Title : Developing resilience-based treatments for glaucoma
Abstract:
We use mice to determine molecular mechanisms that contribute to intraocular pressure (IOP) elevation and glaucoma. Glaucoma is a common neurodegenerative disease that kills retinal ganglion cells. Elevated IOP is an important, causative risk factor for developing glaucoma. I will discuss genome-wide gene expression studies (RNA sequencing) that provided new mechanistic ideas that were then functionally tested. For these studies, we used two human relevant mouse models (DBA/2J mice, develop a form of pigmentary glaucoma caused by mutations in melanosomal protein genes as is a subset of human pigmentary glaucoma; and Lmx1bV265D mutant mice that directly model glaucoma caused by the orthologous human gene LMX1B). In DBA/2J mice, we characterized very early stages of glaucoma that follow IOP elevation but precede neurodegeneration. This demonstrated that mitochondrial abnormalities are among the very earliest changes that are induced by high IOP. We further uncovered a decline in nicotinamide adenine dinucleotide (NAD) an important metabolite for mitochondrial health and function. Treating DBA/2J mice with nicotinamide, a form of vitamin B3 and important NAD precursor, was profoundly neuroprotective against glaucoma. We also detected disturbance in pyruvate metabolism, an important metabolite that links glycolysis to the tricarboxylic acid cycle and so is central in cellular biosynthesis and energy metabolism. Treatment with pyruvate also protected from glaucoma. This led to the Resilience Concept for treating glaucoma. Under this concept, we use dietary nutritional factors to support cellular bioenergetics and improve cellular functions and resources. Cells with improved energy and other molecular supplies are in a more resilient cellular state that can better fend off the stresses of aging and disease. An initial clinical trial using a combination of nicotinamide and pyruvate improved visual performance in POAG patients. We also discovered metabolic abnormalities in trabecular meshwork cells in the Lmx1b mutant mice. These abnormalities primarily occur in a specific subtype of trabecular meshwork cell that we characterized using single cell resolution RNA sequencing. Treating Lmx1b mutant mice with the resilience factors, nicotinamide and pyruvate, protects trabecular meshwork cells, lessens IOP elevation and strongly protects from glaucoma. In conclusion, orally administered, nutritional, resilience factors have great promise for glaucoma prevention and treatment. As their mechanisms of action is distinct to all current glaucoma therapies, they are expected to complement and augment existing treatments.
