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University of Iowa’s Dan Bonthius on Using RNAi to Treat Alexander Disease

Name: Daniel Bonthius
Position: Associate professor, pediatrics/neurology/anatomy/cell biology, University of Iowa College of Medicine
  • Assistant professor, pediatrics/neurology/anatomy/cell biology, University of Iowa College of Medicine — 2001-2003
  • Assistant professor, pediatric/neurology, University of Iowa College of Medicine — 2000-2001
  • Assistant professor, pediatrics, University of Iowa College of Medicine — 1997-2000
  • Resident, pediatric neurology, University of Iowa — 1994-1997
  • Postdoc, University of Virginia — 1991-1994
  • PhD, neuroscience, University of Iowa — 1990
  • MD, University of Iowa — 1990
  • BS, zoology, University of Iowa — 1982

At the University of Iowa, Daniel Bonthius studies disorders of the central nervous system and the impact of neuroteratogenic agents, as well as cancer biology. He is also investigating Alexander disease, a rare genetic condition that affects the brain’s white matter.
Recently, he was awarded a two-year, $405,000 grant from the National Institute of Neurological Disorders and Stroke to develop an RNAi-based treatment for the condition.
This week, RNAi News spoke with Bonthius about his research.
Let’s start with an overview of your lab and research focus.
I’m a pediatric neurologist and I take care of kids with all kinds of neurological diseases including one called Alexander disease, which is one of the areas we’re focusing on now in my laboratory.
Alexander disease is a devastating disease of the pediatric brain in which there is a mutation of a particular gene that is expressed exclusively in astrocytes. This mutant gene [expresses] GFAP, or glial fibrillary acidic protein.
When that is expressed abnormally in astrocytes it causes a toxic gain of function in which those astrocytes no longer perform their normal functions. What happens then is the brain begins to deteriorate [as does] the child’s development. Ultimately, this leads to dementia, seizures, coma, and death.
When does the death usually occur? Within a few years of life?
Babies with Alexander disease are often symptomatic at birth. Then it is a progressive, relentless decline — children rarely live beyond a couple of years.
When did you start looking at RNAi as a possible therapeutic modality for this condition?
We started looking at it a couple of years ago. I have a couple of collaborators here at the University of Iowa — Bev Davidson and Hank Paulson. They have been using RNA interference to treat other autosomal dominant, inherited neurological disorders (see RNAi News, 6/18/2004). So it occurred to us that Alexander disease might also be amenable to this kind of therapy.
It also happens that I do research on a particular virus called lymphocytic choriomeningitis virus. In the course of my research on that disease, we discovered that virus had a very strong tropism specifically for astrocytes in the brain. Therefore, it also occurred to us that we might be able to use that virus as a potential gene therapy vector for treating diseases of astrocytes.
Then we realized that Alexander disease is, in fact, a disease of astrocytes. That’s how we put all this together.
Thus far, have you been doing in vivo work or have things been limited to cell culture?
So far it’s been limited to cell culture because we’re still in the process of developing the forms of the siRNA to achieve allele-specific suppression of the mutant form of GFAP while leaving the wild-type form intact.
And that poses a particular challenge.
Correct. Allele-specific suppression is the most specific form of RNAi.
What about work on the vector itself? Is that more straightforward?
Yeah. We have developed the vector along with [University of Iowa researcher] Paul McCray. He first developed this vector, which is lymphocytic choriomeningitis virus pseudotyped with feline immunodeficiency virus. That way, we’re able to use the tropism of LCV without having the pathology that often goes with it.
Have you actually delivered siRNA or shRNA with this vector?
We have not yet delivered shRNA with it, but we have been able to infect astrocytes with the virus and we have been able to get cells to express genes that the virus is carrying.
Just to clarify, for Alexander disease, shRNA would be the approach you’d want to take to get sustained knockdown.
The NIH grant is to support in vivo studies?
Yeah. The plan is to move into in vivo studies. In fact, part of our funding is to [support our] carrying this all the way into in vivo studies using a mouse model.
One of my other collaborators, Albee Messing at the University of Wisconsin, has developed a mouse model of Alexander disease in which he has knocked the mutant gene into mouse astrocytes. These mice develop much of the hallmark pathology that humans have. Therefore we have a really excellent animal system to work on with our molecular approaches.
Can you give a breakdown of the goals for the grant project?
We have three specific aims in the grant. The first is to selectively suppress the mutant GFAP first in cultured cells. The second aim is to use that siRNA to produce an shRNA, and then selectively suppress the mutant GFAP in astrocyte cultures.
So we’ll move from regular COS-7 cells in aim 1, and then into astrocyte cultures in aim 2. Once we can knock down the mutant gene in astrocyte cultures, we’ll take it in vivo into the mouse model, making injections in the brains of these mice.
To jump back, Alexander disease is a fairly rare condition, right?
It is limited, but exactly how limited isn’t known because there has never been any real epidemiological study with it. It is, however, considered a rare disease.
I asked only to get a sense of how you might approach taking this forward given the limited number of patients with the condition.
That’s true. But right now there is no specific therapy for this disease, and there are organizations that have listings of children with rare diseases. These organizations have at their fingertips the names and address of people who might be interested in development of therapies for their particular rare diseases.

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