Agrins Protease Inhibitor Domains as Therapeutics

Agrin is a recently cloned extracellular matrix (ECM) protein thought to be important in theformation and maintenance of the neuromuscular junction (NMJ). The rat agrin cDNA encodes a 200kdprotein with three regions highly homologous to other known proteins. These domains include ninerepeats of Kazal type serine protease inhibitors, a region similar to domain III of the ECM protein lamininand four epidermal growth factor repeats. Our focus is to test the feasibility of using recombinant agrinprotease inhibitor domains as therapeutic agents. Results from our previous work have demonstratedthat agrin is expressed in a wide variety of tissues and has active protease inhibitory activity. Therefore,our first goal (Phase I) will be to fully characterize this activity; this will be accomplished by expressingand purifying agrin protease inhibitor domains and testing them in vitro in biochemical assays. PhaseII will consist of identifying the natural targets for agrin's inhibition and testing the inhibitors in animaldisease models. The overall goal of commercial development is to use agrin based inhibitors to controlaberrant protease activity in neurologic or other relevant diseases.