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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

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


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 Duchenne Muscular Dystrophy and Beta-Thalassemia USM Pulau Pinang, 29 – 30 June 2010

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!!!


Dmd the gene

X Chromosome Duchenne Muscular Dystrophy and Beta-Thalassemia USM Pulau Pinang, 29 – 30 June 2010

Dystrophin gene (3000 kb)

Dystrophin mRNA (14 kb, 79 exons)

DMD; The Gene


Dmd the genetic basis
DMD; The Genetic Basis Duchenne Muscular Dystrophy and Beta-Thalassemia USM Pulau Pinang, 29 – 30 June 2010


Dmd the molecular pathogenesis
DMD; The molecular pathogenesis Duchenne Muscular Dystrophy and Beta-Thalassemia USM Pulau Pinang, 29 – 30 June 2010


Compensatory mechanism Duchenne Muscular Dystrophy and Beta-Thalassemia USM Pulau Pinang, 29 – 30 June 2010

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


Reading frame rule

Dystrophin Duchenne Muscular Dystrophy and Beta-Thalassemia USM Pulau Pinang, 29 – 30 June 2010 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


Treatment of dmd by exon skipping

? Duchenne Muscular Dystrophy and Beta-Thalassemia USM Pulau Pinang, 29 – 30 June 2010

HI T

AN D

RU N

Treatment of DMD by Exon-Skipping

THE

HIT AND RUN

BO

YMA Y

Takeshima et al., 2006


Compounds inducing splicing alternation
Compounds Inducing Splicing Alternation Duchenne Muscular Dystrophy and Beta-Thalassemia USM Pulau Pinang, 29 – 30 June 2010

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)


Dmd and utrophin
DMD and Utrophin Duchenne Muscular Dystrophy and Beta-Thalassemia USM Pulau Pinang, 29 – 30 June 2010


Utrophin
Utrophin ? Duchenne Muscular Dystrophy and Beta-Thalassemia USM Pulau Pinang, 29 – 30 June 2010

6q24.2


Compounds inducing utrophin upregulation
Compounds Inducing Utrophin Upregulation Duchenne Muscular Dystrophy and Beta-Thalassemia USM Pulau Pinang, 29 – 30 June 2010

Transcriptional Activators

Heregulin, Modulation of calcineurin-NFAT signalling, L-Arginine


What about compounds from our own backyards
What about compounds from our own backyards ? Duchenne Muscular Dystrophy and Beta-Thalassemia USM Pulau Pinang, 29 – 30 June 2010


Seeking collaborators
Seeking Collaborators Duchenne Muscular Dystrophy and Beta-Thalassemia USM Pulau Pinang, 29 – 30 June 2010

  • 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
USM-DMD Group (so far…) Duchenne Muscular Dystrophy and Beta-Thalassemia USM Pulau Pinang, 29 – 30 June 2010

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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