Project description
Protecting sight by keeping nerve cells alive
Glaucoma is a leading cause of irreversible blindness, affecting millions of people worldwide. Current treatments can only slow disease progression and cannot prevent or reverse vision loss. With this in mind, the ERC-funded TARGET-NMNAT2 project aims to find a way to protect neurons under stress. To that end, it will focus on NMNAT2, an enzyme that keeps neurons healthy. By combining advanced drug development with gene therapy, the project seeks to support NMNAT2 levels, protect neurons and, in combination therapies, even trigger regeneration. Project work could pave the way for the first treatment that truly protects and restores vision in glaucoma.
Objective
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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences neurobiology
- medical and health sciences clinical medicine ophthalmology glaucoma
- medical and health sciences basic medicine toxicology
- natural sciences biological sciences biochemistry biomolecules proteins enzymes
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
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Call for proposal
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(opens in new window) ERC-2024-ADG
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171 77 STOCKHOLM
Sweden
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