Data point to role of cellular bioenergetics as a new mechanistic approach to treat immune disorders
Plymouth, Mich. ? January 26, 2011 ? Lycera Corporation, a biopharmaceutical company pioneering an innovative approach to developing novel oral medicines to treat autoimmune diseases, today announced positive data from the University of Michigan demonstrating the role of bioenergetics in selectively inhibiting pathogenic lymphocytes while preserving and enhancing the normal immune system. The findings, published online today in Science Translational Medicine, support Lycera’s promising novel therapeutic approach to treating a broad spectrum of immune diseases.
Cellular bioenergetics is a field of biology focused on studying how energy is made and utilized in living systems in both normal, healthy cells and disease-causing cells. Lycera’s bioenergetics program is focused on developing orally available small molecules that exploit bioenergetic abnormalities in pathologically activated lymphocytes and result in the selective silencing of these cells, while keeping healthy immune cells intact.
The data show that bioenergetic and redox properties of alloreactive T cells differentiate them from other proliferating cells and can be exploited pharmacologically to arrest graft-versus-host disease (GVHD) in mice. In the study, treatment with Lycera’s prototype compound Bz-423, a first-in-class F1F0-ATP synthase inhibitor, induced selective apoptosis of alloreactive donor T cells and reversed GVHD in several bone marrow transplantation models without affecting hematopoietic stem cell engraftment, immune reconstitution or normal resting lymphocytes.
“The preclinical data suggest that alloreactive T cells rely primarily on oxidative phosphorylation for their energy, challenging the current paradigm that activated T cells meet their increased demands for energy through aerobic glycolysis,” said lead author Gary D. Glick, Ph.D., Lycera founder and chief scientific officer, and Werner E. Bachmann Collegiate Professor of Chemistry at the University of Michigan. “This difference, along with the phenotype of T cells, provides a mechanistic basis for the specificity of Bz-423 to eliminate disease causing cells. The specificity and the ability to preserve normal immune reconstitution differentiate Bz-423 from high dose systemic steroids, the current standard of treatment for GVHD. Efficacy has also been demonstrated in autoimmune disease models where pathogenic cells have similar bioenergetic characteristics. The robust body of preclinical research is very compelling, and we look forward to entering the clinic with our lead compound in Lycera’s bioenergetics program this year.”
The researchers tested the potential of Bz-423 to halt the progress of established GVHD in two allogeneic bone marrow transplantation models. Treatment with Bz-423 significantly reduced GVHD clinical scores after one week and improved survival in mice compared to controls treated with vehicle (75% vs. 29%, p< 0.02). Similar improvement in survival was seen when treatment was continued for 10 weeks (74% vs. 29%, p=0.02). In another aggressive model of GVHD using a fully allogeneic donor/recipient strain combination, Bz-423 treatment for seven weeks again significantly reduced all clinical and histological parameters of disease. Bz-423 did not impair immune reconstitution in either the thymus or spleen and all the mice treated with the drug showed complete donor bone marrow engraftment. Additionally, the compound’s favorable toxicity profile is consistent with other studies and with the normal bioenergetic and redox profile of rapidly proliferating bone marrow cells (basal rates of oxygen consumption, normal levels of anti-oxidants and stable mitochondrial membrane potential).