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godmode2019

Can someone answer, what is the entry method of CRISPR in adults, don't it need to change all instances of a cell to be effective?

I don't really understand the delivery method.

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Brute force:

"...some of the patient’s hematopoietic stem cells... [are] harvested for gene editing outside the body. After these cells are removed, the remaining bone marrow is destroyed with chemotherapy to allow space for the repaired and reinfused stem cells to grow."

EDIT: This is apparently the same procedure as conventional bone marrow transplants in SCA patients. CRISPR is just slotted into that workflow to synthesize a transplant, without needing to find a donor.

Even with the amount of hype around CRISPR, that is... incredible. Turning patients into their own donors feels magical.

I suppose in this instance, the patients wouldn’t need immunosuppressants after their treatment, as I’d expect standard care patients currently need for life?

I think it's an open question. After this treatment, the patient's red blood cells will be producing a new protein that they have never produced before. This protein only differs from the previous one by one amino acid, so the question becomes how sensitive the immune system is to such a change. Given that the immune system has some difficulty recognizing cancer cells with multiple protein-coding mutations in them, I think it's likely that a single amino acid change will fly under the radar and not require any immune suppression, at least for the vast majority of recipients of this treatment.

Wiping out the bone marrow should also (essentially) reset the immune system IIRC.

Yes, but T-cells learn to distinguish self from non-self in the thymus, and I don't believe this treatment alters the hemoglobin gene sequence in the thymal epithelial cells. Of course, the thymus, like the rest of the body, will be served by red blood cells containing the new hemoglobin gene, but I'm not sure if this alone is sufficient for immature T-cells in the thymus to learn it as a self protein.

My understanding is that the "fixed" red blood cells antigens would be the same so the T-cell would not be triggered.

All the antigens would be identical except those derived from the modified gene. This tiny difference probably is pretty likely to escape detection, but not 100% guaranteed.

Bone marrow transplant (BMT) recipients can still experience graft versus host disease (GVHD) which is when the transplanted marrow produces healthy cells that start to attack the host body.

Besides GVHD, it is like you said. BMT patients are one of the few transplant types that can eventually come off of immuno-suppressants with a successful transplant. The patient's original bone marrow is supposed to be wiped out by chemotherapy (and sometimes some radiation) to make room for the new marrow transplant.

Can we take a moment to appreciate the straightforward naming of graft-versus-host disease? I couldn't find the history of its discovery beyond this (https://www.sciencedirect.com/science/article/abs/pii/S03014...) and even there, I couldn't find any indication of how it came to receive that name specifically, but it's much better than "[scientist's name]'s disease/syndrome" that we keep running into because people want credits at the expense of accessibility of knowledge.

The fundamental idea of using the donor's own stem cells is known as an Autologous Stem Cell Transplant and has existed for a while. It is used as therapy for a fair number of blood cancers (e.g. multiple myeloma or a few leukemias).

Using "something" to manipulate the donor cells has also been done for these autologous HSCTs. I know of "CAR T cell therapy", but there are likely others. ( https://www.cancer.gov/about-cancer/treatment/research/car-t... )

I think some small number of autologous HSCT recipients require immunosuppressants, but from what I remember the number is very very small. (Allogenic HSCT recipients, who receive cells from a different person, are _much_ more likely to require lifetime immunosuppressants.)

It's super cool that they're able to treat genetic diseases this way!

But does the CRISPR method require the patient to remain on anti-rejection drugs the rest of their life?

I would assume more likely not since they are the patients own cells.

Sickle cell anemia can be "cured" by inducing expression of fetal hemoglobin (fHb). You don't need to shut off the defective gene and the disease is effectively "cured" if you replace enough scHb with fHb.

So you remove bone marrow from the patient, modify the cells, put them back in. The modified cells produce fHb at a high enough level that symptoms of Sickle Cell go away.

Not that different than the already approved CAR-T therapies (with the exception they don't use CRISPR for the genetic modification).

This treatment modifies the adult hemoglobin gene.

That's what I get for not reading the article. But the point stands on correcting genetics for hematopoetic cells. It's possible to fix a small number of cells, then reimplant (often depleting the cells in the person first) and they will replicate.

Easier than trying to fix the cells in a solid organ.

Because this is a blood based disease, I’m guessing they would extract blood from the patient or extract them from bone marrow (more likely), treat the cells outside the body, and then transfuse the modified blood cells back onto the patient to try and engraftment them in the bone marrow.

All of the hard CRISPR stuff is likely in vitro.

However, I don’t know anything about what the specific plans are though, this is just speculation.

For blood diseases it’s enough to replace all blood-producing cells and their producers, I guess?

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