Environmental Factor, June 2007, National Institute of Environmental Health Sciences
Duke Researcher Discusses Models of Neurodegenerative Diseases
By Eddy Ball
On May 11, the NIEHS Frontiers of Environmental Sciences Lecture Series featured a talk by Neurobiology Professor Donald Lo, Ph.D., the director of the Center for Drug Discovery at Duke Medical Center. Lo discussed results of his recent research with new methodologies in drug development during a talk titled "New Brain Tissue-Based High-Throughput Models for Neurodegenerative Diseases."
Lo opened his talk with a review of the time and money involved in drug development - as well as the odds, about one in ten, of getting a candidate through the discovery process. Currently, it takes an average of nearly 14½ years, most of it in the discovery and preclinical phases, to take a drug from discovery to clinical use, and the process costs an average of $802 million.
Those figures encouraged Lo to ask the question, "How do you stack the deck a little bit so that you might have better odds in getting a drug candidate into clinical trial?" Trying to answer that question, Lo and his colleagues borrowed a technique developed for plant research, known as a particle-mediated gene transfer device, to transfect or introduce compounds directly into living brain slices from rodents.
What has emerged is a new high throughput methodology for the discovery stage of drug development. Lo uses what is known as "ballistic delivery" of molecules into the slices. The technique can deliver both the compound(s) that trigger neurodegenerative disease and the compound(s) being tested for potential neuroprotection. Using the technique on disease models they've developed, researchers can screen as many as 1,000 compounds and genes every few months.
Lo conceded that the experiments he has conducted using the new methodology are still classified as in vitro. However, he has hypothesized that because neurons remain surrounded by live brain tissue, their "native tissue context," rather than being isolated into cell lines, the methodology allows researchers to add what Lo called "some in vivo-ness" to the culture and better mimic how the brain in a living mammal will react.
Lo's lab tested brain slices in four types of neurodegenerative disease, following a hierarchy of etiologic complexity. The lab's earliest work focused on ischemic stroke, "a very clean type of trauma," using an oxygen-glucose deprivation model. Next the lab looked at Huntington's Disease (HD), a classic monogenic (single-cause) neurodegenerative disease. In recent years, the researchers have begun preliminary studies on the more complex multigenic Alzheimer's Disease (AD) and Parkinson's Disease (PD), both of which also may have a strong environmental component.
The group's early success in testing the effects of two compounds, the plant extract neriifolin and its relative, the FDA-approved drug digoxin, in a stroke model inspired Lo to use the technique with other disease models. The team tested other compounds in an HD model created by transfection with the compound mutant huttingtin (htt) and discovered a good rate of recovery using several htt-specific inhibitory compounds.
"Things just got harder and harder," Lo admitted as he described preliminary research into more complex disease states. His group's preliminary work on AD has highlighted the interactions and synergistic effects of causative factors. AD seems to depend on the additive effects of tau, beta amyloid and amyloid precursor protein (APP). Lo has had some success with blocking beta amyloid formation by inhibiting the enzyme secretase.
By far the most complex of the neurodegenerative diseases under study in Lo's lab is PD, which, research suggests, involves the interaction of genetic predisposition and formation of certain proteins, such as α-synuclein, to enhance the effects of environmental chemical exposures. Testing is further complicated by the need to get slices containing substantia nigra, the cells impacted in PD, in order to validate results as a step toward developing a PD risk-factor screening test.