Jeffrey Agar

Associate Professor

College of Science, Department of Pharmaceutical Sciences, Faculty

Office: 412 TF

Email: [email protected]

Phone: 617-373-5909

View Résumé/CV

Research Interests

Our research involves target discovery, validation, and preclinical therapy development in ALS (and recently other neurodegenerative diseases like Parkinson’s). The mechanism for how >180 different mutations in Cu-Zn superoxide dismutase (SOD1) caused familial amyotrophic lateral sclerosis (fALS) was unknown. We developed a physicochemical/structural model that implicated aggregation and destabilization of SOD1 as major fALS risk factors. We extended this model to sporadic (idiopathic) ALS using a combination of mass spectrometry of patient’s tissues and neurotoxicology assays. These studies led to the hypothesis, and subsequent in vitro validation, that disease-related SOD1 could be stabilized by a Cys-selective (homo bi-functional) crosslinker. Unfortunately, previous cross-linkers were too toxic for in vivo (therapeutic) use. We therefore developed a less toxic cross-linker, cyclic thiosulfinates, and demonstrate their efficacy in an ALS mouse model. These highly tunable S-cross-linkers solved a general problem by avoiding the toxic “dead-end” modifications that plagued previous cross-linkers, and as a result have many applications beyond SOD1 stabilization.