Gene Therapy

There is a growing interest in the medical world in gene therapy, for patients who have an inherited disease due to a single gene defect. Sickle cell disease fits this bill perfectly. The condition is caused by a mutation, or change in the genetic code, in the gene which makes beta globin, one of the two proteins which make up the adult haemoglobin molecule.

Gene therapy sounds like science fiction medicine, as likely to become reality, as medical practice in the series Star Trek.

Dr McCoy tending to his patients in the medical bay on the Starship Enterprise.

Dr Leonard “Bones” McCoy, Starfleet Medical Officer, ¬†tending to his patients in the hospital wing on the Starship Enterprise.

But the technology has advanced to such a stage that this experimental treatment is now being given to patients with sickle cell disease. The gene therapy company Bluebird Bio Inc. announced recently that the first patient with sickle cell has successfully undergone gene therapy in Paris, using one of their products LentiGlobin BB305. So what is gene therapy and how does it work?

The principle of the treatment is relatively straightforward. It uses a virus, specifically a Lentivirus, as a vector; a vector is a carrier or bearer of a message. In this case the “message” the virus carries is a length of DNA which codes for a new type of beta globin. The Lentivirus carries this “message” into the nucleus of the cell, where the patients’ genes and ¬†chromosomes are located, and there the virus inserts, or integrates, the new DNA into the patient’s own existing DNA. Remarkably, the new DNA then begins to work, like a new gene, and produces the new form of beta globin.

This is a bit of an over simplification and there are, of course, enormous technical problems to overcome if the new gene is to work effectively. The Lentivirus has to insert the new gene into the patient’s DNA in the right place, otherwise the normal mechanisms which control the genetic machinery may be disturbed, with unforeseen and potentially dangerous consequences and, once in position, the new gene must work hard and consistently, over a long period of time, producing large amounts of the new haemoglobin.

These technical difficulties now seem to have been overcome allowing clinical trials of the treatment to begin. How does it work in practice then?

First of all you have to make the new gene. There seem to be two alternatives at the moment, either a new beta globin gene, which is modified so that it does not interact with sickle haemoglobin (there are two types known as beta- T87Q and beta-AS3), or a modified form of the gamma globin gene which can be driven to work by the normal promotors of beta globin gene activity. Gamma globin is the key component of foetal haemoglobin (Hb F), which is normally almost completely absent from adult blood, but again, if it can be made successfully, does not interact with sickle haemoglobin. The idea is that the new form of haemoglobin will out perform sickle haemoglobin and gradually replace it as the main haemoglobin that the patient produces.

Once the new gene has been made it is a simple matter to persuade the Lentivirus to take it up and incorporate it into it’s own DNA. A bit like putting a letter into an envelope. A process which is known as transfection.

Bone marrow stem cells are then collected from the patient, in the same way as if the patient was going to have a bone marrow transplant. The Lentivirus vector and stem cells are then mixed together in a test tube, and the virus delivers the “message” into the stem cells where the new gene is integrated into the stem cell’s DNA.

Before the modified, or transduced, stem cells are given back, the patient is treated with a form of chemotherapy, usually the drug busulphan, which wipes out much of the patient’s own bone marrow, creating space for the modified stem cells to settle in and begin their work.

The modified stem cells are infused into the patient, just like having a blood transfusion, and the patient is watched carefully over the next few weeks for signs that the new gene is working and that the new haemoglobin is being produced. How long this takes is not clear, but in patients with beta thalassaemia who have undergone a similar process, it can take many months to several years before the new genes are working at maximal efficiency. So, recovery is likely to be a long process.

The principle of gene therapy is illustrated in this diagram. Stem cells are collectected from the bone marrow in the pelvic bones, transfected by the Lentivirus carrying the new gene and then the modified stem cells are transfused ack into the patient after they have had myeloablative conditioning with busulphan.

The principle of gene therapy is illustrated in this diagram. Stem cells are collectected from the bone marrow in the pelvic bones and transfected by the Lentivirus carrying the new gene. The modified stem cells are transfused back into the patient after the patient has had myeloablative conditioning with busulphan, to prepare space in the bone marrow for the modified stem cells to grow in..

At least 4 clinical trials have been registered with the National Institutes of Health in the USA this summer. They all aim to recruit patients with severe sickle cell disease for gene therapy, to assess the safety, feasibility and effectiveness of this new treatment. The trials will run over the next three years. Success in these trials will be a huge step forward in the search for a cure for sickle cell.


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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