AAV Targeting Adipose Tissue Summary
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Editor's note: Another special guest post from Rhiannon. To see the first in the series click here.
Another really interesting project I have going on is designing adeno associated viruses to better target adipose tissue, which is essentially fat. When you think of gene therapy, you might just imagine some genes getting injected to the site of where they are missing, but simply injecting genes into a person doesn't work. A vector is needed to safely transport the gene of interest to a particular organ or tissue to reduce degradation, ensure continuous gene expression, and limit broad expression, which may have harmful effects. It's better to limit off-target expression (the virus will go everywhere once injected systemically but will bind and enter certain cells depending on its capsid proteins) to reduce the immune response.
Scientists have discovered the genetic basis of many diseases, and an approach to ameliorate the symptoms, if not cure the disease, has been to introduce genes to produce a protein that is missing or introduce RNA interference to knock out a gene. It can get complicated when designing ways to affect gene expression by coding for RNA or DNA to be expressed in a cell.
In order to do all that, however, you have to deliver it to that particular cell. This is where viruses come in! AAVs are the most common because they are the safest choice, but also difficult to produce in large quantities. AAV's are a naturally occurring virus, but the ones used in gene therapy are so far removed from these wild caught AAVs. The name adeno-associated virus implies that the virus itself is dependent on another virus, indeed for replication. This quality is what makes the virus safe, besides the fact that it is not known to cause disease in humans. In addition, while the wild AAVs out on the street may undergo site-specific integration in the host genome, recombinant AAV vectors designed in the lab have their genome adjacent to the nuclear DNA, otherwise called episomal DNA. This is important because when viruses insert their DNA into the host cell's genome it can cause cancer if the DNA is inserted within genes important for the cell cycle and growth. Interestingly, human papilloma virus (HPV) and hepatitis B virus are known to enhance carcinogenesis by integrating into the host genome and influencing signaling pathways for the cell. HPV actually encodes proteins that set the stage for cancer development. Viruses like cancer because it means cell division and more viruses! Yay!
At least if you get injected with a bunch of AAV for gene therapy you don't have to worry about the viruses inserting into your genome. Or do you… A study published in 2020 of dogs with hemophilia treated with AAV showed DNA integration near genes that control cell growth 10 years after the treatment. This doesn't mean that all gene therapy studies should stop (I need my PhD projects!!) because they saw that integration was limited and didn't seem to have any adverse health effects. The importance of this finding is that we are constantly learning new things about AAV biology, like how they can continue expressing their gene insert in the host cell and may stick around longer than we expected, when integrated into the host's genome. We don't have that much information about the long term health outcomes of gene therapy, and especially not in people. Many of the gene therapy treatments are for people with diseases with few treatment options and reduced life expectancy.
My work is not even pre-clinical necessarily because I am designing AAV mutants that somehow express in the fat tissue more than other tissues in order to look at adipose pathways. Why fat tissue you ask? My lab studies how adipokines (secretory molecules from fat) influence and are influenced by the hypothalamus and how this affects metabolic diseases. Adipose lipid metabolism is involved in the development of obesity and type 2 diabetes. Hopefully I'll find a better virus to target adipocytes to understand adipose tissue biology and disease pathogenesis.