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Second-generation compound for the modulation of utrophin in the therapy of DMD.

Guiraud S, Squire SE, Edwards B, Chen H, Burns DT, Shah N, Babbs A, Davies SG, Wynne GM, Russell AJ, Elsey D, Wilson FX, Tinsley JM, Davies KE - Hum. Mol. Genet. (2015)

Bottom Line: These studies in the mdx mouse demonstrate that oral administration of SMT022357 leads to increased utrophin expression in skeletal, respiratory and cardiac muscles.This results in improved sarcolemmal stability and prevents dystrophic pathology through a significant reduction of regeneration, necrosis and fibrosis.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

No MeSH data available.


Related in: MedlinePlus

SMT022357 treatment improves fibre membrane stability. Immunofluoresence staining for β-dystroglycan, and dystrobrevin in EDL muscle of 7 weeks old mdx mice treated for 5 weeks with 30 mg/kg/day SMT022357 or vehicle shows that key components of the DAPC complex are properly localised to the sarcolemma after SMT022357 treatment. n = 3 per group; Scale bar: 100 µm.
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DDV154F4: SMT022357 treatment improves fibre membrane stability. Immunofluoresence staining for β-dystroglycan, and dystrobrevin in EDL muscle of 7 weeks old mdx mice treated for 5 weeks with 30 mg/kg/day SMT022357 or vehicle shows that key components of the DAPC complex are properly localised to the sarcolemma after SMT022357 treatment. n = 3 per group; Scale bar: 100 µm.

Mentions: Next, we evaluated the restoration of membrane stability in dystrophin-negative myofibres following the increased level of utrophin at the sarcolemma. Key elements of the DAPC complex such as β-dystroglycan, which directly binds to laminin in the extracellular matrix, are not properly localized into the sarcolemma in DMD patients resulting in muscle damage after repeated contractions (50). As illustrated in Figure 4, in EDL muscles treated with SMT022357, localization of β-dystroglycan and dystrobrevin (another member of the DAPC) was restored to the sarcolemma of all fibres. This translated to a 1.7- and 1.3-fold increase of β-dystroglycan and dystrobrevin expression, respectively, when quantified by western blots (Supplementary Material, Fig. S2B). This data predicts an improvement of muscle membrane stability when utrophin acts as a dystrophin surrogate to maintain the DAPC complex including the major component of the DAPC-laminin axis.Figure 4.


Second-generation compound for the modulation of utrophin in the therapy of DMD.

Guiraud S, Squire SE, Edwards B, Chen H, Burns DT, Shah N, Babbs A, Davies SG, Wynne GM, Russell AJ, Elsey D, Wilson FX, Tinsley JM, Davies KE - Hum. Mol. Genet. (2015)

SMT022357 treatment improves fibre membrane stability. Immunofluoresence staining for β-dystroglycan, and dystrobrevin in EDL muscle of 7 weeks old mdx mice treated for 5 weeks with 30 mg/kg/day SMT022357 or vehicle shows that key components of the DAPC complex are properly localised to the sarcolemma after SMT022357 treatment. n = 3 per group; Scale bar: 100 µm.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492389&req=5

DDV154F4: SMT022357 treatment improves fibre membrane stability. Immunofluoresence staining for β-dystroglycan, and dystrobrevin in EDL muscle of 7 weeks old mdx mice treated for 5 weeks with 30 mg/kg/day SMT022357 or vehicle shows that key components of the DAPC complex are properly localised to the sarcolemma after SMT022357 treatment. n = 3 per group; Scale bar: 100 µm.
Mentions: Next, we evaluated the restoration of membrane stability in dystrophin-negative myofibres following the increased level of utrophin at the sarcolemma. Key elements of the DAPC complex such as β-dystroglycan, which directly binds to laminin in the extracellular matrix, are not properly localized into the sarcolemma in DMD patients resulting in muscle damage after repeated contractions (50). As illustrated in Figure 4, in EDL muscles treated with SMT022357, localization of β-dystroglycan and dystrobrevin (another member of the DAPC) was restored to the sarcolemma of all fibres. This translated to a 1.7- and 1.3-fold increase of β-dystroglycan and dystrobrevin expression, respectively, when quantified by western blots (Supplementary Material, Fig. S2B). This data predicts an improvement of muscle membrane stability when utrophin acts as a dystrophin surrogate to maintain the DAPC complex including the major component of the DAPC-laminin axis.Figure 4.

Bottom Line: These studies in the mdx mouse demonstrate that oral administration of SMT022357 leads to increased utrophin expression in skeletal, respiratory and cardiac muscles.This results in improved sarcolemmal stability and prevents dystrophic pathology through a significant reduction of regeneration, necrosis and fibrosis.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

No MeSH data available.


Related in: MedlinePlus