TARGET-NMNAT2 · Pharmacological and gene therapy targeting of NMNAT2 for neuroprotection in glaucoma

The goal of this ERC Advanced Grant is to develop clinically translatable neuroprotective strategies for glaucoma by focusing on NAD metabolism. NMNAT2 is a neuron-specific NAD-generating enzyme and is the upstream enzyme that coordinates axon degeneration. The Williams lab is expert in taking basic biological findings in glaucoma to the clinic, and we will leverage our expertise in this space to develop novel clinically translatable therapeutic interventions for glaucoma based on NMNAT2 biology. In Program 1 my team will further our on-going drug development program developing novel compounds targeting NMNAT2 by:(1)Continuing refining medicinal chemistry to develop an oral and injectable formulation,(2)Confirming NMNAT2 engagement via autoradiography and assessing BBB permeability and distribution via PET radiopharmacology using fluorine-18 radio ligands of these compounds, (3)Assessing the neuroprotective potential of these compounds in proof-of-concept animal models of glaucoma.In Program 2 my team will target neuroprotection and axon regeneration to develop a comprehensive, titratable, single dose treatment for glaucoma via gene therapy by:(1)Combining a regenerative gene therapy (phosphomimetic Protrudin) with neuroprotective treatments (nicotinamide therapy, novel NMNAT2 compounds, NMNAT2 gene therapy),(2)Exploiting the E. coli DHFR and human FKBP destabilising domains to develop a gene therapy product which is rapid, titratable, and switchable (i.e. ON/OFF) and test this in the context of glaucoma.This ERC Advanced Grant will capitalize on my recent findings that targeting NAD can prevent degeneration in animal models and restore vision glaucoma patients and develop crucial in vivo data transitioning this program from TRL 3 to TRL 4. By the end of this funding, we expect to be in a position to perform our regulatory toxicology on our lead drug and gene therapy candidates and file for our IND in preparation for a Phase I clinical trial.