There are some things that viruses do very well. That is: get into cells and delivery their cargo! We at Synthetic Virus Technologies Inc. are using the same model that enveloped viruses use to get into cells without actually using these viruses. This is a big deal because using viruses to deliver genes can go badly wrong.
The earliest example of engineered viruses going wrong was in 1999 with the widely publicized incident at the University of Pennsylvania where a young man named Jesse Gelsinger passed away. He received an adenovirus (cold virus) engineered to produce a liver enzyme he was missing. He was given too high a dose and passed away from the resulting immune response to the virus.
Humans are designed to fight human viruses. When you get a cold, your body fights it. It takes about seven to nine days for a T-cell (white blood cell) that is specific to a virus to be made by your body. It takes about two weeks for a good antibody to be made to get rid of any residual infections and prevent the same infection from happening again. When using an engineered adenovirus to put missing genes into the body, there is a narrow window of about seven to nine days where the treatment can be re-administered. This means that patients can only be treated once or twice at most. Other viruses have similar responses.
Today two viruses are most prevalent in clinical trials: Lentivirus, a retrovirus like HIV, and adeno-associated virus (AAV).
Lentivirus is a non-threatening way of saying “engineered virus in the same family as HIV”. Lentivirus is used because it works in non-replicating cells and inserts the new gene so that its benefits will pass on to daughter cells. Nobody gets the full HIV virus, but safety/ethical issues are always on the mind. For example, when lentivirus inserts it’s DNA into the host cell, there is also a risk that it will insert into a functioning host gene. This has caused fatal leukemias in some human trials using gamma-retroviruses treating Bubble-boy syndrome (see reference in: J Clin Invest. 2008 Sep;118(9):3132-42).
AAV is a tiny benign virus. It’s so small that it can’t fit some of the genes you want to put in it. For example, the full length dystrophin gene that is missing in Duchene’s muscular dystrophy can’t physically fit into the AAV capsule. AAV is fought by the immune system, so the treatment window is at most two weeks. After that a new virus capsule that the immune system hasn’t seen yet is needed. The trouble with switching viruses is that different viruses go to different cells types, making it challenging to treat the same tissue.
Other issues arise when using viruses. For example, making proteins using a virus tends to make the immune system suspicious. If there are too many danger signals, the immune system will attack and kill all the virus treated cells. Engineered viruses also can’t tell the immune system to ignore a “good” protein that it is making. If a designed virus makes clotting factor 9 in the liver of hemophiliacs, for example, the immune system still sees the new protein as bad, creates an antibody to block its function, and often kills the liver cells that make it.
There are many viral gene therapy clinical trials going on today, but they all run up against the same issues: 1) how to avoid the immune system’s response to the virus, 2) how to keep the gene expressed for long enough to do any good, and 3) how to make the immune system think that the new gene is not dangerous.