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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 improves the pathology in the diaphragm. (A) Immunofluoresence staining for utrophin in the diaphragm of 7 weeks old mdx mice treated for 5 weeks with 30 mg/kg/day SMT022357 or vehicle (n = 10 per group). Sections were stained with anti-utrophin polyclonal antibody URD40 and anti-rabbit secondary antibody. H&E-stained transverse muscle sections of diaphragm muscle (7 weeks of age) showed improved morphology in treated vs. vehicle mdx mice (n = 10 per group). Masson's trichrome staining of diaphragm in untreated vs. treated mdx mice (n = 8) indicated that SMT022357 treatment reduced the amount of collagen infiltration (stained in blue); immunofluorescence using anti-collagen type I antibody confirmed a decrease of collagen in the muscular endomysium of SMT022357 treated diaphragm. Scale bar 100 µm. (B) Diaphragms of mice dosed with SMT022357 showed a significant 35.9% decrease in centrally nucleated fibres compared to the vehicle group. Values are mean ± SEM of n = 8 per groups; ***P < 0.001. (C) The necrotic diaphragm area of mice treated with SMT022357 significantly decreased by 56.6% compared to the vehicle group. Values are mean ± SEM of n = 8 per group; *P < 0.05. (D) The vehicle mdx diaphragm exhibits positive staining with Alizarin Red indicating the presence of calcium deposits. SMT022357 treatment completely prevented the calcification. (n = 10 per group); Scale bar: 100 µm.
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DDV154F7: SMT022357 improves the pathology in the diaphragm. (A) Immunofluoresence staining for utrophin in the diaphragm of 7 weeks old mdx mice treated for 5 weeks with 30 mg/kg/day SMT022357 or vehicle (n = 10 per group). Sections were stained with anti-utrophin polyclonal antibody URD40 and anti-rabbit secondary antibody. H&E-stained transverse muscle sections of diaphragm muscle (7 weeks of age) showed improved morphology in treated vs. vehicle mdx mice (n = 10 per group). Masson's trichrome staining of diaphragm in untreated vs. treated mdx mice (n = 8) indicated that SMT022357 treatment reduced the amount of collagen infiltration (stained in blue); immunofluorescence using anti-collagen type I antibody confirmed a decrease of collagen in the muscular endomysium of SMT022357 treated diaphragm. Scale bar 100 µm. (B) Diaphragms of mice dosed with SMT022357 showed a significant 35.9% decrease in centrally nucleated fibres compared to the vehicle group. Values are mean ± SEM of n = 8 per groups; ***P < 0.001. (C) The necrotic diaphragm area of mice treated with SMT022357 significantly decreased by 56.6% compared to the vehicle group. Values are mean ± SEM of n = 8 per group; *P < 0.05. (D) The vehicle mdx diaphragm exhibits positive staining with Alizarin Red indicating the presence of calcium deposits. SMT022357 treatment completely prevented the calcification. (n = 10 per group); Scale bar: 100 µm.

Mentions: The expression of utrophin was analysed by immunofluoresence and western blot. After treatment with SMT022357, utrophin staining appeared more homogeneous around the diaphragm fibre membranes compared with vehicle-treated mice (Fig. 7A). Western blot analysis showed that after 5 weeks of SMT022357 treatment total levels of utrophin protein were increased by 20% in the mdx mouse diaphragm (Supplementary Material, Fig. S2A). Analysis of the diaphragm pathology after SMT022357 treatment demonstrated a significant decrease of centrally nucleated fibres by 35.9% (P < 0.0001), a biomarker of regeneration, and a 56.6% (P = 0.04) reduction of necrotic area compared with vehicle treated (Fig. 7B and C).Figure 7.


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 improves the pathology in the diaphragm. (A) Immunofluoresence staining for utrophin in the diaphragm of 7 weeks old mdx mice treated for 5 weeks with 30 mg/kg/day SMT022357 or vehicle (n = 10 per group). Sections were stained with anti-utrophin polyclonal antibody URD40 and anti-rabbit secondary antibody. H&E-stained transverse muscle sections of diaphragm muscle (7 weeks of age) showed improved morphology in treated vs. vehicle mdx mice (n = 10 per group). Masson's trichrome staining of diaphragm in untreated vs. treated mdx mice (n = 8) indicated that SMT022357 treatment reduced the amount of collagen infiltration (stained in blue); immunofluorescence using anti-collagen type I antibody confirmed a decrease of collagen in the muscular endomysium of SMT022357 treated diaphragm. Scale bar 100 µm. (B) Diaphragms of mice dosed with SMT022357 showed a significant 35.9% decrease in centrally nucleated fibres compared to the vehicle group. Values are mean ± SEM of n = 8 per groups; ***P < 0.001. (C) The necrotic diaphragm area of mice treated with SMT022357 significantly decreased by 56.6% compared to the vehicle group. Values are mean ± SEM of n = 8 per group; *P < 0.05. (D) The vehicle mdx diaphragm exhibits positive staining with Alizarin Red indicating the presence of calcium deposits. SMT022357 treatment completely prevented the calcification. (n = 10 per group); Scale bar: 100 µm.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4492389&req=5

DDV154F7: SMT022357 improves the pathology in the diaphragm. (A) Immunofluoresence staining for utrophin in the diaphragm of 7 weeks old mdx mice treated for 5 weeks with 30 mg/kg/day SMT022357 or vehicle (n = 10 per group). Sections were stained with anti-utrophin polyclonal antibody URD40 and anti-rabbit secondary antibody. H&E-stained transverse muscle sections of diaphragm muscle (7 weeks of age) showed improved morphology in treated vs. vehicle mdx mice (n = 10 per group). Masson's trichrome staining of diaphragm in untreated vs. treated mdx mice (n = 8) indicated that SMT022357 treatment reduced the amount of collagen infiltration (stained in blue); immunofluorescence using anti-collagen type I antibody confirmed a decrease of collagen in the muscular endomysium of SMT022357 treated diaphragm. Scale bar 100 µm. (B) Diaphragms of mice dosed with SMT022357 showed a significant 35.9% decrease in centrally nucleated fibres compared to the vehicle group. Values are mean ± SEM of n = 8 per groups; ***P < 0.001. (C) The necrotic diaphragm area of mice treated with SMT022357 significantly decreased by 56.6% compared to the vehicle group. Values are mean ± SEM of n = 8 per group; *P < 0.05. (D) The vehicle mdx diaphragm exhibits positive staining with Alizarin Red indicating the presence of calcium deposits. SMT022357 treatment completely prevented the calcification. (n = 10 per group); Scale bar: 100 µm.
Mentions: The expression of utrophin was analysed by immunofluoresence and western blot. After treatment with SMT022357, utrophin staining appeared more homogeneous around the diaphragm fibre membranes compared with vehicle-treated mice (Fig. 7A). Western blot analysis showed that after 5 weeks of SMT022357 treatment total levels of utrophin protein were increased by 20% in the mdx mouse diaphragm (Supplementary Material, Fig. S2A). Analysis of the diaphragm pathology after SMT022357 treatment demonstrated a significant decrease of centrally nucleated fibres by 35.9% (P < 0.0001), a biomarker of regeneration, and a 56.6% (P = 0.04) reduction of necrotic area compared with vehicle treated (Fig. 7B and C).Figure 7.

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