Gene therapy saves patient from lifetime of blood transfusions

By Ed Yong | September 15, 2010 1:00 pm

Gene_therapyThe patient known as P2 is just 18 years old, but he has been receiving monthly blood transfusions since the age of 3. P2 has a genetic disorder called beta-thalassaemia. Thanks to a double whammy of faulty genes, he can’t produce working versions of haemoglobin, the protein that allows red blood cells to carry oxygen around the body. Regular transfusions were the only things that kept him alive but for the last 21 months, he hasn’t needed them.

An international team of scientists have managed to partially correct his genetic faults, granting him his independence. It’s a major victory for gene therapy, the act of editing faulty genes within living cells in order to treat diseases.

The haemoglobin protein is a made of two slightly different molecules – alpha-globin and beta-globin – and people with beta-thalassaemia have faults with the latter. P2’s version of beta-thalassaemia is particularly common in southeast Asia. In his genome, neither copy of the beta-globin gene works at full capacity: one is either useless or produces an unstable protein; the other is completely broken.

Around half of all people with these mutations depend on blood transfusions throughout their entire lives. The quality of that life is encumbered, and its length might be curtailed. The only cure is a transplant of blood stem cells from a close relative or preferably an identical twin. As you might imagine, that’s not always possible and even when it is, it’s a risky procedure with no guarantee of success.

Marina Cavazzana-Calvo and Emmanuel Payen opted for a different approach; they tried to directly correct the faulty genes behind the disorder. Working with a large international team, they took some blood stem cells from P2’s bone marrow and infected them with a virus containing a working copy of the beta-globin gene.

The gene was loaded into a modified lentivirus, a type of virus that can shove their DNA into the genome of the cells it infects. Lentiviruses include the notorious HIV, but those that are used in gene therapy are neutered; they can’t reproduce on their own and their only purpose is to act as a vehicle for shuttling genes into cells. As an added safety feature, the virus is designed to inactivate itself after it delivers its payload.

Before receiving the new blood stem cells, P2 had a round of chemotherapy to rid his body of the existing faulty batch. It wasn’t easy, but it prepared his body for the corrected cells, which were loaded up over three years ago, on 7 June 2007. A year later, P2 went for his last blood transfusion. He hasn’t needed one for over two years. He’s still mildly anaemic, but he enjoys a good quality of life.

This new success comes on the back of a lot of hard work. The technique was successfully tested in mice in 2000 and refined in later years. Various groups have done the same thing with human cells. But Cavazzana-Calvo and Payen are the first to successfully transplant these corrected cells back into a patient.

The modified cells make up just 1 in 9 of P2’s collection, and the fixed beta-globin molecules are just a third of this total. Neither is in the majority, but they’re enough to ensure that he has enough working copies of haemoglobin.

This success comes with an important note of caution. One of the viruses had inserted its payload into a gene called HGMA2, making it around 10,000 times more active. HGMA2 controls the behaviour of blood stem cells and with such bolstered activity, the affected cells started making many extra copies of themselves. After 20 months, this set of clones accounted for around half of the modified cells.

The problem is that this sounds rather like what happens in the early stages of leukaemia – a cell shakes of the shackles that control its replication and it starts making copies of itself with reckless abandon. Indeed, faulty versions of HGMA2 have been linked to human cancers. These risks will need to be monitored in the long term and further developments might help to avoid them altogether.

Nonetheless, even these worries may be unfounded. While some HGMA2 mutations have been linked to malignant cancers, the particular fault in P2’s cells is mostly associated with benign tumours.  In some people, who have a rare condition called Paroxysmal Noctural Hemoglobinuris, the entire supply of blood cells comes from ancestors with the same HMGA2 mutation, and one such carrier in Japan has been followed for over 17 years with no trace of cancer.

It’s possible that the rise of this particular line of cells is a coincidence that has nothing to do with HGMA2. With most of P2’s own blood stem cells wiped out by chemotherapy, his new set was repopulated from the small supply of modified cells he was given. With such a small starter set, it’s not unlikely that a specific clone would rise to dominance.

At the time of writing, Cavazzana-Calvo and Payen thought that this unleashed clone was responsible for most of the benefits that P2 experienced. But since then, Philippe LeBoulch, who headed the research group, says that its contribution has apparently fallen. LeBoulch says that he is “cautiously optimistic” and notes that “the transferred globin gene is innocuous and the control elements have been optimised to be as safe as possible”.

Giuliana Ferrari, who has developed similar delivery viruses, agrees. In her work, she mapped where the lentivirus vehicles land when they infiltrate the genomes of host cells, and she found no preference for landing “in cancer-related or ‘dangerous’ genes”. She thinks that the trick for the future is to ensure that the patient receives a large enough “dose” of transplanted cells to reduce the odds of any one line dominating the others.

Reference: Nature http://dx.doi.org/10.1038/nature09328

More on gene therapy: Gene therapy gives full colour vision to colour-blind monkeys

Image courtesy of Nature
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Comments (13)

  1. Dale Sheldon-Hess

    Wow, it’s like living in the future! Would gladly take this technology in place of flying cars…

    One question though: If it’s a genetic problem, how does a transplant from an identical twin help?

  2. ERV

    YAY VIRUSES!

    I LOVE THE FUTURE!!!

  3. B. Neuenschwander

    Identical twins aren’t genetically identical.

  4. Grumpy Bob

    But identical twins *are* genetically identical (at least if one is beta-haemoglobin homozygous null, the other will be too)…there may be epigenetic differences, but if one is homozygous mutant, the other will be too.

  5. Casey

    Wow. Welcome to the revolution! My only question is this (and I’m hoping someone better read than me has an answer): what are the ethical considerations at play? What I mean is this is clearly a great advancement in medicine. As gene therapy becomes a more commonplace treatment for disease, more people are going to be living longer. I’m no mathematician, but more people + same amount of resources = long term problem. Does anyone know if there was serious debate about this question when antibiotics became commonplace treatment to fight infection? Is it even the same/similar argument?

  6. MattK

    Cool story. Casey, I trust that if you saw a young man about to be hit by a bus you would immediately warn him to get out of the way rather than pause to consider the ethical dilemma of saving someone’s life in an era of overpopulation.

  7. Justin Topp

    Ed,
    Do you know how this compares with other studies on patients with severe immunodeficiencies? Been done already, right?

  8. Casey

    MattK – I totally agree with you. It’s a no-brainer to push the guy out of the way of the bus (or treat the sick person to make them better) I just think it’s inevitable that the debate I mentioned will come up and I was hoping someone had some insight to similar discussions.

  9. In some ways the really exciting prospect from of this, IF it turns out to be widely applicable, is not just the potential “liberation” from all the transfusions but the avoidance (if one doesn’t need the transfusions) of “transfusional iron overload”. Severely thalassaemic patients who need repeat transfusions get iron overload over a period of years, as every transfusion contains iron as part of the haemoglobin in the transfused red cells. This iron overload used to kill transfusion-dependent thalassaemia major patients quite young until iron chelation therapy was developed Even with chelation therapy iron overload often kills the patients in adulthood or middle age due to heart or liver damage (heart failure due to cardiac damage from the iron build-up is the leading cause of death). The iron chelation therapy has been a major advance, but it isn’t a total solution and often requires overnight subcutaneous pump infusion of chelators.

    More info on (e.g.) the patient.co.uk site here

    Anyway, a gene therapy / transplant cure for thalassaemia would potentially solve all this… although of course there have been a LOT of false dawns (and a lot of hype) in gene therapy. So still early days. It also serves as a good illustration of all the years of painstaking “background” work that goes into producing these kind of headline advances.

  10. Donna Rogers

    Regarding overpopulation, Mother Nature will fix that, either from pandemic, volcanic apocalypse, or starvation due to ruining the land. Oh, and an asteroid strike might take us out also. In the 60’s, the news was we were heading for nuclear holocost. Nature will get revenge somehow.

  11. For twenty or so years in the field of biology there have been ethics discussions between people of the cloth of the major religions and biologists. The consensus was and is that what makes it acceptable or not is the purpose of the modifications. In short if the mods are for helping the life of an individual it’s good. In the biology field they even have a specific field of ethics just for those kinds of continuing debates.

  12. Callum

    Hey. Thanks Guys. I’m working on a biology paper for my schooling at the moment and well obviously because I’m on this page its about gene therapy and pros and cons to it and things this little convo has helped heaps.

  13. Kidney Cancer Survival Rate

    Hey. Thanks Guys. I’m working on a biology paper for my schooling at the moment and well obviously because I’m on this page its about gene therapy and pros and cons to it and things this little convo has helped heaps.

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