Second-generation compound for the modulation of utrophin in the therapy of DMD.
Duchenne muscular dystrophy (DMD) is a lethal, X-linked muscle-wasting disease caused by lack of the cytoskeletal protein dystrophin. There is currently no cure for DMD although various promising approaches are progressing through human clinical trials. By pharmacologically modulating the expression of the dystrophin-related protein utrophin, we have previously demonstrated in dystrophin-deficient mdx studies, daily SMT C1100 treatment significantly reduced muscle degeneration leading to improved muscle function. This manuscript describes the significant disease modifying benefits associated with daily dosing of SMT022357, a second-generation compound in this drug series with improved physicochemical properties and a more robust metabolism profile. These studies in the mdx mouse demonstrate that oral administration of SMT022357 leads to increased utrophin expression in skeletal, respiratory and cardiac muscles. Significantly, utrophin expression is localized along the length of the muscle fibre, not just at the synapse, and is fibre-type independent, suggesting that drug treatment is modulating utrophin transcription in extra-synaptic myonuclei. This results in improved sarcolemmal stability and prevents dystrophic pathology through a significant reduction of regeneration, necrosis and fibrosis. All these improvements combine to protect the mdx muscle from contraction induced damage and enhance physiological function. This detailed evaluation of the SMT C1100 drug series strongly endorses the therapeutic potential of utrophin modulation as a disease modifying therapeutic strategy for all DMD patients irrespective of their dystrophin mutation.
Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK, simon.guiraud@dpag.ox.ac.uk kay.davies@dpag.ox.ac.uk.
Simon
S
Guiraud
Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK.
Sarah E
SE
Squire
Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK.
Benjamin
B
Edwards
Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK.
Huijia
H
Chen
Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK.
David T
DT
Burns
Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK.
Nandini
N
Shah
Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK.
Arran
A
Babbs
Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.
Stephen G
SG
Davies
Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.
Graham M
GM
Wynne
Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK, Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3PT, UK and.
Angela J
AJ
Russell
Summit Therapeutics plc, 85b Park Drive, Milton Park, Abingdon, Oxfordshire OX14 4RY, UK.
David
D
Elsey
Summit Therapeutics plc, 85b Park Drive, Milton Park, Abingdon, Oxfordshire OX14 4RY, UK.
Francis X
FX
Wilson
Summit Therapeutics plc, 85b Park Drive, Milton Park, Abingdon, Oxfordshire OX14 4RY, UK.
Jon M
JM
Tinsley
Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK, simon.guiraud@dpag.ox.ac.uk kay.davies@dpag.ox.ac.uk.
Kay E
KE
Davies
D000818:Animals; D016189:Dystrophin / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D018101:Mice, Inbred mdx; D009119:Muscle Contraction / Q000187:drug effects / Q000235:genetics; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000473:pathology; D009132:Muscles / Q000187:drug effects / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000235:genetics; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D012508:Sarcolemma / Q000187:drug effects / Q000235:genetics; D049411:Utrophin / Q000096:biosynthesis* / Q000235:genetics
D016189:Dystrophin; D049411:Utrophin