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Gene Therapy, Absolutely and For Real

This weekend brought some really significant news in the long-running effort to use gene editing to treat human disease. As most readers will have heard, Boston Children’s Hospital and a Vertex/CRISPR effort both published papers in the NEJM addressing sickle-cell anemia and beta-thalassemia. (Update: edit to fix attribution).

These diseases have long been linked when it comes to gene therapy ideas, because both of them have defects in the hemoglobin protein as their cause. And it’s long been thought that both could be treated by getting adults to re-express the fetal hemoglobin protein – it’s on a different gene entirely, and thus does not have any of the genetic problems that affect the adult hemoglobin gene. The normal course of events is for babies to stop expressing the fetal form and switch over to “regular” hemoglobin, and it’s been worked out that a particular transcription factor called BCL11a is a key player in that transcriptional repression of the fetal hemoglobin gene. That plays right into the usual way that we tend to think about therapeutic possibilities: whether it’s enzymes, receptors, or expression of whole proteins, we have a lot more tools to mess things up and interrupt processes than we have to make them run faster or better. So the possibility of interrupting BCL11a’s function has been a tempting one for many years.

It’s hard to do by traditional means, though. (Full disclosure: I have, at different times in my career, been involved with such efforts, but none have ever come near the clinic.) Transcription factors are notoriously hard to get a handle on with small molecule therapeutics, and many unsuccessful runs have been taken at BCL11a ligands to try to interrupt its functions in one way or another. My general impression is that the protein doesn’t much care about recognizing small-molecule ligands (and it’s far from the only one in that category, for sure). You’d think that if you ran a few hundred thousand (or a few million) various molecules past any given protein that you’d find a few of them that bind to it, but that assumption is too optimistic for most transcription factors. You’re also going to have a hard row to hoe (to use an old Arkansas expression) if you try to break up their interactions with their DNA binding sites: a significant amount of capital has gone down the chute trying to get that to work, with (as far as I can tell) not much to show for it.

There’s another complication: BCL11a has a lot of other functions. Every protein has a lot of other functions, but for transcription factors, the issue can be especially fraught. If you had a small molecule that really did interfere with its activity, what would happen if you just took a stiff dose of it? Probably a number of things, including some interesting (and not necessarily welcome) surprises. There have been a number of ideas about how to get around this problem, but a problem it is.

So it’s on to biological mechanisms. The BCH team reports on using RNA interference to do the job – they get cells to express a short hairpin RNA that shuts down production of BCL11a protein, with some microRNA work to target this to the right cell lines. And the Vertex/CRISPR team, naturally, uses CRISPR itself to go in and inactivate the BCL11a gene directly. Both approaches take (and have to take) a similar pathway, which is difficult and expensive, but still the best shot at such therapies that we have. You want the fetal hemoglobin expressed in red blood cells, naturally, and red blood cells come from CD34+ stem cells in the bone marrow. Even if you haven’t thought about this, you might see where it’s going: you take a bone marrow sample, isolate these cells, and then do your genetic manipulation to them ex vivo. Once you’ve got a population of appropriately re-engineered cells ready to go, you go kill off the bone marrow in the patient and put the reworked cells back in, so they’re the only source there for red blood cells at all. A bone marrow transplant, in other words – a pretty grueling process, but definitely not as much as having some sort of blood-cell-driven cancer (where the therapy uses compatible donor cells from someone else without such a problem), or as much as having full-on sickle cell disease or tranfusion-dependent thalassemia.

You can also see how this is a perfect setup for gene therapy: there’s a defined population of cells that you need to treat, which are available in a specific tissue via a well-worked-out procedure. The problem you’re trying to correct is extremely well understood – in fact, it was the first disease ever characterized (by Linus Pauling in 1949) as purely due to a genetic defect . And the patient’s own tissue is vulnerable to chemotherapy agents that will wipe out the existing cell population, in another well-worked-out protocol, giving the newly reworked cells an open landscape to expand in. You have the chance for a clean swap on a defined target, which is quite rare. In too many other cases the problem turns out to involve a fuzzy mass of genetic factors and environmental ones, none of which by themselves account for the disease symptoms, or the tissue doesn’t allow you to isolate the defective cells easily or doesn’t allow you to clear them out for any new ones you might generate, and so on.

Both the Vertex/CRISPR and BCH techniques seem to work – and in fact, to work very well. There are now people walking around, many months after these treatments, who were severely ill but now appear to be cured. That’s not a word we get to use very often. They are producing enough fetal hemoglobin, more than enough to make their symptoms completely disappear – no attacks, no transfusions, just normal life. And so far there have been no side effects due to the altered stem cells. An earlier strategy from Bluebird (involving addition of a gene for a modified adult hemoglobin) also seems to be holding up.

These are revolutionary proofs of concept, but at the same time, they are not going to change the course of these diseases in the world – not right now, anyway. Bone marrow transfusion is of course a complex process that costs a great deal and can only be done in places with advanced medical facilities. But what we’ve established is that anything that can cause fetal hemoglobin to be expressed should indeed cure these diseases – that idea has been de-risked. As has the general idea of doing such genetic alteration in defined adult tissues (either RNA interference or CRISPR). From here, we try to make these things easier, cheaper and more general, to come up with new ways of realizing these same goals now that we know that they do what we hoped that they would. This work is already underway – new ways to target the affected cell populations rather than flat-out chemotherapy assault, new ways to deliver the genetically altered cells (or to produce them “on site” in the patients), ways to make the switchover between the two more gradual, and so on. There are lot of possible ways, and we now know where we’re going.

25 comments on “Gene Therapy, Absolutely and For Real”

  1. Morten says:

    You should be able to cure HIV using the same approach, right?

    1. Aleksei Besogonov says:

      Not reliably. It’s impossible to kill ALL cells, so the virus will just re-infect new cells.

      Several patients were functionally cured by using marrow transplants from “elite non-progressors”. In other words, people who are naturally resistant to HIV.

    2. UserFriendly says:

      From my very layman’s understanding the Delta 32 CCR5 mutation is much better at preventing an initial infection because the strain of HIV that is transmitted sexually almost always uses CCR5 to enter t-cells. But “After about five years, viruses evolve in about 50% of patients that are able to use CXCR4, with or without concurrent use of CCR5 (89). ”
      So it isn’t nearly as effective at clearing an already infected person.

      1. UserFriendly says:

        I’ll add that the only reason I know that is because I have the homozygous delta 32 mutation so I spent a bit of time looking into it. I wanted to donate bone marrow after I found out, but of course I can’t because I’m gay. Which is actually quite insane if you think about it.

        1. Morten says:

          Which is insane in itself. For blood donations the product is generally applicable and you have enough donors without non-straight men. And you have frequent donations and the product is used soon after donation.

          For bone marrow you don’t have enough donors. You could test the donor, ask them not to engage in high-risk behaviour (or put them on PrEP), wait, re-test, donate.

        2. Kevin says:

          For what it’s worth, many countries are taking (sometimes painfully slow) steps towards reducing or eliminating barriers to blood and blood product donations by men who have sex with men (MSM).

          In Canada, MSM have been allowed to join the national bone marrow donor registry (OneMatch) since 2009.

          In the United States, MSM have been allowed to join the Be The Match bone marrow registry since 2015.

          (Both countries still restrict whole blood donations by MSM, however. I believe both have moved towards a “it must have been at least this many months since you had sex with a man” model, rather than the absolute ban we saw for most of the last three decades.)

    3. Deniz Erezyilmaz says:

      I think Crispr was used to eradicate SIV in monkeys, pubished last week.

  2. Thomas Lumley says:

    For sickle-cell at least, it seems you would need to shut down Hb-S expression as well as turning on fetal hemoglobin. Even if you don’t need something as drastic as bone marrow transplant, there’s going to be some strategy to wipe out competing RBCs.

    1. Samuel Weller says:

      Maybe not. Sickle cell rbc last 10-20 days in the circulation but normal rbc last 100+ days so even by correcting a small fraction (maybe <10% ??) of the hemopoietic stem cells it’s thought that the proportion of normal rbc in the circulation will be much higher than that and this will be sufficient to return rbc levels to something close to normal

    2. Anonymous says:

      Not in practice – sickle cell patients who also have other mutations leading to high fetal haemoglobin levels have reduced sickle cell symptoms

  3. Wilhelm Cody says:

    Why do humans transfer to a different Hemoglobin gene as adults? There must be some survival advantage to keep the system intact. A quick search turns up little other than the fact that fetal hemoglobin has a higher oxygen affinity than adult, allowing capture of oxygen from the mother’s blood.

    1. Thomas says:

      Perhaps that affinity tells all. When one becomes a mother, the affinity has to drop, or the fetal hemoglobin trick doesn’t work.
      Also, too high an affinity might be problematic on its own.

      1. AVS-600 says:

        This makes a lot of sense, and also raises the question… are there implications for how this therapy might impact the ability of a patient to carry a pregnancy to term later on?

        1. Adrian says:

          My expectation would be that the fetus would die early if a woman who received this therapy becomes pregnant, which is not a huge price for being able to live a normal life.

    2. Pete says:

      The transfer of oxygen between mother and child during pregnancy is reason enough. If adults would still have fetal Hb, this would not work.

      1. Marko says:


        Good thinking. Just wish it had occurred to me first.

      2. Wilhelm Cody says:

        Thank you, this is an excellent hypothesis that I am I clearly didn’t think of. In context, children are parasites and restricting their access to oxygen in utero might help the mother but not the species.

      3. Orange says:

        Then ot would be sufficient for females to switch over. If the fetal hemogoblin would be better males could stick to it and help the species.

        1. Oker says:

          Having more and more sex-dependent transcriptional changes is evolutionally costly. Men have no need for nipples, at all, yet they are still there. I guess fetal Hb could be an advantage, but it is probably not worth the “regulatory burden”, as such things may go wrong occasionally.
          Unnecessary expression regulation complexity is an evolutionary liability.

          1. LdaQuirm says:

            I have oft wondered if there is a “limit of complexity” to naturally evolved systems. I.E. a maximum complexity beyond which the rate of negative mutations for any line of descent is always >= positive ones.

  4. Daren Austin says:

    Any information of relative fitness of the modified cells and the efficacy with which chemo is removing the abhorrent cells? Evolutionary fitness has a habit of coming back to bite you when the numbers are in the trillions.

    1. Charles H. says:

      These diseases are not microbe based, so they don’t evolve over a small span of time. To the extent that they do evolve, it tends to be by disappearing (because of killing those who would propagate them).

      So it’s not like using this technique to suppress, say, measles. Measles will evolve to escape regulation. Thalassemia, not.

  5. Petros says:

    I remember going to CFF meetings in the early 90s when speakers claimed that CF would be cured within 5 years thanks to gene therapy. While some efficacy has been demonstrated there is still no approved gene therapy and the most clinical data has been produced by a group at Imperial College, London

  6. MTK says:

    I was completely unaware of the strategies used here, i.e. turning on fetal hemoglobin expression rather than “fixing” the adult hemoglobin. Pretty cool. Thanks for the info.

  7. T says:

    I’m surprised this article didn’t mention the X-SCID gene therapy trials from some years ago now. The gene modification approach was different (integrating viruses to add in a healthy gene, since they didn’t have the luxury of being able to just turn a problematic one off). And there were some severe adverse effects in the form of cancers caused by the random viral insertion, which unfortunately caused a loss of public support for whole idea for many years, although targeted integration approaches have since been developed to address this. But that was a real proof of concept in term of ex vivo bone marrow gene therapy for blood diseases, and the patients were genuinely cured of something much more deadly than sickle cell anemia. It should certainly count as “Gene Therapy, Absolutely and For Real”.

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