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Gene Editing Therapies Thunder Along

Here’s a one-stop way to get caught up with all the therapeutic gene editing technologies out there, courtesy of Nature Medicine. Huge amounts of money are flowing into this area, because CRISPR/Cas9 looks so solid, compared to the various other things that have been tried in the past. But zinc finger nuclease and TALEN are also getting their shots.
The challenge is often going to be getting the population of new, modified cells to take off. Blood disorders are a natural fit, since you can pull bone marrow, modify it, kill off the original, and replace (as is done with the CAR-T immunotherapies for cancer, another area where dumptrucks of money are pulling up and unloading). But for other cell populations, it’s going to be a bit trickier, and my guess is that the gene editing may (perversely) turn out to be the easy part. We don’t always have a good handle on stem-cell percursors (their behavior or their localization), and clearing out the original defective cell population will (in some cases) be an issue. (In others, you can probably wait for them to die off and cycle in your improved versions).
And gene editing comes in several varieties – disruption of a defective gene alone, replacement of one with a working form, both of those at once, or just splicing in a working form in addition to what’s already there (which in some cases would probably be enough to correct things). There’s a lot of experimentation to be done, and a lot of it is going to end up being done in the clinic, with human patients. It’s an open question how predictive animal models will be for some of these things – you’d think that would work, but we haven’t modified too many living human genomes yet. I would count on all sorts of twists and turns along the way – dramatic successes, dramatic failures, and some that looked like one of those but were actually the other. Deep pockets, patience, and no small amount of courage (both medical and financial) will be needed.

18 comments on “Gene Editing Therapies Thunder Along”

  1. An interesting addition to your list is the idea in diseases such as Duchenne’s muscular dystrophy to edit in a significantly less severe allele — instead of trying to use a drug to drive exon skipping, edit the genome to skip that exon. The resulting allele isn’t wild type, but has the potential to cause much less severe disease. If editing by deletion is significantly more efficient than a repair to wild type, it could be a viable strategy.

  2. Anonymous says:

    Can someone explain why gene editing will be a cure? Assuming something like CRISIP/CAS9 is 99% efficient at finding every defective cell (which it probably isn’t in practice), why wouldn’t those 1% of cells still replicate and propagate the same mutation over time?

  3. steve says:

    The simplest answer is that gene editing can cure diseases where the gene is not dominant. For example, there are many metabolic diseases where the problem is a disrupted gene not making the appropriate product (for example, hemophilias). Replacing enough liver cells with the corrected gene such that the liver now makes the missing product would be a cure. For that type of disease there is no need to worry about stem or progenitor cells. For other diseases, such as sickle cell or thalassemias, you’d need to replace the hematopoietic stem cell in order to make sure you don’t have overgrowth by the affected clone. However, you need to keep in mind that it’s a numbers game and hematopoiesis is driven by only a few stem cells at a time so if you get majority replacement you’ll cure the disease for at least a number of years if not decades.

  4. Anonymous says:

    CRISIP/CAS9 is a fantastic technology. But completely acad mic. Let’s see, one would have to rule out:
    1. All diseases in all but the most accessible tissues (blood, liver, and maybe the eye).
    2. All diseases which are complex and multi-factorial.
    3. All diseases which are non-genetic
    4. All diseases which are dominant gain-of-function genetic diseases (since the technology is not 100% effective).
    5. All diseases which are too rare to generate a return.
    6. All diseases which are not severe enough to justify the safety risks.
    7. And so on…
    Anything left?

  5. steve says:

    Your list leaves quite a lot of disease that can be cured with a novel technology. The ability to do precise genetic engineering on immune cells, liver cells, muscle cells, retinal cells, auditory hair cells and hematopoietic stem cells, all of which satisfy your criteria, is more than enough to keep 100 companies busy generating lots of life-saving products. Once other tissues such as lung, pancreas and heart come online (there are already clinical trials for cell replacement therapies for these tissues) the list will expand even further.

  6. Andre says:

    @5: Could not agree more with your assessment! Gene editing technology with the ability to restore wild type gene function is currently the only realistic hope for curative treatments of rare inherited diseases in the near future. Numerous limitations however apply. Rare diseases manifesting in developmental abnormalities or mental retardation cannot not be cured with this technology, or any other approach that I am aware of. Damage has been done already in the womb. Furthermore the affected patient tissues to be corrected cannot be too extensive. For example, the technology can work for rare metabolic diseases affecting the liver (e.g. tyrosinemia, alkaptonuria), where a few corrected cells will be sufficient to cure a patient. It will likely not be applicable to diseases, such as cystic fibrosis or Duchenne muscular dystrophy, where you need to correct the big majority of mutant cells. Finally, therapeutic gene editing, if successfully implemented, would represent true personalized medical and curative treatment to patients with genetic diseases. This is very different from the promises made in oncology, where we are dealing with cancer cells rapidly accumulating all sorts of mutations.

  7. Anonymous says:

    @5: Continued from #4…
    7. All diseases which can be treated just as easily with the recombinant protein.
    8. All diseases which are reversible, post-development.
    9. All diseases which are not based on a single homogeneous mutation.
    10. All diseases that are no worse than the risk of irreversible long-term damage from gene therapy.
    11. All diseases with less than a few thousand patients having exactly the same mutation.
    12. And so on …
    Any diseases left now?

  8. a.nonymaus says:

    This seems like a very promising route to curing defective genes for L-gulonolactone oxidase. Finally, we can defeat scurvy.

  9. DCRogers says:

    @8: This seems like a very promising route to curing defective genes for L-gulonolactone oxidase. Finally, we can defeat scurvy.
    First I laughed, then I thought: that would be pretty cool!
    Then I thought, maybe it was turned off for a reason; perhaps there would be unexpected effects?
    Then I thought, maybe someone has one this, or identified people in the population with this gene working??
    This is the cool thing about science, even jokes can inspire entire areas of fascinating research!

  10. steve says:

    Anonymous, I’m afraid you’re rather short-sighted. Does your list include engineering T cells to fight cancer (there’s a good deal more engineering to be done beyond replacing the receptor in CAR-T)? Does it include engineering MSCs to produce enzymes for replacement therapies? Does it include replacing defective beta globin genes in HSCs for thalessemias or sickle cell? Does it include engineering cardiac progenitors for replacement therapies after MI? Does it include engineering EPCs for replacement therapies in PAD? Does it include engineering liver cells for replacement therapies in storage diseases? One could go on and on but there are more possibilities under the sun than are dreamt of in your philosophy.

  11. An interesting example that falsifies premise #4 in comment #4 is the recent observation of a spontaneous remission of WHIM syndrome due to natural inactivation of the dominant allele that drives the disease.
    Among the obvious “still left” after these absurdly stringent filters proposed in #4 & #7 are beta thalassemias and sickle cell anemia. Particularly absurd is the idea that a disease must have a single allele to be treatable

  12. DN says:

    The human promoters for ascorbate synthesis have likely had genetic drift. I’d be afraid of filling up with ascorbate crystals the first time I got a sunburn, or something absurd like that.

  13. gippgig says:

    #6: Does alkaptonuria qualify as a disease? As I recall, it’s a harmless condition.
    #9: There was a proposal a while ago that mutation of a myosin gene (don;’t remember which one) responsible for strong jaw muscles permitted the development of speech. I’ve always thought it would be interesting to search for individuals with a reversion to see what the effect would be.

  14. Anonymous with CF says:

    #6 I disagree with you about CF as focusing on just the lungs will be sufficient for a majority of patients, and in the lung you only need enough cells repaired in order to maintain the mucus layer, even if you only had 10% of the cells (though this still might be a high efficiency rate to achieve) dispersed throughout the lung, I am fairly sure that would be enough to have a clinically significant enough result as to reduce the number of exacerbations in patients and give them a bit of stability. Even with Ivacaftor/lumacaftor, the numbers aren’t huge lung function improvements but they saw other markers that point towards a more stable profile for patients, which is good enough for me.

  15. steve says:

    I guess you disagree with me… 😉 Yes, CF is more than just lungs but if you can correct lung function you can certainly help patients. Don’t let perfect become the enemy of good. That’s why Anonymous’ list is so limiting. I’m sure he would have discounted antibodies as a therapy when they first started out as well.

  16. steve says:

    Woops – sorry, misread that. I see you actually agree with what I was saying; sorry about that.

  17. Andre says:

    @13: Alkaptonuria is a devastating rare inherited metabolic disease that manifests, typically from age 30 onwards, with progressive serious health problems due to ochronosis in joints, heart valves, and kidneys. See here for more details:

  18. Andre says:

    @14: Point well-taken with regard to CF and the lungs! Personally, I believe it will be difficult to efficiently penetrate the thick mucus layer to deliver the CRISPR-Cas reagents to the target cells. This problem has also made gene therapy approaches fail to date. Given that homology-direct gene editing using CRISPR-Cas is far less efficient than pure gene disruption, the chances are small to correct sufficient cells for therapeutic benefit. Nevertheless, human ingenuity may prove me wrong in the future!

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