GENE THERAPY IN CYSTIC FIBROSIS
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21-12-2010, 02:33 PM



.ppt   GENE THERAPY IN CYSTIC FIBROSIS.ppt (Size: 2.4 MB / Downloads: 77)
Presented By:M.A.GAYATHRI
KLUNIVERSITY

GENE THERAPY IN CYSTIC FIBROSIS



Cystic fibrosis
Is the lethal inherited disease that effects
-lungs
-pancreas
-sweat glands

characterized by the production of abnormally viscous mucus by the affected glands

Fibrous scar tissue develops in the pancreas

Epidemology
Approximately 30,000 people in the U.S.


Around 2,500 children with CF are born every year


Over 10 million americans are unkown
carriers
Molecular and genetic basis
Mutations in a single gene - the Cystic Fibrosis

Transmembrane Regulator (CFTR) gene on

chromosome 7

The CFTR gene:

Locus 7q31.2

Is 250,000 bp long

Contains 27 exons

Protein has 1,480 aminoacids




The ∆F508 Mutation
A 3 basepair deletion called ∆F508 is the most common mutation causing cystic fibrosis

IN Normal CFTR:
Nucleotide AAT ATC ATC TTT GGT GTT TCC
Aminoacid Asn Ile Ile Phe Gly Val Ser

In ∆F508 CFTR:
Nucleotide AAT ATC ATC GGT GTT TCC
Aminoacid Asn Ile Ile Gly Val Ser

The mutation results in deletion of a single amino acid (Phe) at 508 position
Role of CFTR Protein
Protein moves chloride ions out of an epithelial cell to the covering mucus

In CF
No movement of cl
This means water does not leave and it results in the mucus becoming thick

Gene therapy
Introduction of functional genetic material into the target cell to replace the defective genes

Gene transfer techniques

Exvivo: Cells removed, genetically modified and transplanted back in to the patient

Invivo: Direct transfer of genetic material into patient



Gene transfer
Vectors
-viral
-non-viral

Cells
-germ cells
-somatic cells


How it works
A vector delivers the therapeutic gene into a patient’s target cell

The target cells become infected with the viral vector

The vector’s genetic material is inserted into the target cell

Functional proteins are created from the therapeutic gene causing the cell to return to a normal state

Adenoviral vectors
Double-stranded DNA viruses, usually cause benign respiratory disease
Replication-deficient adenovirus vectors can be generated by replacing the E1 or E3 gene,
The recombinant vectors are then replicated in cells that express the products of the E1 or E3 gene
Cells infected with recombinant adenovirus can express the therapeutic gene, but because essential genes for replication are deleted, the vector can’t replicate.

Generation of non replicative adeno virus vector
Adenoviral vectors- Limitations
Expression lasts for only a short time


Eliciting both the cellular and humoral response.

Generation of antibodies to adenoviral proteins.


Adenoviral vectors
Advantages:
Higher titer
Efficient transduction of nondividing cells
in vitro and in vivo

Disadvantages:
Toxicity
Immunological response
Prior exposure

Adeno associated virus
Non-pathogenic, single stranded DNA virus dependent on the helper virus (usually adenovirus) to replicate .

It has two genes (cap and rep), sandwiched between inverted terminal repeats

The cap gene encodes viral capsid proteins and the rep is involved in viral replication and integration.
 
It can infect a variety of cell types

Adeno-associated viral vectors
To produce an AAV vector, the rep and cap genes are replaced with a transgene

The total length of the insert cannot exceed 4.7 kb

cotransfect two plasmids, one for the vector and another for rep and cap into cells infected with adenovirus.

This method is cumbersome, low yielding and prone to contamination with adenovirus and wild type AAV.

Interest in AAV vectors is due to their integration into the host genome allowing prolonged gene expression.

AAV Vectors
Adeno-associated virus vectors:
Advantages:
All viral genes removed
Safe
Transduction of nondividing cells
Stable expression
Disadvantages:
Small genome limits size of foreign DNA
Labor intensive production
Status of genome not fully elucidated

Problems with gene therapy
Short lived

Immune response

Viral vectors

Multigene disorders

Major challenges
Scientists need better ways to deliver genes to the body, more target specific with higher rate of DNA integration

Ability to deliver genes consistently to a precise DNA location and ensure that the transplanted gene is controlled by the body’s physiologic signals

References
Gibson RL, Burns JL, Ramsey BW: Pathophysiologyand management of pulmonaryinfections in cystic fibrosis. Am J Respir CritCare Med 2003
Smyth A, Walters S: Prophylactic antibioticsfor cystic fibrosis. Cochrane Database SystRev 2003;



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