By Anna Cappella
The words “gene therapy” have been running loose in the biological research community ever since Jennifer Doudna’s 2020 Nobel Prize win. Gene therapy is becoming an option for more patients with diseases caused by gene mutations. In simpler terms: if you’ve inherited, or in some other way obtained DNA with misspellings or letters left out in important places, scientists have figured out ways to erase and replace. Not all of these methods are mediated by Doudna’s claim-to-fame CRISPR, but I’ll get into that later.
One of the most recent applications of gene therapy has been genetically-caused, or hereditary, hearing loss. There are over 120 genes — or stretches of DNA — that encode proteins important enough to hearing to cause hearing loss if the DNA mutates. That’s a rather large number of genes for scientists to target in potential cures, making the disorder a difficult one to research. What’s more, many patients with hereditary hearing loss have mutations in more than one gene, decreasing the potential for a single treatment to be effective for a large group of people.
Consider also that there are many systems involved in hearing. Starting in the inner ear and progressing into the brain, millions of cells work in the hearing factory, and each of those cells have thousands of genes. One small group of cells can be isolated, however, is somewhat easier to access. Hair cells in the cochlea — which are not actually hairs but act like they are — respond to vibrations coming from sound. They translate vibrations into signals for the brain to “hear.” If mutated DNA produces proteins in these hair cells, it can cause deafness.
By focusing on this subset of the hearing system, researchers have developed two therapies that have helped restore hearing in mice and humans. The use of the CRISPR-Cas system was a gimme for researchers — it seems perfect for this application. CRISPR stands for “clustered regularly interspaced short palindromic repeats.” This means that the Cas protein, which is like a pair of scissors, can recognize clustered regularly interspaced short palindromic repeats of nucleotides in the genetic code. This is helpful because we can guide our protein scissors right where we need them with this pattern of nucleotides. Scientists can cut out a mutated gene and replace it with a correctly-spelled version. Doing this in the Tmc1 gene in mice with deafness caused by that gene restored their hearing.
The issue with CRISPR is that it sometimes recognizes and cuts sequences that you did not intend for it to, a phenomenon known as off-target editing. This variability is often why researchers hesitate to apply CRISPR-based therapies in human models. The alternative to this, which has resulted in hearing restoration in human patients, might surprise you.
Researchers at Harvard used a virus to give five children the ability to hear for the first time. These children had mutations in a gene called otoferlin (OTOF). The point of a virus is to “infect” cells by giving them their own DNA and forcing them to make proteins out of it, producing more viruses and propagating the infection. Now, viruses are a tool for scientists, who can replace the DNA inside the virus. In this case, they placed a healthy version of otoferlin (more specifically, they put half of the gene in each of two viruses — the gene was too big to fit inside just one virus). By just dripping a few drops of the viruses into the ear canal, doctors exposed the cells of the inner ear that have the otoferlin mutation and caused an infection. Eventually, those cells incorporated the viral otoferlin, and the patients began to hear.
Viruses are hard to use in treatments because many people are afraid of what else they might do. A lot of gene editing may seem scary — it’s hard to grasp what might happen if we change something that nature gave us, never intending for us to mess with it. The promising results from this hearing loss treatment — and so many others — will hopefully persuade more of the general public to support and trust gene therapies.
Leave a Reply