Project Reference: TRG27-PHA-PM1

Project title: Engineering antibody modulators of GABA-A receptors to ameliorate fear/anxiety disorder behaviour

Project outline

GABA-A receptors are the principal mediators of inhibitory neurotransmission in the central nervous system (CNS). Small molecule positive allosteric modulators (PAMs) such as benzodiazepines (e.g. Valium) act on GABA-A receptors to treat generalized anxiety disorder, but limited selectivity causes side effects such as addiction, sedation and amnesia, limiting use. This project will study antibody modulators of GABA-A receptors against the alpha2 and 3 subtypes, targets for anxiolysis, autism and pain. The Miller lab and collaborators have shown these antibodies offer game-changing improvements in selectivity and modulatory power to control neuronal excitability and reduce anxiety [1]. This PhD project will further engineer these antibodies for modulation of anxiety and fear processing in whole animal behaviour models through collaboration with the Milton lab. Antibodies will be administered locally via post-surgical delivery through cannula, or via systemic administration using an antibody shuttle system that has been established in the Miller lab [2]. This will allow us to evaluate for the first time: (1) The potential of antibody modulators to treat a mental health disorder, in this case anxiety and post-traumatic stress disorder. (2) The contribution of alpha2 versus 3 to desirable behavioural effects versus side effects such as addiction/sedation. (3) A comparison of how behavioural effects manifest when delivered locally versus systemically. Breakthroughs in this area will offer new insight into receptor subtype contributions to behaviour and evaluate delivery methods and side effect risks, offering translational capability to develop antibody modulators of GABA-A receptors into anxiety therapeutics in the future.

[1] Gonzalez-Prada JE…Miller PS. Science Advances. 2026.

https://doi.org/10.1126/sciadv.aeg3548

[2] Liu S...Miller PS. Biorxiv. 2026.

https://www.biorxiv.org/content/10.64898/2026.06.30.735565v1

Principal Supervisor

Dr Paul Miller

Email address: pm676@cam.ac.uk

Department / Partner Institute: Pharmacology

Website: https://www.phar.cam.ac.uk/research/miller

BBSRC strategic theme

Transformative technologies