April 30, 2006
Gene Therapy Researchers Find Better Vectors

MIT's Technology Review has an interview with gene therapy researcher James Wilson MD Ph.D. who is a professor at University of Pennsylvania's School of Medicine. Wilson has been searching for better and safer gene therapy delivery vehicles (vectors) and he thinks he's found some very promising ways to deliver gene therapy.

Fortunately, evolution has generated a diversity of viruses. We screened monkeys and humans for lingering adenovirus-associated viral infection. Adenovirus-associated viruses infect humans and primates. No one knows what the virus does, what the infection looks like or whether it hurts or helps you. We discovered that 40 percent of human livers have persistent infections, and we identified over 100 new subtypes.

Parenthetically, Paul Ewald is looking more and more correct with his argument that we've underestimated the degree to which pathogens play a role in development of human diseases. Think about all those viruses these researchers found while looking for better viruses to use for gene therapy.

Now we are looking at the properties of the vectors and how well they can be transferred to different organs. We found that a variation of a vector called AAV9 can efficiently transfer genes to the heart.

TR: Have AAV vectors been tested in human trials? How safe are they?

JW: Yes. AAV2 has been tested for cystic fibrosis, muscular dystrophy, neurological disease, and hemophilia. Two patients in the hemophilia trial developed liver inflammation, although they did recover. Other than that, there have been no safety issues.

Since then, we've tried to determine if the new AAV vectors will have the same response. We don't think they will -- we think we've figured out what happened in those patients and how to get around it.

The identification of the genetic causes of disease has been done for a long list of disorders such as sickle cell anemia, cystic fibrosis, Huntington's disease, Marfan syndrome, Gaucher disease, and Werner syndrome. For the vast bulk of such diseases no effective treatments followed from identification of their genetic causes. Why? We still need really good ways to deliver gene therapy. Once we develop excellent methods to deliver gene therapy into cells and into chromosomes many diseases will become treatable.

Gene therapy has uses for diseases beyond the classic single mutation diseases. For example, cancers could be stopped if heavily mutated cancer cells could be reprogrammed by gene therapy to restore genes that normally control cell growth. Also, many mutations that accumulate with age that cause cells to work less well could be repaired with appropriate gene therapies. So the stakes are high for the development of excellent gene therapy delivery vehicles and techniques. I cheer every success of Dr. Wilson and other scientists working on gene therapy methods.

Share |      Randall Parker, 2006 April 30 08:56 PM  Biotech Gene Therapy

T. J. Madison said at May 1, 2006 1:31 AM:

And most important of all, we need gene therapy to MAKE PEOPLE SMARTER.

AMac said at May 1, 2006 10:03 AM:

This diverges a little from the topic of the post, but not too much.

When I was in grad school in the '80s, the lab down the hall was working with Coxsackie viruses that infect mice. It turns out that you can infect a mouse with the standard type that binds to and infects cardiomyocytes, causing damage to the muscle of the heart. If you sacrifice the mouse, remove and homogenize the heart, and filter, you will end up with solution that contains infectious Coxsackie virus. Infect a second mouse, sacrifice, remove and homogenize heart, and filter: the process can be repeated indefinitely.

The interesting variant is what happens if you pick a different organ from the one the virus targets--say the pancreas, or the brain. In the first round of filtration, you won't recover a high-titer lysate (i.e. you won't get a high concentration of infectious viruses). However, after every cycle, the titer increases. At each iteration, the virus becomes more specific to the new organ. This procedure creates conditions for natural selection to operate on the pool of viruses; those that have mutations that make them better at infecting the chosen organ are overrepresented in the pool of viruses that is recovered from the homogenate. Thus, there are now stocks of Coxsackie viruses that are quite specific to every major organ of the mouse (they are useful experimental tools for studying inflammation and other processes). I assume this approach is effective with many viruses.

This is a conceptually simple and low-tech approach that requires no knowledge of what causes viral adaptation to the chosen target. Create the circumstances for Darwininan selection, and the virus does the rest by itself. Add the insights and improved techniques that molecular biology offers, and I would expect that targeting can be tailored with quite exquisite sensitivity.

Fly said at May 1, 2006 3:42 PM:

Amac, interesting comment.

The same approach could be used with tissue cultures instead of animals. E.g., by using a cancerous tissue culture, a virus that is highly infectious for specific cancer cells could be selected.

AMac said at May 2, 2006 8:08 PM:

> by using a cancerous tissue culture, a virus that is highly infectious for specific cancer cells could be selected.

That's correct; there have been some promising efforts along those lines. One methodology that's more clever (and therefore more involved) is called panning, or bio-panning.

Obviously too, the usual caveat for inventors applies: If it was that easy, it would have been done already.

Cancer cells are very much like the noncancerous cells from which they sprang, so distinguishing between the two is hard. I'm also wrong to describe cancer cells as a single entity; one of their fundamental traits is that they mutate as they grow--so it's unlikely that any single identifier will describe all of the cancer cells in a tumor.

Another problem is that there are hundreds of types of cancers; the present state of the art lumps them into a few dozen classes. For example, "Small Cell Lung Cancer" will probably turn out to be a composite class made up of SCLC-Type 1, SCLC-Type 2, ... A targeted therapy might work with great efficacy against Type 1, modestly against Type 2, and not at all against Types 3 to 50.

That's one of the drivers of the Cancer Genome Project: to supply the genetic information that would allow meaningful typologies of cancers to be created.

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