Lots of genetic diseases come down to a small change to a single gene. So you would think that with genetic engineering we would be able to treat or even cure these diseases, an idea which is known as gene therapy.
The viral genes have been stripped to only ones absolutely essential for inserting DNA, so there are fewer genes around that might make them more likely to insert the genes where they don’t belong. Plus, the viruses self-destruct after they do their job to make sure they don’t accidentally start replicating and causing problems, like the viruses they are based on.
There are still some concerns about the effectiveness and side effects, though, for example, it’s hard to be completely, 100% sure that the place where you put the extra DNA won’t interfere with the cell’s genome in a way that could lead to cancer. That’s why other researchers are trying to edit the cell’s beta-globin gene directly, replacing the disease-causing DNA with a working sequence. Editing a gene rather than adding a new one tends to be very effective but without the same risk of side effects.
In one 2016 study, for example, researchers successfully edited the beta-globin genes in 90% of the human marrow cells they tested. But when they moved on to animal trials, only 10% of cells actually survived and were incorporated into bone marrow.
So, something about the editing process either makes the cells less viable or the immune system recognizes the foreign DNA somehow and kills them off. Researchers are working out these kinks, though, and this kind of editing technique is close to ready for human trials.
But there’s another way to treat the sickle cell with gene editing, and it might be the one that ultimately wins the race: getting cells to express a different protein they already have. During fetal development, we don’t actually make haemoglobin using beta-globin. We use a different protein, called gamma-globin, instead. The gene for it never goes away, it just gets turned off shortly after birth by regulatory genes, which tell the cell to produce beta-globin instead.
Doctors discovered that some people with sickle cell disease had fewer symptoms because they never stopped producing gamma-globin. And that gave them the idea that instead of using beta-globin, they could reactivate the gene for gamma-globin by targeting one of the genes that regulate its expression.
It turns out that strategy might actually be easier because it involves editing a gene to deactivate it rather than putting in new DNA. And because of this, more of the cells seem to go back into the bone instead of dying.
Also, it’s not just a treatment for sickle cell, several other blood disorders that are caused by issues with the beta-globin gene could potentially be treated by turning gamma-globin back on. Like beta-thalassemia, for example, where errors in the beta-globin gene mean the person makes very little or no haemoglobin.
So far, animal studies have suggested the technique is really effective enough for human trials in patients with beta-thalassemia, which started in Europe in 2018. Of course, only time will tell which, if any, of these gene therapies, ends up becoming readily available.
But with so many ways to get at the problem nearing or already in human trials, researchers are hoping that something will prove effective in the near future. And they have learned a lot from all the challenges in developing a treatment for sickle cell.
The challenges with engineering bone marrow cells and beta-globin genes have led to all kinds of creative solutions, like those lentiviruses and the new research on gamma-globin. Researchers might have set out to treat sickle cell disease, but in the process, they have made discoveries that could help with all kinds of treatments. Which hopefully means the future of gene therapy development will go a little more smoothly in the future.
Source:- The American Society of Gene & Cell Therapy (ASGCT)
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