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1.
Hum Mol Genet ; 24(15): 4212-24, 2015 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-25935002

RESUMEN

Duchenne muscular dystrophy (DMD) is a lethal, X-linked muscle-wasting disease caused by lack of the cytoskeletal protein dystrophin. There is currently no cure for DMD although various promising approaches are progressing through human clinical trials. By pharmacologically modulating the expression of the dystrophin-related protein utrophin, we have previously demonstrated in dystrophin-deficient mdx studies, daily SMT C1100 treatment significantly reduced muscle degeneration leading to improved muscle function. This manuscript describes the significant disease modifying benefits associated with daily dosing of SMT022357, a second-generation compound in this drug series with improved physicochemical properties and a more robust metabolism profile. These studies in the mdx mouse demonstrate that oral administration of SMT022357 leads to increased utrophin expression in skeletal, respiratory and cardiac muscles. Significantly, utrophin expression is localized along the length of the muscle fibre, not just at the synapse, and is fibre-type independent, suggesting that drug treatment is modulating utrophin transcription in extra-synaptic myonuclei. This results in improved sarcolemmal stability and prevents dystrophic pathology through a significant reduction of regeneration, necrosis and fibrosis. All these improvements combine to protect the mdx muscle from contraction induced damage and enhance physiological function. 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.


Asunto(s)
Distrofina/biosíntesis , Fibras Musculares Esqueléticas/efectos de los fármacos , Distrofia Muscular de Duchenne/tratamiento farmacológico , Utrofina/biosíntesis , Animales , Distrofina/genética , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Ratones Endogámicos mdx , Contracción Muscular/efectos de los fármacos , Contracción Muscular/genética , Fibras Musculares Esqueléticas/patología , Músculos/efectos de los fármacos , Músculos/patología , Distrofia Muscular Animal/genética , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/patología , Sarcolema/efectos de los fármacos , Sarcolema/genética , Utrofina/genética
2.
Eur J Med Chem ; 220: 113431, 2021 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-33915371

RESUMEN

Duchenne muscular dystrophy is a fatal disease with no cure, caused by lack of the cytoskeletal protein dystrophin. Upregulation of utrophin, a dystrophin paralogue, offers a potential therapy independent of mutation type. The failure of first-in-class utrophin modulator ezutromid/SMT C1100 in Phase II clinical trials necessitates development of compounds with better efficacy, physicochemical and ADME properties and/or complementary mechanisms. We have discovered and performed a preliminary optimisation of a novel class of utrophin modulators using an improved phenotypic screen, where reporter expression is derived from the full genomic context of the utrophin promoter. We further demonstrate through target deconvolution studies, including expression analysis and chemical proteomics, that this compound series operates via a novel mechanism of action, distinct from that of ezutromid.


Asunto(s)
Descubrimiento de Drogas , Hidrazinas/farmacología , Distrofia Muscular de Duchenne/tratamiento farmacológico , Pirimidinas/farmacología , Utrofina/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Hidrazinas/síntesis química , Hidrazinas/química , Estructura Molecular , Distrofia Muscular de Duchenne/metabolismo , Pirimidinas/síntesis química , Pirimidinas/química , ARN Mensajero/metabolismo , Relación Estructura-Actividad
3.
Sci Rep ; 7: 43697, 2017 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-28252048

RESUMEN

Despite promising therapeutic avenues, there is currently no effective treatment for Duchenne muscular dystrophy (DMD), a lethal monogenic disorder caused by the loss of the large cytoskeletal protein, dystrophin. A highly promising approach to therapy, applicable to all DMD patients irrespective to their genetic defect, is to modulate utrophin, a functional paralogue of dystrophin, able to compensate for the primary defects of DMD restoring sarcolemmal stability. One of the major difficulties in assessing the effectiveness of therapeutic strategies is to define appropriate outcome measures. In the present study, we utilised an aptamer based proteomics approach to profile 1,310 proteins in plasma of wild-type, mdx and Fiona (mdx overexpressing utrophin) mice. Comparison of the C57 and mdx sera revealed 83 proteins with statistically significant >2 fold changes in dystrophic serum abundance. A large majority of previously described biomarkers (ANP32B, THBS4, CAMK2A/B/D, CYCS, CAPNI) were normalised towards wild-type levels in Fiona animals. This work also identified potential mdx markers specific to increased utrophin (DUS3, TPI1) and highlights novel mdx biomarkers (GITR, MYBPC1, HSP60, SIRT2, SMAD3, CNTN1). We define a panel of putative protein mdx biomarkers to evaluate utrophin based strategies which may help to accelerate their translation to the clinic.


Asunto(s)
Biomarcadores , Proteínas Sanguíneas , Utrofina/sangre , Animales , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Humanos , Ratones , Ratones Transgénicos , Distrofia Muscular Animal , Distrofia Muscular de Duchenne/sangre , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/terapia , Proteoma , Proteómica/métodos , Investigación Biomédica Traslacional , Utrofina/uso terapéutico
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