Data Point to Role of Cellular Bioenergetics as a New Mechanistic Approach to Treat Immune Disorders

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).

Source: Eurekalert

Cause of a Fatal Immune Disorder is Genetic

An inherited, fatal, immune disorder characterized by uncontrolled activation of immune cells known as lymphocytes and macrophages

Risk Of Skin Damage Increases In Smokers With Autoimmune Disorder

Reports say researchers have come up with another reason to stay away from cigarettes after linking smoking to skin problems in people with systemic lupus erythematosus (SLE).

Critical Molecule to Celiac Disease, Other Autoimmune Disorders Identified

A mysterious human protein called zonulin plays a critical role in celiac disease and other autoimmune disorders, such as multiple sclerosis and diabetes.

New Protein Identified to Help Researchers Understand Autoimmune Disorders

A protein that could open fresh possibilities of understanding both APS-1, the rare hereditary disease where the immune system attacks the body's own organs, and other autoimmune disorders.

Myasthenia Gravis

Myasthenia gravis is the commonest disorder of neuromuscular transmission. Autoimmune myasthenia gravis needs to be distinguished from congenital myasthenic syndromes.