Research updates
7 - The sickling disease page 7
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5. Looking to the future Link to the Medical Research Council web site
Antisickling agents
Much research has been directed at developing anti-sickling agents which would, for example, disrupt bonds, so preventing the polymerisation of haemoglobin S. However, no agent has yet stood the test of a properly designed clinical trial. Fetal haemoglobin (HbF) inhibits the polymerisation of haemoglobin S and so interferes with the sickling process. However, the activity of the HbF gene is normally suppressed after birth (see section 2). How can the gene be 'switched on' again to by-pass the effects of the defective b-globin gene?
The precise mechanism which regulates the activity of the various globin genes is a major focus of research. A recent clinical trial has shown that hydroxyurea (a bone marrow toxin used in the treatment of leukaemia) may be useful in preventing painful crises, particularly in adults. It is not absolutely clear how this drug works, but it appears to increase the amount of foetal haemoglobin produced, which may help to protect against sickling. Hydroxyurea also reduces the number of white cells. Since white cells may cause some of the tissue damage that occurs during sickling crises, this reduction in white cells could contribute to the drug's effect.
The success in reactivating the HbF gene with hydroxyurea is encouraging, though further work is needed to ensure its long-term safety.
Gene therapy
A vision for the future is somatic gene therapy which involves altering the genetic make-up of the marrow stem cells from which red blood cells develop. Experiments have shown that retroviruses can be used to transfer correct versions of the b-globin gene, together with regulatory DNA sequences, into stem cells. However, formidable technical problems remain. Few stem cells seem to take up the DNA introduced and, so far, it has not been possible to achieve long term, high level production of the corrected b-globin chain.
Another approach involves correction of the defective b-globin gene by lining it up alongside a normal gene under conditions in which recombination will occur. Such site-directed recombination has been achieved in tissue culture.
In Professor Weatherall's words: "It seems likely that somatic gene therapy for the haemoglobin disorders may be feasible, although at present an ideal solution for sickle cell anaemia would seem to be the reactivation of the fetal haemoglobin gene".
It is clear that both focused research and effective screening programmes will continue to play a major role in the prevention and management of sickle cell anaemia in the immediate future.
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