WELCOME

ANTISENSE OLIGONUCLEOTIDE THERAPY

UNDER GUIDENCE OF:

Mrs. GeetaAssociate ProfessorDept of Biotechnology

BY:G.RaginiM.PharmPharmacology.10T21S0114

Contents :IntroductionDefinitionMechanism of actionAdvantagesLimitations ApplicationsExamplesClinical trialsFuture Conclusion

Introduction:

Many pharmacological approach involve creating compounds that bind and disable proteins

For e.g.: Propranolol which blocks

the ß adrenergic receptors. Cimitidine which blocks

the H2 receptors.

A new way to block protein function is to prevent the translation of mRNA into protein.

An Antisense oligonucleotide therapy is one such approach which blocks the protein formation by inhibiting translation step.

Definition: Oligonucleotides are chemically

synthesized using phosphoramidites. The oligonucleotide chain proceeds in

the direction of 3’ to 5’ terminus.

Antisense oligonucleotides are the molecules made of synthetic genetic material, which interact with the natural genetic material that codes the information for production of proteins.

Antisense RNA prevent protein translation of certain mRNA strands by binding to them.

Antisense DNA can be used to target a specific complementary RNA.

Mechanism of action of antisense therapy:

Translational arrest by blocking ribosome.

Activation of RNase enzyme:

Triplex antisense technology (ANTIGENE)

Inhibition of angiotensinogen by antisense oligonucleotide therapy

Advantages:Oligonucleotides are manufactured

quickly I.e. within a week.

Sensitivity of therapy can be easily measured.

Potential to produce longer lasting responses.

Potential for enhanced binding affinity to target.

Limitations:Antisense agents have to be

protected against nucleolytic attack.

Large doses are required for therapeutic response.

The difficulty in directing to a particular cells.

The half-life in plasma is short.

Antisense oligonucleotide

therapy

oncology

CVS & CNS therapeutics

As Antiviral and antibacterial

agent.

Inflammation therapeutics

APPLICATIONS

Other disease states like:

DiabetesAmyotrophic

lateral sclerosis(ALS)

Duchene muscular dystrophy

AsthmaHair loss.

Role in Genomics:

Antisense therapy in genomic technology provide:

Ease of protein synthesis.

Target of a single intended gene.

Quick reproducible laboratory results.

Genes responsible for the cause of disease can be predicted.

Technetium-99m labeled antisense probes are radiolabelled agents. These are injected intravenously and those are imaged in early stages.

Examples:Fomivirsen for the treatment of

cytomegalovirus retinits.Mipomersen for high cholesterol.Affinitak and Genasense against

cancer.AV 1-6002 & AV 1-6003 for the

treatment of Hemorrhagic fever.AP 1-2009 for the treatment of

high grade gliomas.

Product

Sequence

Target Disease

Vitravene GCGTTTGCTCTTCTTCTTGCG

IE 2 Cytomegalovirus retinitis.

Affinitak GTTCTCGCTGGTGAGTTTCA

PKC-α Cancer

Genasense (genta)

TCTCCCAGCGTGCGCCAT

BCl 2 Cancer

Clinical trials:In 1996 only a

handful of antisense molecules was in clinical trials.

Currently there are nearly 50 antisense compounds are under clinical trials for various diseases, out of them 10 are under phase III & 30 are under phase II clinical trials.

Future of antisense based technology:Currently over 30

pharmaceutical & biotechnology companies have declared an interest in developing the antisense based therapeutics.

Conclusion:Antisense oligonucleotide

therapy blocks the translation process where there is no formation protein responsible for a particular disease.

THE PROMISE OF ANTISENSE BASED BIOTECHNOLOGY IS THEREFORE STRONGER THAN EVER…….

QUERIES….????

THANK YOU