Imagine a world of silence. You could hear no traffic noises, no music, and not even the subtle sound of blood pumping through your veins and arteries. There would simply be silence.
This is everyday life for approximately 70 million people. Deafness occurs for a variety of reasons, but for some, deafness is an inherited genetic trait. It is for these people specifically that recent research has focused on gene therapy as a potential method of hearing restoration.
Between 4 and 8% of all cases of deafness occur from a genetically inherited mutation of the TMC1 gene. This gene encodes a specific protein that is integral to the conversion of sound waves into electrical signals that can be read by the brain.
A collaborative study performed by Harvard Medical School, Boston Children’s Hospital, and the Ecole Polytechnique Federale in Swtizerland tested two types of mice, one with the TMC1 gene completely deleted and the other with a mutation in the TMC1 gene. Both genetic manipulations simulate forms of TMC1 related hearing loss in humans. Scientists then introduced a healthy TMC1 gene to the chromosomes of the affected sensory cells (hair cells) in the inner ear. The results surpassed expectation, as the healthy gene restored hearing to the mice whose TMC1 genes contained mutations.
Scientists acquired these results by putting the mice in a startle box to measure their reaction to noise. The mice with the gene mutation remained still at the noise stimulus and the mice that received gene therapy reacted in the same manner as the normal hearing mice. The mice that had the TMC1 completely deleted showed some improvement, with their hearing partially restored.
It is easy to see how the results of this study are generating excitement in the improvement of human hearing loss. However, before we announce genetically inherited deafness cured, it is important to further examine the procedure of the experiment.
Scientists took mice with mutated or deleted genes and introduced a healthy version of the TMC1 gene. This introduction was done by the injection of a created adeno-associated viral 1 (AAV1) into the affected cells. This virus was a vector coupled with a promoter that would turn on the gene when it reached the chromosomal sequence of the target cell.
Yes, scientists inserted viruses into the sensory cells of the mice.
Viral transportation is an effective method because of the genetically integrative procedure that viruses use to infiltrate target cells. While this method accomplishes delivery of the new gene, is it really the safest, most ideal method for use in humans? Is it a good idea to inject a foreign invader into human cells that will take over the host cells and replicate indefinitely?
Common sense says no, and because of this gene therapy strategies have been dismissed in the past. However, scientists have recently found a way to use the AAV1 vector in a non-pathogenic form.
First, let’s get an understanding of the two methods of viral replication. As explained in this article, a virus infects a cell by attaching to the cell wall and releasing either its DNA or RNA into the host cell. The viral DNA then undergoes the lytic cycle, the lysogenic cycle, or both in corresponding phases. In the lytic cycle, which is the main method of viral replication, the viral DNA transcribes into the host cell’s RNA and takes over the control center of the cell. The host cell’s DNA is completely destroyed and the virus runs the cell’s activities, using the cell’s energy to produce its own progeny. When the cell fills up with viruses, the membrane bursts and the viruses are released freely into the body. This is when symptoms of a viral infection occur. In the lysogenic cycle, the viral DNA or RNA enters the host cell and is physically worked into the existing DNA of the host cell. The viral DNA becomes a new part of the cell’s genetic material, producing a prophage. No virulent progeny are produced as in the lytic cycle, rather the cell replicates as normal but carries the newly integrated DNA with it. The AAV1 vector used in this experiment was designed to replicate via the lysogenic cycle, integrating the healthy TMC1 gene into the host hair cells.
Adeno-associated virus vectors in general are becoming the most frequently used viral vectors in gene therapy because they have been identified to be non pathogenic but still very persistent. They house a linear single stranded DNA genome. And pathogenic infection occurs only in the presence of a helper virus, either adenovirus or herpesvirus. When these helper viruses are absent, AAV vectors can still set up the host cell’s environment by integrating to specific sites of the chromosome. In short, the AAV vector apart from the helper virus enters the host cell and undergoes the lysogenic cycle, integrating into the host cell’s genetic material at a very specific location.
In using and AAV vector however, one must proceed with great caution. The lytic and lysogenic cycles are not mutually exclusive and it is entirely possible for a virus to switch from one method to the other spontaneously. This presents a very dangerous aspect to the procedure with consequences that would outweigh the benefits of hearing restoration.
This study, as well as other associated gene therapies, has certainly made great strides in developing methods for hearing restoration, but further research and experimentation is needed to find a treatment that delivers safety equivalent to efficacy.
Daya, S., & Berns, K. (2008). Gene Therapy Using Adeno-Associated Virus Vectors. Clinical Microbiology Review. doi:10.1128/CMR.00008-08, Retrieved from <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2570152/>.
Lam, P. (2015, July 13). Deaf mice able to hear again thanks to gene therapy. Medical News Today. Retrieved from <http://www.medicalnewstoday.com/articles/296576.php>.
Panse, S. (2010, January 21). Bright Hub. Retrieved from <http://www.brighthub.com/science/genetics/articles/30611.aspx>.
Featured image via Ecouterre