Development of a rapid protein deletion platform for central nervous system neurons

The National Eye Institute awarded Texas A&M Agrilife Research $432,061 on September 1, 2026, under the Vision Research program (CFDA 93.867) to develop a rapid protein deletion platform for central nervous system neurons.

The project will design and validate an innovative molecular genetic tool that enables rapid, reversible protein deletion in adult CNS neurons through controlled proteasomal degradation using antibody-based engineered protein degraders delivered intracellularly via endosomal escape peptides. The platform will employ these degraders to bind target proteins and recruit the ubiquitin-proteasome system to induce acute, tunable target degradation in less than an hour, providing temporal control of proteostasis and protein function. Aim 1 will optimize degrader design and delivery parameters in neuronal cultures. Aim 2 will validate the system's ability to delete key intracellular proteins in primary retinal ganglion cells by targeting known suppressors of axon regeneration in adult CNS neurons that act on distinct pathways, have different protein stabilities, and function in different intracellular compartments. The capability to rapidly delete proteins in neurons would enable studies into dynamic neural functions and processes and has significant translational potential for treating acute neurological perturbations such as traumatic injury.

Performance occurs in College Station, Texas, with a period of performance from September 1, 2026, through August 31, 2028.

Abstract

Development of a rapid protein deletion platform for central nervous system neurons the ability to rapidly delete proteins in neurons would enable studies into dynamic neural functions and processes. However, current genetic approaches such as knockout or RNA interference are slow, irreversible, or poorly suited to postmitotic cells. This project will develop an innovative platform that will enable specific protein deletion in adult central nervous system (CNS) neurons. This approach would have a broad range of applications to probe the molecular function of CNS proteins. Further, development of effective protein deletion technologies would have significant translational potential for treating acute neurological perturbations, such as traumatic injury. This project will develop a novel molecular genetic tool that enables rapid and reversible protein deletion in neurons through controlled proteasomal degradation. The approach employs antibody- based engineered protein degraders that are delivered intracellularly using endosomal escape peptides optimized for efficient cytosolic delivery and neuronal biocompatibility. Once inside neurons, these degraders bind a desired protein target and recruit the ubiquitin-proteasome system to induce acute, tunable target degradation in less than an hour, providing temporal control of proteostasis and protein function. As proof-of-principle, this technology will be applied to delete known suppressors of axon regeneration in adult CNS neurons. The targeted proteins act on distinct pathways, have different protein stabilities, and function in different intracellular compartments, testing the range of the approach. Aim 1 will optimize degrader design and delivery parameters in neuronal cultures. Aim 2 will validate the system's ability to delete key intracellular proteins in primary retinal ganglion cells, establishing feasibility in a model relevant to central nervous system injury. Successful completion will yield a broadly applicable platform for manipulating protein levels in neurons, providing the neuroscience community with a new class of molecular tools that complement genetic approaches to study the cellular basis of neuronal function, degeneration, and repair.