Limits...
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 skeletal muscles. (A) Immunofluoresence staining for utrophin in EDL and SOL muscles of 7 weeks old mdx mice treated for 5 weeks with 30 mg/kg/day SMT022357 or vehicle. Transverse sections were stained with anti-utrophin polyclonal antibody URD40 and anti-rabbit secondary antibody. Scale bar: 100 µm. (B) Longitudinal cryosections of TA muscle following treatment of mdx mice homogenously increased the utrophin expression along the myofiber after treatment with SMT022357 compared to vehicle group. Scale bar: 100 µm. (C) Co-immunohistochemical staining of TA muscle with utrophin, α-Bungarotoxin and DAPI prepared from mdx mice treated with SMT022357. White arrows indicate utrophin expression in extra-synaptic regions of the sarcolemma. Scale bar: 50 µm.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4492389&req=5

DDV154F2: SMT022357 increases utrophin expression in skeletal muscles. (A) Immunofluoresence staining for utrophin in EDL and SOL muscles of 7 weeks old mdx mice treated for 5 weeks with 30 mg/kg/day SMT022357 or vehicle. Transverse sections were stained with anti-utrophin polyclonal antibody URD40 and anti-rabbit secondary antibody. Scale bar: 100 µm. (B) Longitudinal cryosections of TA muscle following treatment of mdx mice homogenously increased the utrophin expression along the myofiber after treatment with SMT022357 compared to vehicle group. Scale bar: 100 µm. (C) Co-immunohistochemical staining of TA muscle with utrophin, α-Bungarotoxin and DAPI prepared from mdx mice treated with SMT022357. White arrows indicate utrophin expression in extra-synaptic regions of the sarcolemma. Scale bar: 50 µm.

Mentions: To investigate the in vivo activity of SMT022357, 2-week-old mdx mice were orally dosed daily with 30 mg/kg of SMT022357 or vehicle for 5 weeks. Immunofluorescence using a utrophin antibody revealed a qualitative increase in sarcolemma-bound utrophin in the transverse of EDL and SOL muscles (Fig. 2A). In the mdx mouse, utrophin localization is fragmented and discontinuous along the myofibre highlighting the regions within the fibre where regeneration is taking place in order to repair the damaged membrane (Fig. 2A–C). After treatment with SMT022357, utrophin was continuously localized along the entire length of the sarcolemma in longitudinal tibialis anterior (TA) sections suggesting that drug treatment is modulating utrophin transcription in myonuclei along the length of the fibre (Fig. 2B). The integrity of the membranes was confirmed with desmin immunostaining (Fig. 2B). Co-localization with α-bungarotoxin antibody in TA muscles confirmed, despite a preferred accumulation at the neuromuscular junction, a qualitative increase of utrophin at extra-synaptic regions of the sarcolemma (Fig. 2C). Western blot analysis and quantification in EDL and SOL muscles demonstrated a 1.8- and 1.9-fold increase, respectively, of the utrophin protein levels after treatment with SMT022357 (Supplementary Material, Fig. S2A).Figure 2.


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 skeletal muscles. (A) Immunofluoresence staining for utrophin in EDL and SOL muscles of 7 weeks old mdx mice treated for 5 weeks with 30 mg/kg/day SMT022357 or vehicle. Transverse sections were stained with anti-utrophin polyclonal antibody URD40 and anti-rabbit secondary antibody. Scale bar: 100 µm. (B) Longitudinal cryosections of TA muscle following treatment of mdx mice homogenously increased the utrophin expression along the myofiber after treatment with SMT022357 compared to vehicle group. Scale bar: 100 µm. (C) Co-immunohistochemical staining of TA muscle with utrophin, α-Bungarotoxin and DAPI prepared from mdx mice treated with SMT022357. White arrows indicate utrophin expression in extra-synaptic regions of the sarcolemma. Scale bar: 50 µm.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

DDV154F2: SMT022357 increases utrophin expression in skeletal muscles. (A) Immunofluoresence staining for utrophin in EDL and SOL muscles of 7 weeks old mdx mice treated for 5 weeks with 30 mg/kg/day SMT022357 or vehicle. Transverse sections were stained with anti-utrophin polyclonal antibody URD40 and anti-rabbit secondary antibody. Scale bar: 100 µm. (B) Longitudinal cryosections of TA muscle following treatment of mdx mice homogenously increased the utrophin expression along the myofiber after treatment with SMT022357 compared to vehicle group. Scale bar: 100 µm. (C) Co-immunohistochemical staining of TA muscle with utrophin, α-Bungarotoxin and DAPI prepared from mdx mice treated with SMT022357. White arrows indicate utrophin expression in extra-synaptic regions of the sarcolemma. Scale bar: 50 µm.
Mentions: To investigate the in vivo activity of SMT022357, 2-week-old mdx mice were orally dosed daily with 30 mg/kg of SMT022357 or vehicle for 5 weeks. Immunofluorescence using a utrophin antibody revealed a qualitative increase in sarcolemma-bound utrophin in the transverse of EDL and SOL muscles (Fig. 2A). In the mdx mouse, utrophin localization is fragmented and discontinuous along the myofibre highlighting the regions within the fibre where regeneration is taking place in order to repair the damaged membrane (Fig. 2A–C). After treatment with SMT022357, utrophin was continuously localized along the entire length of the sarcolemma in longitudinal tibialis anterior (TA) sections suggesting that drug treatment is modulating utrophin transcription in myonuclei along the length of the fibre (Fig. 2B). The integrity of the membranes was confirmed with desmin immunostaining (Fig. 2B). Co-localization with α-bungarotoxin antibody in TA muscles confirmed, despite a preferred accumulation at the neuromuscular junction, a qualitative increase of utrophin at extra-synaptic regions of the sarcolemma (Fig. 2C). Western blot analysis and quantification in EDL and SOL muscles demonstrated a 1.8- and 1.9-fold increase, respectively, of the utrophin protein levels after treatment with SMT022357 (Supplementary Material, Fig. S2A).Figure 2.

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