Recent advances in Duchenne muscular dystrophy

Figures & data

Table 1 Animal models used in assessing therapeutic strategies for Duchenne muscular dystrophy (DMD)

model	Providence	Mutation	Pathology and comments	Gene and protein replacement	Gene repair and exon skipping	Cell/pharmacological therapy
mdx^Citation24§ mouse	Spontaneous	3185C>T (exon 23) nonsense^Citation25	Muscle fiber degeneration/regeneration, myopathy less severe later in life, normal lifespan^Citation24 used for most strategies owing to breeding and experimental simplicity^Citation23‡	Gene replacement** adenovirus: mini-(mDYS), micro-(µDYS) dystrophin.^Citation77‡ Cell/gene replacement lentiviral: mDYS-MDSC^Citation91, plasmid: mDYS-MDSC^Citation95 - myoblast^Citation96,Citation97 DYS- HAC(FL)-iPS^Citation100, MAB^Citation101 Protein compensation utrophin (TAT-mUtr)^Citation180, biglycan (rhBGN)^Citation185, laminin (LAM-111)^Citation193,Citation194 utrophin upregulation	Gene repair^Citation102,Citation103 exon skipping 2’OMePS/PMO†, 2’OMePS/PMO MSTN^Citation273 2’OMePS MSTN/DYS^Citation274	Cell: allogenic human and mdx myoblasts‡^Citation55 allogenic murine and human MDSC^Citation62^–^Citation64* Pharmacological: Dystrophin gene: negamycin, gentamicin^Citation147,Citation148,Citation152 functional compensation/membrane stability: utrophin†, α7 integrin^Citation191,Citation192, PA188^Citation200, ROS inhibitors: antioxidants†, BGP-15^Citation215, Necrosis: PDE5 inhibitors^Citation230,Citation231, NO-releasing agents† MPTP/calpain inhibitors† Fibrosis: TGF-β/BMP/RAS antagonists† MSTN inhibition‡^Citation255 inflammation: prednisolone†, TNF-α/NF-κB inhibition^Citation162‡, IGF-1†
mdx4Cv^Citation27 mouse	ENU mutagenesis	7925C>T (exon 53) nonsense	10 times fewer fiber revertants than mdx-2Cv with essentially identical muscle pathology^Citation27	Gene replacement plasmid: mDYS^Citation86, adenovirus: mDYS^Citation77‡ Cell/gene replacement lentivirus: µDYS-SC^Citation92	Exon skipping 2’OMePS/PMO^Citation117 Multiple	None reported
mdx5Cv^Citation27 mouse	ENU mutagenesis	1306a>t SD (exon 10) missense	Pathology as per mdx4Cv^Citation27	Cell/gene replacement lentivirus: µDYS-MDSC^Citation90	Gene repair^Citation107,Citation108	Pharmacological ROS inhibitors/antioxidants: melatonin^Citation206
mdx52^Citation29 mouse	Targeted disruption	Δexon 52	Similar pathology to mdx, with limb muscle hypertrophy^Citation29	None reported	Exon-skipping PMO^Citation115	None reported
mdx;utrn-/- (dko)^Citation36 mouse	Targeted disruption	mdx:utrn tm1Jrs (exon 7) Nonsense	Considered a DMD phenocopy over mdx due to earlier onset of muscle dystrophy and premature death^Citation36	Gene replacement** adenovirus: mini-(mDYS) and micro-(µDYS) dystrophin^Citation77‡ Protein compensation utrophin (TAT-µUtr)^Citation180, α7 integrin peptide^Citation189	Exon-skipping in vivo: PMO adenovirus U7snRNA^Citation131	Cell Lentiviral systemic allogenic (donor derived) and autologous MAB^Citation73 Pharmacological Membrane stability: VPA^Citation191, ROS inhibitors: BGP-15^Citation215, fibrosis: RAS†^Citation267, BMP^Citation263, TGF-β^Citation249 antagonists, inflammation: IGF-1^Citation277
hDMD^Citation30 mouse	YAC insertion of full-length human dystrophin^Citation30	Telometric (chr 5) integration^Citation139	Complements dystrophic pathology in mdx (hDMD/mdx)^Citation30 and dko crosses (hDMD/dko)^Citation139	Not applicable	Exon-skipping in vivo: 2’OMePS single^Citation115 multiple^Citation30, 2’OMePS/PMO single^Citation124, adenovirus - U7snRNA multiple^Citation132	Not applicable
GRMD^Citation39 golden Retriever	Spontaneous	739-2a>g^Citation39 SA (intron 6) deletion	Most similar to DMD pathology of all models^Citation23 limitation of phenotypic variation between sibs^Citation39	Gene replacement adenovirus: mini-(mDYS) dystrophin^Citation77,Citation81‡, miniutrophin (mUtr)^Citation77‡^Citation80 Cell/gene replacement lentiviral: µDYSMDSC^Citation91, MAB^Citation93	Gene repair^Citation104 exon-skipping in vitro: 2’OMePs/PMO single^Citation113‡ in vivo: AAVU7snRNA single^Citation133,Citation134	Cell Systemic allogenic (donor-derived) canine MAB^Citation93 Pharmacological Membrane stability: PA188^Citation201 calpain inhibitors: C101^Citation237
CXMDJ^Citation40 beagle	Spontaneous	739-2a>g^Citation39 SA (intron 6) deletion	Phenotype as per GRMD; smaller breed size^Citation40	Gene replacement adenovirus: mini-(mDYS) dystrophin^Citation82	Exon-skipping in vitro: PMO single^Citation113 in vivo: 2’OMePS/PMO Multiple^Citation47,Citation116	Cell Systemic/intramuscular allogenic (donor-derived)^Citation72
CKCSMD^Citation44 spaniel	Spontaneous	7294+5t>g SD (intron 50) deletion	Phenotype as per GRMD; smaller breed size^Citation44	None reported	Exon-skipping cell based: PMO single^Citation44	None reported

Notes:

‡ Overview of experimental approach/pathology;

† multiple studies: refer to relevant sections;

* using mdx/severe combined immunodeficiency mice;

** dystrophin constructs only;

# human specific sequence. Approaches not reported for

§ mouse: mdx variants: mdx-2cv²⁷ (6326+2a>t)-3cv²⁷ (9772–16t>a);

‡ canine: (see³⁸), rottweiler⁴¹, German pointer⁴² and Japanese spitz⁴³, other: feline HFMD model (del Dp427m+Dp427p⁴⁹) and pig DMD-238 (Δexon 52)⁵⁰.

Abbreviations: SA/SD, splice acceptor/splice donor; ENU, N-ethyl-N-nitrosourea; SC, satellite cell; 2′OMePS, 2′-O-methyl oligoribonucleotide; PMO, phosphorodiamidate morpholino oligomer; iPS, induced pluripotent stem cells; FL, full length; rhBGN, recombinant human biglycan; MSTN, myostatin; MDSC, muscle derived stem cells; MAB, mesoangioblasts; HAC, human artificial chromosome; YAC, yeast artificial chromosome; PA188, polyaxamer188; TAT, HIV-1 trans activator of transcription protein; BMP, bone morphogenic protein; BGP-15, O-(3-piperidino-2-hydroxy-1-propyl) nicotinic amidoxime; TNFα, tumour necrosis factor alpha; TGFβ, transforming growth factor beta; IGF-1, insulin growth like factor 1; RAS, Renin-Angiotensin system; PDE5, phosphodiesterase 5; VPA, valproic acid.

Figure 1 Current genetic and pharmacological targets of dystrophic pathology.

Notes: Receptor or structural protein components at the skeletal muscle sarcolemma targeted for therapeutic purposes are represented in dark grey. Components of signaling pathways specifically targeted for intentional downregulation are represented in yellow boxes, with two key regulators of dystrophic pathology NFκB, and TNFα, highlighted in light blue. Associated white boxes contain the therapeutic compound(s) used to modulate either a positive (+) or negative (−) effect on a particular protein/receptor. Arrow-headed lines represent a simplified version of the signaling pathways involved in inflammatory, fibrotic, and hypertrophic responses, symbolizing only regulatory proteins that are covered in the text. The background-shaded section represents cellular process affected by calcium influx, with the red line representing the feedback mechanism with ROS, TNFα, and NFκB. The interactions delineated between and within signaling pathways are not an exhaustive representation and pharmacological compounds that act in a nonspecific or undetermined mode of action have been excluded. Red dots, representative mRNA sequence leading to translation stop codon; black dots, promoter elements; red squares, representative of gene modification by repair or insertion/deletion by zinc finger or meganucleases.
Abbreviations: PA, polyaxamer 188; TGF-β, transforming growth factor beta; PI3K, phosphatidylinositol 3-kinase; AKT, protein kinase B (PKB); IKK, IκB kinase; NF-κB, nuclear factor kappa-light-chain enhancer of activated B cells; BMP, bone morphogenic protein; AngII, angiotensin II; RI/RII, receptor I/II; AT, angiotensin; ACE, angiotensin-converting enzyme; NBD, NEMO binding domain; IGF-1, insulin growth factor 1; LAM-III, laminin-111 protein; VPA, valproic acid; ALK-4, activin receptor-like kinase; ActRII, activin receptor type II; BCL/ABL, breakpoint cluster region/Abelson murine leukemia viral oncogene homologue 1; Akt, acutely transforming retrovirus AKT8 in rodent T-cell lymphoma; [Ca²⁺]i, intracellular calcium; L-Arg, L-arginine; NO, nitric oxide; nNOS, neural nitric oxide synthase; cGMP, cyclic guanosine monophosphate; GMP, guanosine monophosphate; GC, guanylate cyclase; BGP-15, O-(3-piperidino-2-hydroxy-1-propyl) nicotinic amidoxime; PDE5, cGMP-specific phosphodiesterase type 5; TNF-α, tumour necrosis factor alpha; CsA, cyclosporine A; ROS, reactive oxygen species; MPTP, mitochondrial permeability transition pore; cycD, cyclophilin D; HSP72, heat shock protein 72; SERCA, sarco/endoplasmic reticulum Ca²⁺-ATPase; SG, sarcoglycans; Src, sarcospan; syn, sytrophin; db, dystrobrevin; RDO, RNA/DNA oligonucleotide; AON, antisense oligonucleotide; 2′OMePS, 2′-O-methyl oligoribonucleotide; PMO, phosphorodiamidate morpholino oligomer; AICAR, 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide; UTRN/DMD/MSTN, utrophin/DMD/myostatin gene; DAPC, dystrophin-associated protein complex; LAM, laminin; Utr, utrophin minigene construct; cDNA, complementary DNA.

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