Connexins and gene therapy

Last post, I looked quickly at how genetic treatments worked. It seems that restoring hearing through genetic therapy is still far away. But progress is being made.

From what I gather, there are 3 phases to testing gene therapies. First is in a test tube or lab dish (in vitro), next is in live creatures (in vivo); mice or other animals, and finally humans. I don't believe there are any human trials for hearing and gene therapy underway - at least I haven't found any publications. However there are a lot of animal trials out there.

Some of these use a virus called AAV to transfer genes to the ear. Viruses work by injecting their DNA into our cells. Our cells then make the proteins the virus wants. This video explains more about viruses if you are interested.

AAV is a virus which infects people but doesn't seem to do any damage, and your body doesn't seem to be bothered by it - it doesn't trigger much of an immune response. In fact there is a good chance you have already been infected by it.

AAV only needs some of its own DNA to spread itself. To use it in gene therapy, scientists keep this bit of DNA and replace the rest with whatever they want- such as GJB2, the gene for creating Connexin 26.

Testing this on mice and guinea pigs does lead to the cells creating good Connexin proteins, and restores the ear battery I described in a previous post. But this did not repair their hearing. The problem is is that many Cx26 and Cx30 mutations lead to the death of hair cells in the ear, and these don't grow back in mammals. Hair cells are the cells that detect sound and convert it to a nerve signal. So if you fix the mutation after the hair cells are dead, it's not going to make much difference.

This leads to a problem for human treatments. Most of the time, the hair cells are dead at birth, or soon after. Which would mean trying to carry out treatment when a baby is still in the womb; a lot more risky than treating adults or even children. But there is research being done on how to regenerate hair cells, meaning the treatment could work after birth.

So it looks like we wont be seeing genetic remedies for Connexin mutations any time soon. Perhaps the CRISPR technology I mentioned in my last post will change that - you can already buy CX26 CRISPR bacteria online, so I guess someone is doing research with them.

Finally, here's something not related to hearing but still interesting. Connexin 26 is actually being looked at in gene therapy to fight cancer. Scientists have come up with DNA which will kill a cancer cell. But they have difficulty getting it into them. For some reason, cancer cells don't produce much Connexin protein. Connexins are used to allow stuff to pass between cells, so if they aren't there its harder to get new DNA into the cancer cells. Using AAV, scientists stick in the GJB2 gene alongside the new cancer-killing DNA, and it has shown to be pretty effective in some cases.

However in other cases it has allowed the tumors to spread more quickly - so more research needed! Still, looks promising.