Viruses, Gene Therapy, & Ethical Concerns

    The first time I had heard about adeno-associated viruses (AAV) was during my third year of undergrad. I worked in a neuroscience lab and my PI introduced me to the idea of DREADDs (designer receptors exclusively activated by designer drugs). These DREADDs are synthetic g-protein-coupled receptors that are genetically expressed on the cell membrane. An AAV is used to mutate (mutagenesis) the genome in order to express these receptors. We were able to selectively express these receptors in a specific area of the brain (hippocampus). From there we could inject a chemical that is not endogenously found in mammals to activate those receptors. The specific receptor that was expressed in our project was a calcium ion channel. Activating this channel with administration of the non-endogenous chemical inhibits the release of neurotransmitters which subsequently silences neurons in that area of the brain. After a period of time, the chemical washes away from the receptors and brain function returns to normal in that area of the brain. I thought it was pretty interesting that we were basically able to turn on and off areas of the brain chemically and thought that these viruses could have many applications.

    Recently, I have been more exposed to and learned more about the use of AAVs in gene therapy. Gene therapy is an emerging and controversial technology that has been explored for the treatment of a few different genetic disorders. AAVs have been the primary source used to genetically modify specific genes that are defective in a disorder. An example of a gene therapy treatment being investigated is for the treatment of phenylketonuria (PKU). PKU is a genetic disorder that affects a gene that expresses an enzyme used to convert phenylalanine into tyrosine. A research group in 2019 created a patent for gene therapy treatment that uses an AAV to mutate the genome and express the enzyme that is typically defective in PKU. There are now three companies that are currently applying for pre-clinical trials using this patent (Isabella et. al., 2018).

    There are clear and obvious challenges with gene therapy including problems with immune defense, off-target effects, and targeting enough cells to be effective. Researchers must be cautious when attempting clinical trials with gene therapies. Should people with disorders be the only ones with access to gene therapies or could physicians administer approved gene therapies for non-essential or cosmetic changes. How could this potentially affect future populations through epigenetics? A lot of questions will be raised in the future as to where to draw the line on therapy and will likely be a controversial topic for the rest of our lives.  

 

Isabella, V. M., Ha, B. N., Castillo, M. J., Lubkowicz, D. J., Rowe, S. E., Millet, Y. A., Anderson, C. L., Li, N., Fisher, A. B., West, K. A., Reeder, P. J., Momin, M. M., Bergeron, C. G., Guilmain, S. E., Miller, P. F., Kurtz, C. B., & Falb, D. (2018). Development of a synthetic live bacterial therapeutic for the human metabolic disease phenylketonuria. Nature Biotechnology, 36(9), 857–864. https://doi.org/10.1038/nbt.4222

 

Wilson, J. M., Sidrane, J. A., & Ashley, S. (2019). GENE THERAPY FOR TREATING PHENYLKETONURIA (20190336550A1). U.S. Patent and Trademark Office.