Stephen Kaler's Section on Translational Neuroscience studies human disorders of copper transport, including Menkes and occipital horn syndrome (OHS), and their murine counterparts. Kaler previously defined the molecular basis for OHS and is P.I. on the lead protocol in the United States for treatment of Menkes disease. Taking a "bedside to bench" approach, we seek to identify and characterize under-appreciated cellular and genetic phenomena suggested by patients' phenotypes or their responses to treatment, and use animal models to test novel therapeutic approaches.
Early Diagnosis and Treatment of Menkes Disease
Menkes disease is an X-linked recessive disorder of copper transport caused by defects in a gene that encodes an evolutionarily conserved copper-transporting ATPase. In mammals, this gene product functions as an intracellular pump to transport copper into trans-Golgi spaces for incorporation into copper-requiring enzymes, and also mediates copper exodus from cells. The disorder presents in infancy with delayed development, failure to thrive, neurodegeneration, and premature death (typically by three years of age). Our work on this disorder includes development of rapid and reliable neurochemical and molecular techniques for very early diagnosis, efforts which dovetail with a clinical trial of very early copper histidine treatment for affected infants. We employ cell biological, molecular, and biochemical approaches to characterize enrolled patients and correlate with neurodevelopmental outcomes.
Animal Studies of Novel Brain-directed Therapies
The blood-brain barrier poses a challenging treatment obstacle in many Menkes disease patients, i.e., those with ATP7A mutations not associated with residual copper transport. Consequently, we are developing alternative therapeutic approaches that bypass the blood-brain barrier, including intracerebroventricular (ICV) administration of copper and adeno-associated virus (AAV) gene transfer via ICV administration in a murine model of Menkes disease, mottled-brindled. Efficacy is evaluated by examination of life span as well as biochemical parameters that are abnormal in both mottled-brindled mice and Menkes disease patients. If successful, these experiments will lay the groundwork for clinical trials of brain-directed therapies in Menkes disease patients with complete loss-of-function mutations for whom clinical responses to conventional therapy are typically suboptimal.