Eli5 How do gene therapy eye drops work?


Saw an article about gene therapy eye drops restoring a child’s vision due to a disease (dermatosis bulbosa?). Wonderful accomplishment. But how?

In: 2

dystrophic epidermolysis bullosa. (Totally butchered that in the original post)

Tldr: they only needed the working gene to be in the cells in the surface of the eye, so literally dropping the drug onto the surface gets the drug to where it needs to be.

Now a longer but hopefully still ELI5 level explanation.

Gene therapy is to insert a functioning gene into cells that lack the functioning gene.

All the cells in the body will lack the functioning gene, but you don’t necessarily need to put the working gene into all the cells. You need to put it into only the cells that need that gene to work properly. For example, all cells have the genes with info on how to make stomach acid, but only the specialised cells in the stomach actually use that gene, so it is silenced in all other cells.

For any gene therapy to work, you need to get the drug (for lack of a better term) to the site you need the gene to work. You don’t need it in cells that would normally have it silenced anyway.

First step: get the gene therapy to where you need it.

In the case you described, the area that they wanted the gene to get to was on the surface of the eye. This is obviously easily accessible as it is literally right there. So if they could make a gene therapy that would work by just putting drops onto the surface, rather than needing to get another route (usually by injecting it into the blood so it goes round the whole body and into lots of cells and hopefully enough into where you want. This means you can give smaller does that an injection into the blood, possibly reduce side effects because it’s not going to other sites in the body, and it is physically easier to do. Boom, the drug is exactly where it needs to be.

Next how the gene actually gets into the cells and into the nucleus to start working.

The new gene needs a way into a cell. The few working gene therapies we have use modified viruses. Viruses do there thing by entering cells, and depending on the virus, also entering the nucleus and inserting their own DNA into our DNA. Gene therapy uses a virus where the virus DNA it’s self shouldn’t cause problems in the cell, but with the new gene attached to it, the new gene also gets inserted into the out DNA and starts working. Ta da, working gene where it needs to be.

Next part: do you need to give the therapy once or will they still need to get the drug over and over?

If the cell type you need to get the gene into is a cell that will last a lifetime (eg nerve cells), then it might be possible that a once off will do the trick. There is a condition called SMA type 1 that is lethal early in life. It is one of the few diseases we have working gene therapy for. The important cells in the disease are nerve cells. And the gene therapy is a one time thing which should last a lifetime (it’s new so we may find that years down the line it does need repeated. Hopefully not).

In your example, the cells on the surface of the eye probably do die and get replace (I’m not entirely sure). If this is the case, the kid might need repeated doses over their life to maintain the effect of the gene therapy as the cells affected by the condition and with the new working gene die off and get replaced by new cells without the working gene.

However, it could be that once the damage that caused the vision loss is healed, there is a non-gene therapy way to protect the now healed surface of the eye (again I don’t know what, but might be specialist lubricating eye drops or something). This non-gene preventative therapy would likely be far less expensive, and often less chance of side effects, so would be used instead of repeated gene therapy treatments.

Final thing to think about: if it is something where you would need to repeat treatments over and over through out life, is that possible?

Because the method of getting the gene into the cells is a virus, our immune system will recognise it as a virus and act to kill it off. Usually to start, this response is slow. But with repeated exposure to the virus, that response would get faster and stronger, likely killing off the virus and gene therapy before it can do its work. So might be that the gene therapy would only work for a limited time. If that time is so that an area can heal, and then be protected by other methods, then fine, that would work. But if it would need to be done over and over, then it may not work in the long term. That is why finding new ways to insert the gene is important and a major area of research.