TEPP-46 Might Worsen MS Rather Than Treat It, Study Suggests
Using a small molecule called TEPP-46 to block the non-metabolic function of the enzyme pyruvate kinase M2 (PKM2) in T-helper (Th) immune cells did not lessen disease severity and redirected inflammation and neural damage from the spinal cord to the brain in a mouse model of multiple sclerosis (MS), a study reported.
These findings challenge previous preclinical data supporting TEPP-46 as a potential MS therapy, and more studies are needed to clarify the compound’s effects.
“It was not at all what we expected,” Alban Gaultier, PhD, said in a press release. Gaultier is the study’s first author, a neuroscientist with University of Virginia’s School of Medicine and its Center for Brain Immunology and Glia.
“The take-home message is that we should be very careful and do more fundamental research before we propose to take this to clinical trials,” Gaultier added.
The study, “Modulation of PKM activity affects the differentiation of TH17 cells,” was published in the journal Science Signaling.
T-helper cells work by recruiting and activating other immune cells. Two of its subsets, Th1 and Th17, produce pro-inflammatory molecules — IFN-gamma by Th1 and IL-17 by Th17 — that, when present at unusually high levels, are associated with the development of autoimmune diseases such as MS.
PKM2 is an enzyme mainly known for its role in glycolysis — the energy-producing metabolic reaction based on the breakdown of sugar (glucose) inside cells. However, increasing evidence suggests that PKM2 has a number of non-metabolic functions dependent on its entry into the cell nucleus, where it interacts with other molecules to regulate genes’ activity.
Previous studies highlighted that PKM2 is a key factor of Th17 and Th1 cell maturation and autoimmune inflammation. While some of these data derived from the genetic deletion of PKM2 from Th cells, most were based on PKM2 suppression via TEPP-46.
Originally developed to fight cancer, TEPP-46 is a small molecule that selectively prevents PKM2 translocation to the nucleus and, therefore, its non-metabolic and gene regulatory functions.
Notably, previous data showed that treating Th cells with TEPP-46 significantly reduced their maturation into Th17 and Th1 cells, and eased disease severity in a mouse model of MS called experimental autoimmune encephalomyelitis (EAE).
However, Gaultier and his colleagues now show that TEPP-46 may in fact promote changes in Th maturation and activity associated with MS development.
Using Th mouse cells grown in the lab, the team found that while TEPP-46 effectively suppressed Th17 maturation and IL-17 production, it also promoted the maturation of IFN-gamma–producing Th1 cells and Th17 cells that produced a molecule called GM-CSF. GM-CSF-producing Th cells are being “increasingly recognized as contributors to MS,” the researchers wrote.
In addition, TEPP-46 also blocked the maturation of regulatory T-cells (Tregs), immune cells that typically dampen immune and inflammatory responses by suppressing the activity of pro-inflammatory cells such as Th17 and Th1. In MS patients, Tregs often show impaired activity or are found in reduced numbers.
These TEPP-46-induced changes in T-cell populations were found to redirect — by unclear processes — immune cells, inflammation, and nerve cell damage from the spinal cord to the brain in the EAE mouse model.
“In this animal model of MS, most of the inflammation takes places in the spinal cord,” Gaultier said. “By using [TEPP-46] and reprogramming the immune cells, we were able to move the pathology [disease features] from the spinal cord to the brain, which better mimics human disease,” he added.
This approach, while hardly a treatment, “could be very useful” in creating better mouse models of MS, he also added.
Researchers also found evidence that TEPP-46’s effects were not all associated with PKM2, suggesting the existence of other targets, which can lead to unwanted “off-target” effects and side effects.
Overall, these findings do not support TEEP-46’s therapeutic potential and its use in MS, in clear contrast to previous data. As the researchers do not fully understand the reasons behind these discrepancies, they emphasized that further research is needed to clarify them.