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Successful gene therapy of pulmonary hypertension

Target of the Month, TherapeuticAdvances, May, 200 Posted on: 20 May 03

Summary

Canadian researchers have successfully treated animals with experimental pulmonary hypertension with a vector expressing the Kv1.5 potassium channel gene
Successful gene therapy of pulmonary hypertension (Target of the Month, TherapeuticAdvances, May, 2003)

Pulmonary hypertension (PHT) exists in a rare primary form (which occurs in familial and sporadic forms) called pulmonary arterial hypertension (PAH) and a relatively common form of secondary PHT, as occurs in patients with heart disease, chronic lung disease (COPD), sleep apnea etc. Due to the high incidence of these conditions the number of patients with secondary PHT is large however many of these are undiagnosed and the actual frequency of secondary PHT is therefore unknown. As an indicator however, in individuals older than 50 years of age, cor pulmonale, the consequence of untreated PHT, is the third most common cardiac disorder. Cardiac diseases produce secondary PHT via volume or pressure overload; although vascular remodeling of pulmonary resistance vessels adds an obstructive element. The pulmonary circulation manifests, in varying degrees, excessive vasoconstriction, obstructive vascular remodeling, inflammation and thrombosis in situ. These changes narrow or obliterate the pulmonary artery lumen, which increases right ventricular afterload and ultimately precipitates failure of the afterload-intolerant right heart. Vascular remodelling changes along with pulmonary vasoconstriction are the mechanism of PHT in respiratory diseases. Unrelieved PHT, regardless of the underlying cause, leads to right ventricular failure and can cause death.

Although the pathophysiology of PHT is unclear, K+ channels appear to be involved in this disease. Hypoxia has been shown to selectively inhibit the function and expression of voltage-gated K+ channels (Kv) in pulmonary arterial smooth muscle cells. Acute hypoxia inhibits Kv channel function, inducing membrane depolarization and a rise in cytosolic Ca2+ that triggers vasoconstriction. Chronic hypoxia may inhibit Kv channel activity by directly or indirectly downregulating mRNA and protein expression of Kv channel subunits. In particular the expression of O2- and 4-aminopyridine (4-AP)-sensitive, voltage-gated K channels (Kv1.5 and Kv2.1) is reduced. Hence gene therapy strategies that reintroduce Kv channel activity may be of therapeutic use. Field leaders from the Vascular Biology Group at the University of Alberta in Canada have recently investigated this possibility.

In their recent publication, Drs. Stephen Archer, Evangelos Michelakis and colleagues report the effects of Kv1.5 gene therapy in a chronic hypoxia model of rat PHT. Nebulization of rats with the human Kv1.5 gene (delivered in an adenoviral vector with a GFP reporter) produced an airway selective overexpression of the Kv1.5 channel and reversed changes in cardiac indices of rats subjected to chronic hypoxia back towards normoxic levels; in particular, changes in pulmonary vascular resistance. This study not only demonstrates the feasibility of airway delivery of the Kv1.5 gene but it also establishes a therapeutic proof of concept for this approach. Further advances in this technology that may allow prolonged overexpression of Kv1.5 through gene therapy are eagerly awaited. Alternatively the development of Kv1.5 channel openers may offer an alternative approach to the treatment of PHT and readers may be interested to learn about the "Potassium channel Enterprise library" an assay ready library of candidate potassium channel modulators which may be used to screen for therapeutic candidates targeting multiple potassium channels and indications (for further details of this library click here).

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Important notes
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his abstract has been produced by LeadDiscovery Ltd. Founded by life scientists for life scientists we aim to help industry identify cutting edge drug discovery options and academic/biotech institutions maximize the potential of their research. Visit our website for more details. Abstracts strictly reflect the opinion of LeadDiscovery's editorial panel. While all reasonable efforts are made to ensure the accuracy of information provided LeadDiscovery takes no responsibility for incorrect or misleading information. LeadDiscovery is designed for educational and drug development purposes only and is not intended or designed to offer medical advice or advice of any sort, and must not be used for such purpose. The information provided through LeadDiscovery should not be used for diagnosing or treating a health problem or a disease and no reliance should be placed on any information contained in this abstract or elsewhere on LeadDiscovery's website. It is not intended to be a substitute for professional care. If you have or suspect you may have a health problem, you should consult your physician or other health care provider

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Last updated on: 27/08/2010 11:40:18

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