Pathobiology and Treatment of Lysosomal Disorders of Brain
Training in Comparative Medicine and Neuroscience provided the basis for my career interests in neurogenetic disease, particularly those disorders impacting neuronal homeostatic mechanisms and resulting in intellectual disability and related neurobehavioral abnormalities. My lab has published extensively in the area of pathogenic cascade analysis in lysosomal disease, defining key changes in neuronal structure and function as a consequence of lysosomal compromise. Current studies include: (i) the causes and consequences of ectopic dendritogenesis and neuroaxonal dystrophy, (ii) altered synaptic function underlying intellectual compromise, (iii) involvement of mTOR and TFEB/TFE3 in homeostatic dysregulation following lysosomal compromise and its impact on endosomal and autophagasomal function, and (iv) the importance of metabolite salvage in lysosomal processing.
Diseases of current focus include the lysosomal diseases Niemann-Pick types A and C, mucolipidosis IV, cystinosis, GM1 and GM2 gangliosidosis, Sanfilippo type A (MPS IIIA), Batten disorders (CLN2 and CLN3) and a newly discovered endosomal disorder known as Christianson syndrome.
My lab is also significantly involved in therapy development for genetic brain disease. We were the first to show essentially complete correction of CNS disease in the lysosomal disorder known as alpha-mannosidosis through the use of bone marrow transplantation and this treatment approach is now the standard of care for children diagnosed with this rare disorder. A disease of current focus toward therapy is Niemann-Pick type C (NPC), a fatal cholesterol-glycosphingolipid lysosomal storage disorder of children. Based on our studies of glycosphingolipid processing abnormalities in NPC disease we developed the first and presently only approved (by EMEA; FDA pending) therapy for this disorder. This is the imino sugar known as N-butyldeoxynojirimycin, or miglustat, which is a partial inhibitor of glycosphingolipid synthesis.
More recently we discovered that the FDA-approved excipient known as hydroxypropyl beta-cyclodextrin is efficacious in limiting intraneuronal accumulation of both unesterified cholesterol and glycosphingolipids, and dramatically extends the lifespan in animal models of NPC disease. Research and clinical trial development was subsequently pursued through a unique scientist/clinician/parent consortium known as SOAR (Support Of Accelerated Research) for NPC disease (SOAR-NPC) and through collaboration with TRND (Therapeutics for Rare and Neglected Diseases) and NCATS (National Center for Advancing Translational Sciences) at NIH. Phase 1 trials of this compound in NPC patients began in February, 2013, with Phase 2/3 planned to begin in the latter half of 2015. To see a short video related to the trial development, go to: