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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
Recommended