Presentation on theme: "Duchenne Muscular Dystrophy Therapeutic Approaches through Phytochemicals Exposure to Induce Exon- Skipping and Upregulation of Utrophin USM – DMD Group."— Presentation transcript:
Duchenne Muscular Dystrophy Therapeutic Approaches through Phytochemicals Exposure to Induce Exon- Skipping and Upregulation of Utrophin USM – DMD Group Presented at the Transdisciplinary Research Seminar USM Health Campus, 27 July 2010
Workshop on Current Approaches in Gene Therapy for Duchenne Muscular Dystrophy and Beta-Thalassemia USM Pulau Pinang, 29 – 30 June 2010
DMD; The Burden Commonest Neuromuscular Genetic Disorder Most Severe form of MD Progressive Muscle Weakness 1:3500 males Reduced Life Expectancy and Quality of Life Wheelchair-Bound NO CURE!!!
DMD; The Gene Dystrophin gene (3000 kb) Dystrophin mRNA (14 kb, 79 exons) X Chromosome
DMD; The Genetic Basis
DMD; The molecular pathogenesis
Pathophysiology of DMD Natural Products Phenotype- Genotype correlation study Targeting the mRNA splicing Upregulating Utrophin The effect on MDX model Compensatory mechanism dystroglycan- associated protein complexes Other molecular pathways DMD: FROM BENCH to BEDSIDE STUDIES
Reading Frame Rule DMD and BMD Dystrophin Deletion Ex.45 (176nt) DMD Dystrophin Deletion Ex (1104nt) BMD THE BOY MAY HIT AND RUN (NORMAL)(BMD) THE BOY MAY HIT AND RUN (DMD) THE BOYMA YHI TAN DRU N
Treatment of DMD by Exon-Skipping THE Takeshima et al., 2006 YMA Y HI T AN D RU N BO HIT AND RUN ?
Compounds Inducing Splicing Alternation Histone Deacetylase Inhibitors (sodium butyrate, valproic acid, phenylbutyrate, etc…) Kinase Inhibitors (aclarubicin, camptotechin, isodiospyrin, lithium chloride, etc…) Phospatase Inhibitors (sodium orthovanadate, tautomycin, cantharidin, etc…) cAMP Pathway (indoprofen, salbutamol) SR Protein-Protein Interactions (isoquinoline) Coupling of Transcription and Splicing (dexamethazone, dihydroepiandrosterone, steroid hormones) Ion-channels and Electrochemical Gradients (amiloride, glutamate) Unknown Role (hydroxyurea, kinetin, curcumin, etoposide, etc…) European Alternative Splicing Network (www.eurasnet.info)