice. Mol Ther, 2008; 16:657–664.
BostickB, ShinJH, YueYet al. 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.
60.
BurrAR, MolkentinJD. Genetic evidence in the mouse solidifies the calcium hypothesis of myofiber death in muscular dystrophy. Cell Death Differ, 2015; 22:1402–1412.
61.
van der LooJC, WrightJF. Progress and challenges in viral vector manufacturing. Hum Mol Genet, 2015. [Epub ahead of print]
