by Tom Wilemon
Jeffrey Rathmell, PhD, director of the Vanderbilt Center for Immunobiology and Cornelius Vanderbilt Professor of Immunobiology, is a 2019 recipient of the Dr. William E. Paul Distinguished Innovator Award in Lupus and Autoimmunity.
The award from the Lupus Research Alliance will support work by Rathmell to better understand the role T cell metabolism plays in lupus-related inflammation and to test whether two cancer drugs currently in clinical development could potentially reduce or prevent lupus symptoms. The award supports up to $1 million in research costs over a five-year time frame.
Lupus is a chronic, autoimmune disease that can damage any part of the body. Although it can strike both sexes, it is more common among women of childbearing age.
“Lupus has been very challenging clinically,” Rathmell said. “It’s a very heterogeneous disease. It shows up differently in different individuals, and because of the mixed nature of the disease, it has been difficult for pharmaceutical companies to set up clinical trials to identify few drugs.”
The goal of the Innovator Award is to provide robust and sustained support for research that is highly innovative and establish new directions toward curing lupus.
“Our strategy is to take two targets that are already in clinical trials as anti-cancer metabolism agents and try them in lupus settings,” Rathmell said. “We have some data that those targets will affect specific T cell populations, specifically the most inflammatory ones.”
One target is the T-helper 17 cell. The other target is the follicular helper T cell. One depends upon the metabolic enzyme glutaminase, while the other depends upon another metabolic enzyme called methylene tetrahydrofolate dehydrogenase 2.
Each of the two investigational cancer drugs blocks one of those enzymes.
The drugs will be tested in mouse models with transgenic-induced lupus.
Amy Major, PhD, associate professor of Pathology, Microbiology and Immunology, will collaborate on lupus biology in the mouse models. Michelle Ormseth, MD, MSCI, assistant professor of Rheumatology and Immunology, is a clinical coordinator who will recruit tissue donations from lupus patients.
The other area of research will use CRISPR genome editing to identify metabolic regulators of lupus-related inflammation.
“It’s a more unbiased approach,” said Rathmell, where the goal is to identify primary regulators of inflammation other than those targeted by the experimental cancer drugs.
“We have set up a system in the lab where we can do in vivo primary T cell CRISPR screens to identify potential metabolic targets that could be useful with lupus,” Rathmell said.
“By performing this genetic screen in lupus models this approach will complement studies on the two defined targets and may identify new drug tests that could be tested as therapeutics in lupus.”
