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Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy. USM – DMD Group. Therapeutic Approaches through Phytochemicals Exposure to Induce Exon-Skipping and Upregulation of Utrophin. Presented at the Transdisciplinary Research Seminar USM Health Campus, 27 July 2010.

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Duchenne Muscular Dystrophy

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  1. Duchenne Muscular Dystrophy USM – DMD Group Therapeutic Approaches through Phytochemicals Exposure to Induce Exon-Skipping and Upregulation of Utrophin Presented at the Transdisciplinary Research Seminar USM Health Campus, 27 July 2010

  2. Workshop on Current Approaches in Gene Therapy for Duchenne Muscular Dystrophy and Beta-Thalassemia USM Pulau Pinang, 29 – 30 June 2010

  3. Commonest Neuromuscular Genetic Disorder Most Severe form of MD Progressive Muscle Weakness 1:3500 males Reduced Life Expectancy and Quality of Life Wheelchair-Bound DMD; The Burden NO CURE!!!

  4. X Chromosome Dystrophin gene (3000 kb) Dystrophin mRNA (14 kb, 79 exons) DMD; The Gene

  5. DMD; The Genetic Basis

  6. DMD; The molecular pathogenesis

  7. Compensatory mechanism DMD: FROM BENCH to BEDSIDE STUDIES Pathophysiology of DMD dystroglycan-associated protein complexes Other molecular pathways Targeting the mRNA splicing UpregulatingUtrophin Natural Products The effect on MDX model Phenotype-Genotype correlation study

  8. Dystrophin Deletion Ex.45 (176nt)  DMD Dystrophin Deletion Ex.45-51 (1104nt)  BMD THE BOY MAY HIT AND RUN (NORMAL) THE BOY MAY HIT AND RUN (BMD) THE BOYMA YHI TAN DRU N (DMD) Reading Frame Rule DMD and BMD

  9. ? HI T AN D RU N Treatment of DMD by Exon-Skipping THE HIT AND RUN BO YMA Y Takeshima et al., 2006

  10. 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)

  11. DMD and Utrophin

  12. Utrophin ? 6q24.2

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

  14. What about compounds from our own backyards ?

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

  16. 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

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