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Chayathri Obeysekera

Cystic Fibrosis (CF) is the most common genetic condition in the UK; occuring as a result of defective Cl- transport across epithelial cells
Defective Cl- transport results in abnormalities in the composition of body secretions CF affects many organs in the body The pulmonary manifestations are a leading cause of mortality and morbidity in the disease and are the focal point of gene therapy A rise in life expectancy in CF suffers has called for increased research into gene therapy for the disease

The CFTR protein that regulates Cl- transport is an ABC transporter protein also responsible for the transport of other molecules

The CFTR protein is coded for by a large gene located on the long arm of chromosome 7. This CFTR gene was discovered in 1989.

A vast spectrum of genetic mutations in CFTR gene exist with the most common being the F508 mutation

Gene therapy sees the insertion of a normal gene into the patient DNA
CF is recognised as a prime candidate for gene therapy In CF, the target cells are the airway epithelial cells (AECs) There are a number of things that need to be considered during gene therapy: the gene product the vector host factors the delivery method

Two vectors have been tried thus far Viral vectors show much promise Non viral vectors are less efficient Host factors present the most pertinent barrier to effective gene transfer The amount of gene transferred has been too small for therapeutic benefit

The duration of gene expression is also deemed less than favourable

Much work remains to be done to make gene therapy for CF a reality A suitable vector must be decided upon A means of reducing the immune response to gene therapy must be sought A means of transferring sufficient genetic material must be established Research is limited by a lack of a suitable animal model

Further research requires the design of suitable clinical trials

Effective gene therapy for CF is promising


The two most important barriers to overcome are adequate gene transfer and innate lung defenses An optimal vector would be one which is less likely to induce an immune response whilst delivering genetic material efficiently. The most promising of these vectors is the lentivial vector The identification of a suitable animal model will enable further research into finding a vector There is great hope that gene therapy for CF will be available for patients in the future

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Griesenbach U, Alton E. Gene transfer to the lung: lessons learned from more than 2

decades of CF gene therapy. Adv Drug Deliv Rev. 2009 Feb;61(2):128-39.

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Kreindler J. Cystic fibrosis: exploiting its genetic basis in the hunt for new therapies.

Pharmacol Ther. 2010 Feb;125(2):219-29.

3.

Castellani S, Conese M. Lentiviral Vectors and Cystic Fibrosis Gene Therapy. Viruses.

2010 Jan:2:395-412.

4.

Wenger J. Understanding Genetics [Online]. Ask A Geneticist. [Cited 10 May 2010];

Available via www.thetech.org/genetics/images/ask/cfgene.gif

5.

Morale M. Cystic Fibrosis Revisited: An In depth Look at the CFTR Protein. 2005 Nov

[Cited 10 May 2010]; Available via www.cfgenetherapy.org.uk

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Accessed on 10 May 2010 via www.mcgill.ca

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