Researchers Successfully Deliver Drugs To The Primate Brainstem

"It's difficult to safely treat the brainstem with available techniques because it's so intricate and complex, and because of the blood-brainstem barrier," says NINDS neurosurgeon and researcher Russell Lonser, M.D. "These findings suggest that we can reach the brainstem to treat diseases, and we can ensure that treatment is targeted to the critical region by monitoring it in real time." The blood-brainstem barrier is a type of lining in blood vessels that protects the brainstem against potentially harmful substances.

Co-author Edward H. Oldfield, M.D., chief of the Surgical Neurology Branch at NINDS, and colleagues developed CED in 1994. The technique uses small differences in pressure to make infused molecules flow through solid tissue. This enables large molecular weight molecules, such as those used in drugs, to penetrate the brainstem. Researchers have refined and expanded the uses of CED during the past 8 years, but until now, there has been no way to track precisely where the drugs were going and therefore no way to predict or prevent adverse side effects.

In the new study, Dr. Lonser and his colleagues first tested the safety of the tracer molecule, called Gd-albumin, by infusing it into the brainstems of rats. Gd-albumin molecules are similar in size to the molecules of most tumor-killing drugs. The rats showed no loss of function after 60 days, and tissue analyses showed only a normal amount of gliosis, or scar tissue, in the area immediately surrounding where the needle was inserted during the infusion.

The researchers then used a needle to target and deliver Gd-albumin into the pontine region (pons) of the brainstem in three healthy adult monkeys. Tumors in the pontine region are the most common type of brainstem tumor found in children. The animals were imaged in a magnetic resonance scanner during the infusion and 1, 2, 4, and 7 days after infusion.

The imaging studies showed a steady perfusion of the tracer through the brainstem with uniform concentrations throughout the perfused area. CED distributed amounts of the tracer that were comparable to the amount of drugs needed to treat brainstem diseases. Tests up to 35 days after infusion showed no neurological abnormalities, and the brainstem tissues appeared normal, except for a small amount of scar tissue near the site where the needle was inserted during the infusion, as was seen in the rodent model.

The brainstem consists of the midbrain, pons and medulla, structures located deep in the back of the brain. Tumors that arise in the brainstem are called brainstem gliomas and account for more than 10 percent of pediatric brain tumors. Since chemotherapy and other existing treatments for brainstem tumors are largely ineffective, more than 90 percent of children with these tumors die within 18 months of diagnosis, according to the National Cancer Institute. Brainstem tumors are less common in adults but account for more than two percent of adult brain tumors.

Drug delivery imaging with CED may ultimately be able to improve outcomes for children with brainstem gliomas, the researchers say. If it's proven safe and effective, the technique might also be used to treat other neurological diseases, such as Parkinson's disease, other tumors, epilepsy, and pain disorders. "This kind of imaging should provide novel treatment paradigms not only for brainstem gliomas, but also for other diseases for which treatment involves targeted delivery of therapeutic agents across the blood-brain barrier," says Dr. Lonser.

The researchers are currently testing several drugs for toxicity and effectiveness using CED and MRI in animal studies. "Once we show that these drugs can safely be given to animals in this manner and that they're effective, we can move on to human trials," says Dr. Lonser. "Right now, this method looks promising as a potential method for treating pediatric brainstem gliomas."

The research team also recently signed a Cooperative Research and Development Agreement (CRADA) with Kaleidos Pharma, Inc., of Seattle, Washington, to test CED and an experimental drug called TGF-alpha in an animal model of Parkinson's disease.

The NINDS is a component of the National Institutes of Health in Bethesda, Maryland, and is the nation's primary supporter of biomedical research on the brain and nervous system.

Reference:

Lonser RR, Walbridge S, Garmestani K, Butman JA, Walters H, Vortmeyer AO, Morrison PF, Brechbiel MW, Oldfield EH. "Successful and safe perfusion of the primate brainstem with a macromolecule: in vivo magnetic resonance imaging of macromolecular distribution during infusion." Journal of Neurosurgery, Vol. 97, No. 4, October 2002, pp. 905-913.