Johns Hopkins School of Medicine

Biotechnology and therapeutic development for neurological and neuromuscular disease

In the early period of my academic laboratory, we discovered novel mechanisms by which AMPA- and NMDA-type glutamate receptors traffic through the endocytic and secretory pathways in neuronal dendrites.  We embarked on a program of research over the ensuing decade that discovered and described zones for clathrin-mediated endocytosis in dendrites and spines, large scale ubiquitin-dependent remodeling of the postsynaptic density (PSD), Golgi outposts in dendrites as specialized compartments for secretory cargo trafficking and processing, and exocytic domains lateral to the PSD in dendritic spines.  

Upon my move to industry, we described a novel structure and phospholipid binding property of LIMP-2, a lysosomal trafficking chaperone and glucocerebrosidase receptor implicated in Gaucher and Parkinson’s disease.  We have identified a novel non-catechol binding mode of D1 dopamine receptor agonists that fails to recruit arrestins with a corresponding lack of desensitization and for which compounds are now in clinical development.  Finally, in a close collaboration with Mark Schnitzer, we defined unexpected neural ensemble dynamics in striatal spiny projection neurons that define parkinsonian and dyskinetic states in disease- and treatment-models of Parkinson’s disease. 

Most recently, I have focused on scientific entrepreneurship by translating breakthrough science into novel medicines through the creation of biotechnology companies. A specific focus has been on RNA therapeutics.  One key area we are pursuing is trans-splicing and the editing of pre-mRNA at kilobase scales.  A second key area of focus is on mining and engineering self-replicating viral RNA genomes as a quantum leap in mRNA therapeutics.  These efforts have led to new therapeutic modalities that have entered clinical testing and which hold promise for the treatment of neurological, ophthalmological, and infectious diseases.