The foetal haemoglobin story just got more complicated

Many of us think that foetal haemoglobin (Hb F) is the key to a “cure” for sickle cell disease. The genes that make Hb F are switched off shortly after we are born and then remain inactive throughout the rest of our lives. But we know, that if we can only reactivate these genes, so that they once again produce large amounts of Hb F, less sickling would occur and patients would have many fewer symptoms as a result.

How do we know this? Well, hydroxycarbamide (or hydroxyurea) is the only disease modifying drug, which is approved for use in sickle cell by both the Food and Drug Administration (FDA) in the US and the European Medicines Agency (EMA) in Europe. It works mainly by increasing the amount of Hb F in patient’s blood, although the exact way in which it does this remains elusive (see : More on hydroxycarbamide – 07/01/15). There is now conclusive proof of the clinical benefit of hydroxycarbamide; it reduces the frequency and severity  of painful crises, reduces the number of attacks of the acute chest syndrome, reduces the need for blood transfusion and, most importantly, improves life expectancy by reducing deaths from sickle cell.

Not everyone responds to hydroxycarbamide and there remain some residual concerns, particularly among patients, about side effects, including effects on fertility, risks of infection and possible cancer causing properties. The evidence base for any of these side effects is minimal and the cancer risk, in particular, has been proven to be non-existent. Nevertheless, the hunt is on for other drugs which work in the same way by reactivating Hb F production.

Clinical trials are already underway on two drugs, panobinostat and vorinostat, which are HDAC inhibitors (see: What are HDAC inhibitors? – 13/06/14). Both drugs inhibit the enzyme HDAC which removes acetylene groups, or de-acetylates, histone proteins. Histones are a group of proteins which wrap themselves around our DNA and help to control gene expression. The fewer the number of acetylene groups on the histones, the tighter the histones are bound to DNA and the more effectively the underlying genes are repressed and inactivated. Prevent the removal of acetylene groups and the histones are less tightly bound allowing the genes to be more active. It is hoped that panobinostat and vorinostat, by preventing the removal of acetylene groups, will allow the reactivation of Hb F genes, increase levels of Hb F in the blood and so reduce the activity of the patient’s sickle cell disease.

Another possible drug target is BCL11A (see: Homing in on BCL11A – 13/06/14). This is a protein which is intimately involved in regulating the switch from Hb F to adult haemoglobin (Hb A) production after birth . Drugs which inhibit the activity of BCL11A would be expected to lead to a reawakening of the Hb F genes and increased Hb F production. Simvastatin, a drug currently in widespread use to reduce cholesterol levels, has multiple beneficial effects in sickle cell disease, including the fact that it inactivates BCL11A. This drug is also currently undergoing clinical trials in sickle cell disease.

One other name to look out for is decitabine. This is a chemotherapy agent used to treat different types of cancer and as such comes with a range of significant side effects. It works by inhibiting the activity of an enzyme called DNA methyl-transferase. This enzyme is responsible for adding methyl groups to our DNA. The more heavily methylated DNA is the less active are the genes involved. Reduce the amount of methylation by inhibiting the enzyme, which is what decitabine does, then the more active the genes become and, in the context of sickle cell, levels of Hb F would be expected to rise. Decitabine is also part of a current clinical trial in sickle cell disease.

So, in addition to hydroxycarbamide, there are at least four other drugs, panobinostat, vorinostat, simvastatin and decitabine, currently being trialled in sickle cell patients. All four drugs act in different ways but all have the potential to reactivated Hb F genes and promote Hb F synthesis.

But the story isn’t over yet. A group of scientists from Boston have just described another, different pathway, influencing Hb F synthesis. They found, that just as in DNA, methylation of the histone proteins, the ones that are wrapped around our DNA, also has the effect of repressing underlying gene activity. In particular they discovered a specific pathway which appears to be important for Hb F gene expression. A gene, EHMT-1 produces an enzyme, histone methyl-transferase, which methylates a particular histone protein, known as H3K9, and this seems to be important in silencing Hb F gene expression. They are currently investigating a potential drug, which is called rather unimaginatively at the moment UNCO638. This chemical inhibits EHMT-1 and, at least in the test tube, results in bone marrow cells increasing synthesis of Hb F.

The hope must be that at least some of these agents will be shown to be both effective and safe, allowing their routine use by patients, either on their own, together in different combinations or possibly sequentially, one after the other, in whichever way maximises the effect on Hb F. For many years patients and some doctors viewed hydroxycarbamide with misplaced suspicion. As a result large numbers of sickle cell patients have been denied or have refused treatment with this potentially life saving drug. It is very important that these new developments are understood and embraced by the sickle cell community so that, if and when clinical usefulness is proven, the drugs can be adopted as quickly and as widely as possible.

EHMT-1 and EHMT-2 inhibition induces fetal haemoglobin expression. Renneville A, van Galen P, Canver MC, McConkey M, Krill-Burger JM, Dorfman DM, Holson EB, Bernstein BE, Orkin SH, Bauer DE and Ebert BL. Blood (2015) volume 126, page 1930-39.

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About rogerjamos

I am a consultant haematologist who has worked in Hackney, London, UK with patients who have sickle cell disease for many years. Knowledge is power; the hope is that this blog will empower patients by putting them in touch with contemporary research into sickle cell disease and facilitating informed discussion on the issues raised. Dr Roger Amos MA, MD, FRCPath
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