October 15, 2008 (Vol. 28, No. 18)
Richard A. A. Stein M.D., Ph.D.
Advanced imaging has found important applications in many facets of drug discovery. In a revolutionary approach, Scott Malstrom, Ph.D., former head of in vivo imaging at Ore Pharmaceuticals, describes the use of in vivo biophotonic imaging to explore an ACE2 inhibitor of the NF-kB pathway in the gastrointestinal tract (a methodology that can be applied to investigate the effect of any therapeutical agent on any organ or system).
Using mice transgenic for the firefly luciferase gene, Dr. Malstrom and collaborators showed that when inflammation was induced with lipopolysaccharide, the ACE2 inhibitor GL1001 exerted effective anti-inflammatory activity, suppressing inflammation in the gastrointestinal tract. The compound is currently in the drug development pipeline.
Aside from its use in the discovery and validation of new therapeutic agents, this approach shows promise in unveiling side effects. “We obtain images of the whole animal and, as we observe discreet changes throughout the animal, we can then perform further subscreens in that particular area,” notes Dr. Malstrom.
He calls this methodology “a more holistic approach to studying drug effects as compared with traditional organ or system-based analysis.”
“Seeing, in real time and under natural conditions, is believing,” says Ute Frevert, D.V.M., Ph.D., associate professor of medical parasitology at New York University School of Medicine.
“Intravital microscopic imaging has had a major impact on the way we perceive the dynamics of Plasmodium biology and the immune response of the infected host.”
In her presentation, relevantly entitled “From the skin via the liver to the brain: imaging Plasmodium in the vertebrate host,” delivered at the “Gordon Conference” in Rhode Island, Dr. Frevert revealed how live-cell imaging can provide an analysis of the spatial and temporal involvement of T lymphocytes in eliminating the liver stages of the malaria infection.
After transmission by an infected mosquito, Plasmodium sporozoites cross endothelial cells and travel via the bloodstream to the host liver, where they traverse Kupffer cells and gain access to hepatocytes. By using mice expressing green fluorescent protein in endothelial or Kupffer cells for intravital microscopy, Dr. Frevert and collaborators visualized and characterized the sequential events associated with sporozoite migration through the liver parenchyma.
Her approach has fundamentally enhanced our understanding of malaria infection establishment and progression.