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Our Research

All of our projects depend on the creation and advancement of direct infusion of drugs and therapies into the brain. We have developed a technique in which nanoparticles, including viral vectors and liposomes can be infused directly into brain tumors to give enhanced drug efficacy. For many years, and continuing still, we have been working on development of direct drug delivery into the brain including cell transplantation, gene transfer and growth factor infusions for Parkinson's disease. Through gene therapy, we are working to eliminate the gene responsible for Niemann-Pick (acid sphingomyelinase). By studying the effects of L-Dopa on the brain, we are developing gene therapy for L-Dopa-induced dyskinesia.

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This video shows how Convection-Enhanced Delivery (CED) works
3D animation created by John Doval

Focus

The underlying focus of our laboratory is to understand and master the technology of drug delivery to the brain. The various techniques that we have developed over the last decade has equipped us to explore therapies in various neurological disease from to brain cancer to genetic diseases. Our goal in all these areas is to bring new therapies to the clinic that will have a significant impact on the course of the disease.

The Blood-Brain Barrier

Getting drugs into the brain is a difficult process. Pharmaceutical companies have struggled over the years to develop effective medicines for neurological disorders only to be forced to make uncomfortable compromises with efficacy in order to enhance brain penetration. The reason for this is that brain tissue is sequestered away from the peripheral circulation by a membrane called the blood-brain barrier. This barrier lines all of the approximately 1800 miles of blood vessels in the human brain, and is very selective about the substances (and cells) that it will allow to cross into contact with neurons. In the case of anti-cancer drugs, the problem is very serious indeed. Many drugs that dramatically slow the growth of peripheral tumors do not get into the brain at effective concentrations. Other drugs do get into the brain but the doses of drug needed are high enough to cause serious side effects. Consequently, brain cancers are very poorly treated. Whereas primary tumors of the brain are fortunately uncommon, metastases to the brain are a common result of peripheral cancers averaging about 10% of all primary peripheral tumors.

Convection-Enhanced Delivery

One way of approaching the problem of brain penetration is to infuse drugs directly into the brain. However, it is not as simple as drilling a hole in the skull and inserting a hypodermic needle. The brain itself is divided into distinct substructures that affect the movement of molecules through brain tissue. Over the last 10-15 years, we have developed a number of solutions to the problem of distributing drugs and genes into large regions of the brain, and more recently of brain tumors. The first thing we learned is that molecules do not diffuse very well in the brain because the concentration of drug decreases as the square of the distance from the infusion needle. Fortunately, we and others have been able to take advantage of a kind of subway system that runs throughout the brain. Surrounding the millions of blood vessels in the brain is a perivascular zone that appears to be a major conduit for macromolecules. Rapid, long-distance transport of nanoparticles and viruses is powered by the fact that all vessels have a pulse that provides the motive force for this type of perivascular movement. To learn more about this process, please read Hadaczek et al (2006). We call this type of infusion "convective delivery" or "convection-enhanced delivery". In order to engage this mechanism, infused materials must be fed into the tissue under pressure to push the interstitial fluid out of the way. This elevated pressure can result in a phenomenon known as reflux where infused material, taking the path of least resistance, leaks out back up the outside of the infusion needle or cannula. To defeat this problem, we developed a type of cannula that resists reflux. It is designed to have several sharp gradations in the outside diameter, and these gradation seem to increase the binding of the outside of the cannula to the surrounding tissue. As a result, we can now infuse at rates of up to 5 micro liters/min and cover brain volumes of about several cc.

Imaging

Another important aspect of our delivery technology has been the addition of visualization to our infusions. By adding nanoparticles () filled with a contrast reagent (), we can conduct infusions in a Magnetic Resonance Imager (MRI). In this way, we can closely monitor the progress of a brain infusion, and quickly stop or make adjustments if something is not right. This unprecedented ability to "see" infusions in real time has told us a lot about what to do and how to do it. In the accompanying pages on this site, you can read a description of how we are applying this technology to the treatment of serious neurological diseases.