BACKGROUND
GRIN disorders encompass a group of neurodevelopmental conditions caused by mutations in genes encoding the N-methyl-D-aspartate receptor (NMDAR) subunits, including GRIN1, GRIN2A, GRIN2B, and GRIN2D1. NMDA receptors are crucial for synaptic transmission and plasticity in the central nervous system, playing a vital role in learning and memory. Pathogenic variants in GRIN1, which encodes the GluN1 subunit, lead to altered receptor function, impacting neuronal communication and brain development. GRIN1-related disorders are characterized by a range of clinical phenotypes, including intellectual disability, epilepsy, movement disorders, and developmental delays. Small molecule therapeutic approaches that act directly on NMDARs have limited effects on GRIN patients, necessitating the development of more effective modalities.
TECHNOLOGY
Researchers at the University of Toronto have proposed the overexpression of GRIN1 as a novel and effective treatment for patients with GRIN1 variants. This produces more functional copies of the NMDA receptor as a larger pool of wildtype GluN1 subunits results in a greater replacement of the dysfunctional subunit. Further, as NMDA receptor expression is governed by the GluN2 and GluN3 family of subunits, receptor levels are not affected by the higher levels of GluN1. Cells often express a pool of extra, unassembled GluN1 subunits endogenously and can remove excessive GluN1 subunits that are not assembled into NMDAR. Testing has been conducted in mouse models of missense patient variants GRIN1Y647S and GRIN1Q536R. A construct containing GRIN1-1a has been packaged into an AAV capsid that can efficiently penetrate blood-brain barrier to deliver the synthetic GRIN1gene into the brain, resulting in rescue of synaptic NMDAR responses and synaptic plasticity in brain slices.
COMPETITIVE ADVANTAGE
- One-time treatment for patients with GRIN1 variants regardless of the type and specific location of the GRIN1 gene mutation
- Overexpression of GRIN1 does not alter the endogenous levels of NMDA receptor
APPLICATIONS
- Gene therapy for GRIN disorder
INTELLECTUAL PROPERTY STATUS
- Provisional patent application (April 2024)
PROJECT STATUS
Proof-of-concept studies have been conducted in mice engineered to model a GRIN1Q536R and GRIN1Y647S patient variants. Preliminary results show successful delivery and expression of functional GRIN1 gene product (GluN1), as well as rescue of synaptic NMDAR responses and synaptic plasticity in brain slices at a dose that does not cause toxicity or neuroinflammation. Further studies are being conducted in mouse models carrying different GRIN1 patient variants.
