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 (

DMD and Utrophin

Utrophin ? 6q24.2

Compounds Inducing Utrophin Upregulation Transcriptional Activators Heregulin, Modulation of calcineurin-NFAT signalling, L-Arginine

What about compounds from our own backyards ?

Seeking Collaborators Botanist (FRIM) “Pathway Studio” (Centre for Chemical Biology, USM) Chemist Pharmacist; Dr. Habibah Abdul Wahab Biologist Prof. Syed Mohsin Syed Sahil Jamalullail

USM-DMD Group (so far…) Teguh Haryo Sasongko, Abdul Aziz Mohd. Yusoff, Muzaimi Mustapha, Ong Ming Thong, Sarina Sulong, Chia Boon Hock, Khairani Idah Mokhtar, Wan Rohani Wan Taib, Rowani Mohd. Rawi, Rani Abdulqawee, Khaleed, Zilfalil Alwi, Zabidi Hussin, Shaharum Shamsuddin, Md. Azman Seeni, Badrul Hisham Yahaya