4 ms·

First human Crispr gene-editing trial gets early approval

46 points by jerryhuang100 10y ago

jessriedel 10y ago
> The small study, which has been funded by ex-Facebook president Sean Parker, will augment T cells – potentially a way to treat cancer – but will be used to see whether Crispr is safe in humans, rather than being used as an actual treatment. This is misleading, right? Yes, it's true that Stage I trials are designed (and in particular, statistically powered) to test safety rather than effectiveness. But that doesn't mean they are making gene edits with no therapeutic purpose. That would be highly unethical. The gene edits are definitely intended to be an "actual treatment". It's just that the number of subjects is so low there isn't any hope of measuring the effect.
- tgokh 10y ago
  I believe you're right. For a Phase 1, you would need to try the same treatment that you want to use for therapeutic purposes, not a "sham" treatment
- manmal 10y ago
  I haven't run the numbers, but I guess if more than, say, 17 patients go into full remission, then the results will be significant.
- mikeyouse 10y ago
  Typically in Stage 1 trials, they test safety effectiveness by giving doses of varying size, often times below the level of clinical effectiveness. They also give these to much smaller populations, usually fewer than 25 people. The main goal of these trials is to figure out "safety and dosage" -- so they measure side effects at each dosage and try to discern interactions with the body. They'll be especially careful with the CRISPR drugs due to the disasters that Gene Therapy trials have previously undergone. Most notably, TGN1412 was given at a dosage about 500x smaller than the safe dosage in animals but caused almost immediate cytokine storms that nearly killed all 6 participants in the trial.
  - jessriedel 10y ago
    > they test safety effectiveness by giving doses of varying size, often times below the level of clinical effectiveness. OK, good point. But even then there needs to be a reasonable belief that either (1) the likelihood of clinical effectiveness is nonzero, and is still worth trying compared to the smaller chance of bad effects, or (2) the same patient will be able to receive a clinically effective dose in the future based on the safety information gained testing the smaller, clinically ineffective dose on them.
maga 10y ago
Since T cells do not reproduce by themselves, I presume the effects of modified T cells will only last until the cells exist in the body. This reminds me of a question I was wondering about since I heard about Crispr: can we use this method to make permanent changes in the DNA of grown up humans, and if so, do we have clear understanding of how to do it? The thing that puzzles me most is that if we do it by creating some cells and injecting them, how do we guarantee that these cells replace their existing unmodified counterparts?
- patall 10y ago
  I would not be so sure about that. They do not state which kind (or state) of T cells they target but it is not unlikely that they do not draw them from the blood but from bone marrow. May also be memory T cells ... This should also answer your second question: You target some cells higher up in the hirachy like CMPs or even MPP and HSC (stem cells). Other tissue, other stem cell type. And ultimately obviously some lineage commited (cells aimed to become a certain cell type) iPS cells (which are stem cells generated from normal body cells). Thats all possible, the only thing really missing is good understand of epigenetics (only a question of time) and some way for reliable epigenetic programming/modification. (Sorry if thats too short too complicated but maybe it guides you in the right direction) Edit: And third question: I am not entirely sure why you would need to replace all the existing cells. Some additional functionality might be sufficent. Where this is not the case, you usually go for irradition (and full replacement).
  - maga 10y ago
    Thanks for the detailed answer! >This should also answer your second question: You target some cells higher up in the hirachy like CMPs or even MPP and HSC (stem cells). Other tissue, other stem cell type. And ultimately obviously some lineage commited (cells aimed to become a certain cell type) iPS cells (which are stem cells generated from normal body cells). Thats all possible, the only thing really missing is good understand of epigenetics (only a question of time) and some way for reliable epigenetic programming/modification. (Sorry if thats too short too complicated but maybe it guides you in the right direction) If I understand you correctly, we can replace the cells in charge of producing other cells (stem cells) to make the changes lasting, but we are not yet certain how the changes will play with the rest of their environment (epigenetics). >I am not entirely sure why you would need to replace all the existing cells. Some additional functionality might be sufficent. Where this is not the case, you usually go for irradition (and full replacement). To make an example, let's say I'm a secret ginger carrying the mutation that makes me far more susceptible to skin cancer[1]. And let's say we know what exactly to change in DNA to fix my problem. Now, I don't know how the skin producing machinery works, but I guess replacing it in one go isn't an option. So, if we go with changing cells higher up in skin production, can we guarantee that in due time they will replace all (or most of) the skin with modified cells? As a bonus question, since we limit ourselves to targeting only particular cell types (skin in this case) that means the rest of the body is carrying unmodified DNA, hence, those changes are not hereditary, right? [1] http://www.telegraph.co.uk/science/2016/07/12/one-quarter-of-britons-carry-ginger-gene-which-raises-risk-of-sk/ http://www.telegraph.co.uk/science/2016/07/12/one-quarter-of...
themartorana 10y ago
I know the people in this trial probably have nothing to lose, but I do wish there was a way to recognize them (and others like them in similar trials). There are times when human testing must happen. With civilization-altering possibilities like this, these people are pioneers whether it works or helps us figure out why it doesn't and move the needle forward.

46 points by jerryhuang100 10y ago

> The small study, which has been funded by ex-Facebook president Sean Parker, will augment T cells – potentially a way to treat cancer – but will be used to see whether Crispr is safe in humans, rather than being used as an actual treatment. This is misleading, right? Yes, it's true that Stage I trials are designed (and in particular, statistically powered) to test safety rather than effectiveness. But that doesn't mean they are making gene edits with no therapeutic purpose. That would be highly unethical. The gene edits are definitely intended to be an "actual treatment". It's just that the number of subjects is so low there isn't any hope of measuring the effect.

tgokh 10y ago
I believe you're right. For a Phase 1, you would need to try the same treatment that you want to use for therapeutic purposes, not a "sham" treatment
manmal 10y ago
I haven't run the numbers, but I guess if more than, say, 17 patients go into full remission, then the results will be significant.
mikeyouse 10y ago
Typically in Stage 1 trials, they test safety effectiveness by giving doses of varying size, often times below the level of clinical effectiveness. They also give these to much smaller populations, usually fewer than 25 people. The main goal of these trials is to figure out "safety and dosage" -- so they measure side effects at each dosage and try to discern interactions with the body. They'll be especially careful with the CRISPR drugs due to the disasters that Gene Therapy trials have previously undergone. Most notably, TGN1412 was given at a dosage about 500x smaller than the safe dosage in animals but caused almost immediate cytokine storms that nearly killed all 6 participants in the trial.
- jessriedel 10y ago
  > they test safety effectiveness by giving doses of varying size, often times below the level of clinical effectiveness. OK, good point. But even then there needs to be a reasonable belief that either (1) the likelihood of clinical effectiveness is nonzero, and is still worth trying compared to the smaller chance of bad effects, or (2) the same patient will be able to receive a clinically effective dose in the future based on the safety information gained testing the smaller, clinically ineffective dose on them.

maga 10y ago

Since T cells do not reproduce by themselves, I presume the effects of modified T cells will only last until the cells exist in the body. This reminds me of a question I was wondering about since I heard about Crispr: can we use this method to make permanent changes in the DNA of grown up humans, and if so, do we have clear understanding of how to do it? The thing that puzzles me most is that if we do it by creating some cells and injecting them, how do we guarantee that these cells replace their existing unmodified counterparts?

patall 10y ago
I would not be so sure about that. They do not state which kind (or state) of T cells they target but it is not unlikely that they do not draw them from the blood but from bone marrow. May also be memory T cells ... This should also answer your second question: You target some cells higher up in the hirachy like CMPs or even MPP and HSC (stem cells). Other tissue, other stem cell type. And ultimately obviously some lineage commited (cells aimed to become a certain cell type) iPS cells (which are stem cells generated from normal body cells). Thats all possible, the only thing really missing is good understand of epigenetics (only a question of time) and some way for reliable epigenetic programming/modification. (Sorry if thats too short too complicated but maybe it guides you in the right direction) Edit: And third question: I am not entirely sure why you would need to replace all the existing cells. Some additional functionality might be sufficent. Where this is not the case, you usually go for irradition (and full replacement).
- maga 10y ago
  Thanks for the detailed answer! >This should also answer your second question: You target some cells higher up in the hirachy like CMPs or even MPP and HSC (stem cells). Other tissue, other stem cell type. And ultimately obviously some lineage commited (cells aimed to become a certain cell type) iPS cells (which are stem cells generated from normal body cells). Thats all possible, the only thing really missing is good understand of epigenetics (only a question of time) and some way for reliable epigenetic programming/modification. (Sorry if thats too short too complicated but maybe it guides you in the right direction) If I understand you correctly, we can replace the cells in charge of producing other cells (stem cells) to make the changes lasting, but we are not yet certain how the changes will play with the rest of their environment (epigenetics). >I am not entirely sure why you would need to replace all the existing cells. Some additional functionality might be sufficent. Where this is not the case, you usually go for irradition (and full replacement). To make an example, let's say I'm a secret ginger carrying the mutation that makes me far more susceptible to skin cancer[1]. And let's say we know what exactly to change in DNA to fix my problem. Now, I don't know how the skin producing machinery works, but I guess replacing it in one go isn't an option. So, if we go with changing cells higher up in skin production, can we guarantee that in due time they will replace all (or most of) the skin with modified cells? As a bonus question, since we limit ourselves to targeting only particular cell types (skin in this case) that means the rest of the body is carrying unmodified DNA, hence, those changes are not hereditary, right? [1] http://www.telegraph.co.uk/science/2016/07/12/one-quarter-of-britons-carry-ginger-gene-which-raises-risk-of-sk/ http://www.telegraph.co.uk/science/2016/07/12/one-quarter-of...

themartorana 10y ago

I know the people in this trial probably have nothing to lose, but I do wish there was a way to recognize them (and others like them in similar trials). There are times when human testing must happen. With civilization-altering possibilities like this, these people are pioneers whether it works or helps us figure out why it doesn't and move the needle forward.