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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 increases utrophin expression in the mdx heart. (A) H&E staining of transverse heart sections in 7-week-old, vehicle- and SMT022357-treated mdx mice. n = 10 per group. Scale bar: 100 µm. (B) Immunostaining showed an increase of utrophin in the heart of 7-week-old mdx mice after SMT022357 (30 mg/kg/day) treatment compared to the vehicle group. (n = 10 per group); Scale bar: 100 µm.
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DDV154F8: SMT022357 increases utrophin expression in the mdx heart. (A) H&E staining of transverse heart sections in 7-week-old, vehicle- and SMT022357-treated mdx mice. n = 10 per group. Scale bar: 100 µm. (B) Immunostaining showed an increase of utrophin in the heart of 7-week-old mdx mice after SMT022357 (30 mg/kg/day) treatment compared to the vehicle group. (n = 10 per group); Scale bar: 100 µm.

Mentions: Cardiomyopathy is a major cause of death in boys with DMD (60). Preventing pathology in the heart, a muscle notoriously difficult to reach, is crucial as the benefits could lead to a significant improvement in patient survival. Western blots demonstrated a 50% increase of the utrophin protein level in the heart after 5 weeks of daily treatment with SMT022357 (Supplementary Material, Fig. S2). This increase in utrophin was wide spread throughout the heart and localized to cardiomyocyte membranes (Fig. 8). Nevertheless, analysis of 2-month-old mdx mouse hearts did show 1–2% fibrosis in the mid-ventricle regions and an initial increase in myocardial wall strain and torsion (61). Older 9–10-month-old mdx mice present distinct signs of cardiomyopathy (61,62). Further studies are on-going to determine the benefits of SMT022357 in the mdx heart.Figure 8.


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 increases utrophin expression in the mdx heart. (A) H&E staining of transverse heart sections in 7-week-old, vehicle- and SMT022357-treated mdx mice. n = 10 per group. Scale bar: 100 µm. (B) Immunostaining showed an increase of utrophin in the heart of 7-week-old mdx mice after SMT022357 (30 mg/kg/day) treatment compared to the vehicle group. (n = 10 per group); Scale bar: 100 µm.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

DDV154F8: SMT022357 increases utrophin expression in the mdx heart. (A) H&E staining of transverse heart sections in 7-week-old, vehicle- and SMT022357-treated mdx mice. n = 10 per group. Scale bar: 100 µm. (B) Immunostaining showed an increase of utrophin in the heart of 7-week-old mdx mice after SMT022357 (30 mg/kg/day) treatment compared to the vehicle group. (n = 10 per group); Scale bar: 100 µm.
Mentions: Cardiomyopathy is a major cause of death in boys with DMD (60). Preventing pathology in the heart, a muscle notoriously difficult to reach, is crucial as the benefits could lead to a significant improvement in patient survival. Western blots demonstrated a 50% increase of the utrophin protein level in the heart after 5 weeks of daily treatment with SMT022357 (Supplementary Material, Fig. S2). This increase in utrophin was wide spread throughout the heart and localized to cardiomyocyte membranes (Fig. 8). Nevertheless, analysis of 2-month-old mdx mouse hearts did show 1–2% fibrosis in the mid-ventricle regions and an initial increase in myocardial wall strain and torsion (61). Older 9–10-month-old mdx mice present distinct signs of cardiomyopathy (61,62). Further studies are on-going to determine the benefits of SMT022357 in the mdx heart.Figure 8.

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