Section on Translational Neuroscience
Stephen Kaler, Section Head
Stephen Kaler M.D. is a physician-scientist who has focused on inborn errors of metabolism throughout his career and maintained an active basic science and clinical research program. He identified the molecular basis for occipital horn syndrome and, with international collaborators, has delineated several other conditions affecting copper homeostasis. These include ATP7A-related isolated distal motor neuropathy, and unique syndromes caused by mutations in SLC33A1 (an acetylCoA transporter), CCS (a copper chaperone), and AP1S1 (adapter protein complex 1 sigma subunit). His laboratory’s work has illuminated mechanisms underlying ATP7A–related motor neuron degeneration, establishing a link between genetically distinct forms of motor neuron disease, and highlighting the role of ATP7A in the peripheral nervous system. Kaler pioneered early identification of infants at-risk for Menkes disease using plasma neurochemical measurements and his laboratory utilized a yeast complementation assay to develop a predictive test for responsiveness to copper treatment. They lead a clinical service for patients with this illness and related disorders of copper metabolism at the NIH Clinical Center. The Kaler laboratory recently rescued a lethal mouse model of Menkes disease by brain-directed adeno-associated virus (AAV)-mediated gene addition. Extension of these latter proof-of-concept investigations, in tandem with preclinical toxicology studies, will pave the way for a first-in-human gene therapy trial for Menkes disease patients with complete loss-of-function ATP7A gene defects. Using biochemical and cell biological techniques, he and his colleagues are also working to distinguish the mechanisms responsible for normal copper transport activity and intracellular trafficking of ATP7A and ATP7B, a related copper ATPase.