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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 prevents muscular dystrophy in skeletal muscle. (A) Creatine kinase (CK) levels in serum following daily oral gavage of mdx mice with 30 mg/kg of SMT022357 or vehicle from two weeks of age for five weeks. A 47% decrease in serum CK was observed after treatment with SMT022357 compared to vehicle-treated animals (n = 7-9 per group). (B) H&E-stained transverse muscle sections of EDL muscle (7 weeks of age) in untreated vs. treated mdx mice (n = 10 per group) showing necrotic areas (black stars) and regenerating fibres (black arrows). Scale bar: 100 µm. (C) Muscle from mice dosed with SMT022357 showed a significant 20.1% (P = 0.03) decrease in centrally nucleated fibres compared to the vehicle group in EDL muscles. Values are mean ± SEM of n = 9 per groups; *P < 0.05. (D) The necrotic muscle area in EDL of mice treated with SMT022357 significantly decreased by 63.1% (P = 0.02) compared to the vehicle group. Values are mean ± SEM of n = 9 per groups; *P < 0.05. (E) Muscle from mice dosed with SMT022357 showed a significant 19.6% (P = 0.02) decrease in centrally nucleated fibres compared to the vehicle group in SOL muscles. Values are mean ± SEM of n = 7 per groups; *P < 0.05. (F) The necrotic muscle area in SOL of mice treated with SMT022357 decreased by 57.3% (P = 0.06) compared to the vehicle group. Values are mean ± SEM of n = 7 per groups.
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DDV154F5: SMT022357 prevents muscular dystrophy in skeletal muscle. (A) Creatine kinase (CK) levels in serum following daily oral gavage of mdx mice with 30 mg/kg of SMT022357 or vehicle from two weeks of age for five weeks. A 47% decrease in serum CK was observed after treatment with SMT022357 compared to vehicle-treated animals (n = 7-9 per group). (B) H&E-stained transverse muscle sections of EDL muscle (7 weeks of age) in untreated vs. treated mdx mice (n = 10 per group) showing necrotic areas (black stars) and regenerating fibres (black arrows). Scale bar: 100 µm. (C) Muscle from mice dosed with SMT022357 showed a significant 20.1% (P = 0.03) decrease in centrally nucleated fibres compared to the vehicle group in EDL muscles. Values are mean ± SEM of n = 9 per groups; *P < 0.05. (D) The necrotic muscle area in EDL of mice treated with SMT022357 significantly decreased by 63.1% (P = 0.02) compared to the vehicle group. Values are mean ± SEM of n = 9 per groups; *P < 0.05. (E) Muscle from mice dosed with SMT022357 showed a significant 19.6% (P = 0.02) decrease in centrally nucleated fibres compared to the vehicle group in SOL muscles. Values are mean ± SEM of n = 7 per groups; *P < 0.05. (F) The necrotic muscle area in SOL of mice treated with SMT022357 decreased by 57.3% (P = 0.06) compared to the vehicle group. Values are mean ± SEM of n = 7 per groups.

Mentions: The mdx mouse exhibits a mild form of muscular dystrophy with elevated serum levels of creatine kinase (48) and histological changes consistent with myofibre damage (49). Treatment with SMT022357 results in a 47% decrease of serum CK levels (Fig. 5A), demonstrating that the increased levels of utrophin derived from drug treatment is reducing the amount of membrane damage reducing the rate of CK leaking into general circulation.


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 prevents muscular dystrophy in skeletal muscle. (A) Creatine kinase (CK) levels in serum following daily oral gavage of mdx mice with 30 mg/kg of SMT022357 or vehicle from two weeks of age for five weeks. A 47% decrease in serum CK was observed after treatment with SMT022357 compared to vehicle-treated animals (n = 7-9 per group). (B) H&E-stained transverse muscle sections of EDL muscle (7 weeks of age) in untreated vs. treated mdx mice (n = 10 per group) showing necrotic areas (black stars) and regenerating fibres (black arrows). Scale bar: 100 µm. (C) Muscle from mice dosed with SMT022357 showed a significant 20.1% (P = 0.03) decrease in centrally nucleated fibres compared to the vehicle group in EDL muscles. Values are mean ± SEM of n = 9 per groups; *P < 0.05. (D) The necrotic muscle area in EDL of mice treated with SMT022357 significantly decreased by 63.1% (P = 0.02) compared to the vehicle group. Values are mean ± SEM of n = 9 per groups; *P < 0.05. (E) Muscle from mice dosed with SMT022357 showed a significant 19.6% (P = 0.02) decrease in centrally nucleated fibres compared to the vehicle group in SOL muscles. Values are mean ± SEM of n = 7 per groups; *P < 0.05. (F) The necrotic muscle area in SOL of mice treated with SMT022357 decreased by 57.3% (P = 0.06) compared to the vehicle group. Values are mean ± SEM of n = 7 per groups.
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Related In: Results  -  Collection

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DDV154F5: SMT022357 prevents muscular dystrophy in skeletal muscle. (A) Creatine kinase (CK) levels in serum following daily oral gavage of mdx mice with 30 mg/kg of SMT022357 or vehicle from two weeks of age for five weeks. A 47% decrease in serum CK was observed after treatment with SMT022357 compared to vehicle-treated animals (n = 7-9 per group). (B) H&E-stained transverse muscle sections of EDL muscle (7 weeks of age) in untreated vs. treated mdx mice (n = 10 per group) showing necrotic areas (black stars) and regenerating fibres (black arrows). Scale bar: 100 µm. (C) Muscle from mice dosed with SMT022357 showed a significant 20.1% (P = 0.03) decrease in centrally nucleated fibres compared to the vehicle group in EDL muscles. Values are mean ± SEM of n = 9 per groups; *P < 0.05. (D) The necrotic muscle area in EDL of mice treated with SMT022357 significantly decreased by 63.1% (P = 0.02) compared to the vehicle group. Values are mean ± SEM of n = 9 per groups; *P < 0.05. (E) Muscle from mice dosed with SMT022357 showed a significant 19.6% (P = 0.02) decrease in centrally nucleated fibres compared to the vehicle group in SOL muscles. Values are mean ± SEM of n = 7 per groups; *P < 0.05. (F) The necrotic muscle area in SOL of mice treated with SMT022357 decreased by 57.3% (P = 0.06) compared to the vehicle group. Values are mean ± SEM of n = 7 per groups.
Mentions: The mdx mouse exhibits a mild form of muscular dystrophy with elevated serum levels of creatine kinase (48) and histological changes consistent with myofibre damage (49). Treatment with SMT022357 results in a 47% decrease of serum CK levels (Fig. 5A), demonstrating that the increased levels of utrophin derived from drug treatment is reducing the amount of membrane damage reducing the rate of CK leaking into general circulation.

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