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ALZHEIMERS DISEASE

It is a progressive and fatal brain disease.

Alzheimer's destroys brain cells, causing memory lossand problems with thinking and behavior.

It is the most common form of dementia, a general termfor memory loss and other cognitive abilities.

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Hypotheses for Alzheimers Disease

Cholinergic Hypothesis

Amyloid Hypothesis

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Amyloid Hypothesis

Itpostulates that amyloid beta (A) deposits arethe fundamental cause of the disease which are

generated by -secretase

Support for this postulate comes from the locationof the gene for the amyloid beta precursor protein(APP) on chromosome 21.

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Explanation

Secretase are enzymes that snip pieces off a longerprotein that is embedded in the cell membrane.

The aggregation of these peptide fragements in clumpscalled plaques in brain is supposed to be the cause ofAlzheimers disease.

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Present Day Cure

There are currently 4 FDA approved medicationsavailable for treating the disease

These drugs are acetylcholine esterase inhibitors

The drugs used are Tacrine, Donepezil,Galantamine, Rivastigmine

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Drawbacks of Present Day Cure

One of the major drawback is the inability to effectivelycross the blood brain barrier (BBB)

These drugs essentially increase acetylcholine levels in thebrain and theydont tackle the root cause of the disease

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Blood-Brain Barrier Transport Properties

Most substances that must cross the blood-brain barrier are not lipid soluble and

therefore cross by specific carrier-mediated transport systems

A complex system of polarized

transporter proteins and ionicchannels determine the specific

movement of water-soluble

compounds and ions across

barrier endothelial cells.

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Drawbacks

Increased Dosage

Side Effects such as nausea and vomiting

Secondary Effects like muscle cramps, decreased heart rate,

decreased appetite etc.

Sometimes antipyschotic drugs are used which areassociated with increased mortality.

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Antisense Technology

This type of oligonucleotide is designed to bind to a complementary sequence

(referred to as the target sequence) in a selected mRNA, inhibiting gene

expression at the translational level.

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Hypothesis

The use of antisense technology to treat

Alzheimer's Disease

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Objective

To develop a delivery system incorporating antisensetechnology to treat Alzheimer's disease

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Aim To find a material that would be able to deliver the

antisense molecule across the BBB.

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Poloxamers(Pluronics) Bifunctional non-ionic triblock copolymers

Consist of ethylene oxide (EO) and propylene oxide

(PO) segments arranged in the basic ABAstructure: EOaPObEoa

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Reasons for choosing Pluronics

Ability to block P-gp efflux proteins.

Less toxic to cells than.

Display profound membrane Fluidization

The encapsulated material in the core of the micelles formed byPluronic results in increased solubility.

Bioavailability of the material is high.

Pluronics have been reported for use in gene therapy.

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Unique properties

Molecular size, hydrophilicity and lipophilicity can byvaried by changes in the number EO and PO.

Because of their amphiphilic structure, the polymershave surfactant properties.

Form micellar structures above critical micellar

concentration(CMC).

The temperature at which they form micelles is calledthe critical micelle temperature (CMT)

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How Pluronics work?

Fig:Schematic Illustrating Effects of pluronic Block Copolymeron P gp Drug Efflux System

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Mechanism Of Delivery

Above CMC the copolymers remain in micelle form but as the

concentration decreases/micelles(in body fluid) are diluted below

CMC they disintegrate and release the therapeutic agent.

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Conclusion This system will be effective as the antisense works

at the translational level.

Side effects of drugs will be minimized.

Bioavailability of the therapeutic agent will beincreased across the blood brain barrier.

As antisense oligonucleotides are highly specific,there are minimal specficity concerns.

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The effect of Pluronic copolymers on other transportsystems is unknown.

Toxicity issues and development of safety formulations ofPluronic still have to be addressed.

Micelles may disintegrate as a result of interactions with

blood components, serum proteins.

The cost analysis of the project is to be done.

Future Work