Varghese John, Ph.D.

Faculty Member

Professor
Department of Neurology
David Geffen School of Medicine 
University of California, Los Angeles

Personal Statement

I have the expertise, leadership skills, intellectual focus and motivation necessary to successfully carry out the role of contact PI on the proposal entitled “Development and testing of brain permeable MARK4-PROTAC in VCID and AD models”. I am a medicinal chemist with over 20 years of experience leading small-molecule drug discovery projects in the pharmaceutical industry in CNS related disorder with focus on Alzheimer’s disease. My research has resulted in several key publications in Alzheimer’s disease (AD) and I am a co- inventor in over 100 issued and pending patents. During my tenure in industry, I was part of the original Athena/Elan AD team for 18 years. In this period I was the lead chemist of a team that made several important discoveries in AD, including identification and development of early inhibitors for the g-secretase enzyme that led to a more selective (lacking Notch activity) clinical candidate Semagecestat that proceeded into Phase 3 clinical trials sponsored by our collaborator Eli Lilly, and the purification of the beta-amyloid cleavage enzyme (BACE) from AD brain tissue using an affinity purification approach and the first-in-class potent BACE peptide inhibitor (Sinha S. et. al., Nature 1999). Using drug design and structure-based approaches, my group at Elan converted the statine-based peptidic inhibitor of BACE into small molecule (MW ~ 400Da) brain-permeable peptidomimetic inhibitors. This work was done as part of a corporate collaboration with Pharmacia/Pfizer. After leaving the pharma industry I moved to the Buck Institute in the bay area where I established the Alzheimer’s Drug Development Network (ADDN) to discover novel targets for new therapeutic development in AD. In mid-2014 I joined the UCLA Department of Neurology and my lab in Reed became fully operational in Jan of 2015. Currently, I am Professor and PI of the Drug Discovery Lab (DDL) in the UCLA Department of Neurology and a member of the Mary S Easton Center for Alzheimer’s disease research at UCLA. The lab is focused on new therapeutic approaches in AD, PD and other CNS disorders using a pharma model for drug discovery in an academic setting. UCLA is a highly collaborative academic institution and is a great place to conduct new drug discovery research on complex diseases such as AD. Our discovery efforts have led to a candidate drug , DDL110, moving through IND enabling studies and for clinical testing in AD patients. The research activities in the DDL can be characterized by an impact pyramid – one aspect focusing on high throughput screening (HTS) and analog synthesis, the second aspect focusing on CNS drug delivery of CRISPR and macromolecules including proteins and nucleotides using Synthetic Exosomes (SE) made of deformable nanoscale-vehicles, a third aspect focusing on preclinical testing for identification of candidate drugs, and a fourth aspect focusing on detection and isolation of brain derived exosomes in body fluids like blood to monitor drug efficacy and identify new targets for CNS disorders and obtain a “window into the brain”. Working with the PI Dr. Jason Hinman and the Hinman lab and DDL team on the proposal, I will apply my previous drug discovery experience which includes coordinating project research activities, providing scientific direction, facilitating communication to to achieve the proposal goals. This proposal follows logically with my training and expertise in Alzheimer’s Disease research in my Drug Discovery lab.