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Gene manipulation applications in autoimmune diseases 3

Part 3 of 3
Published on April 30, 2026   44 min

Other Talks in the Series: Gene Manipulation - How and Why?

Other Talks in the Series: Periodic Reports: Advances in Clinical Interventions and Research Platforms

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0:04
Another approach in which gene manipulation can help with. autoimmune disease is to gene-edit the cell types that are targeted by the immune attack. You would do gene editing not on the immunosuppressive regulatory T cells, but on the cells that are being transplanted to be protected.
0:26
In this approach, you can think of either gene editing primary β cells or whatever other cells are needed for autoimmune diseases, or you can start with pluripotent stem cells, which is easier to edit their genome and to grow in unlimited amounts and then differentiate those into cells of interest. This is a field of universal stem cells or hypoimmune stem cells. There's work from different groups. We've done some work in this field as well and also others. How does this work?
0:59
One way this works, if you think about it, is, well, if T cells see MHC, if I delete, if I ablate MHC expression, then the cells become invisible. I could make β cells that are not recognized by T cells, which seem to be the problem in diabetes, so let's do that. One simple way of doing this is if you knock out the B2M gene, remember it being the accessory chain on MHC class 1. That's why it's relevant here. If you knock out the B2M gene, the entirety of MHC class 1 molecules is no longer on the cell surface. That means that cytotoxic T lymphocytes CTLs can no longer kill these cells. Now the immune system is not so easy to fool. If you have an MHC-negative cell going around or engrafted natural killer cells, which are innate lymphocytes that are specifically trained, if you will, to kill cancer cells, or rather infected cells, come and kill the cells. It turns out that a lot of viruses downregulate MHC expression in infected cells precisely to evade T cells and a lot of cancer cells downregulate the MHC again to evade T cells. In this armwrestling evolution, our body came up with NK cells to do that. That's usually good news, but for us, it makes our life harder because now, just simply making MHC-deficient cells is not sufficient to protect them from immune and autoimmune attack. Then we can maybe put in a molecule to inhibit the NK cells on top of heavy notice recognition. Different molecules exist. One of them is HLA-G. HLA-G is a non-classical MHC molecule dedicated to suppressing NK cells in pregnancy. So at the maternal-fetal interface fetal trophoblasts express HLA-G and don't express HLA and HLA-B. We're basically mimicking a fetal trophoblast in this type of hypommune universal stem cell. There are other genes as well.

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Gene manipulation applications in autoimmune diseases 3

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