Researchers at the Institute of Functional Genomics in Montpellier, France, have developed a novel nanobody therapy derived from llama antibodies that successfully crosses the blood-brain barrier and reverses cognitive symptoms in mouse models of schizophrenia. The study, published in Nature, represents a significant departure from traditional dopamine-focused treatments and offers new hope for addressing the cognitive deficits that severely impact patients' daily functioning.
Targeting an Unmet Medical Need
Schizophrenia affects approximately 1% of the global population and remains a leading cause of disability and premature death. Current medications primarily target positive symptoms like hallucinations and delusions through dopamine receptor modulation, but they do little for the memory, attention, and reasoning problems that make everyday life challenging for patients. These cognitive symptoms are strongly linked to poorer long-term outcomes, yet no widely effective treatments exist for them.
The research team focused on glutamate signaling in the brain, specifically targeting reduced function of N-methyl-d-aspartate (NMDA) receptors. Previous attempts to address this pathway through mGlu2/3 receptor agonists or positive allosteric modulators showed initial promise but mostly failed in late-stage clinical trials, likely due to insufficient selectivity and reduced effectiveness in patients already treated with antipsychotics.
Nanobody Engineering and Design
The researchers developed DN13-DN1, a bivalent nanobody created by combining two fragments: one that boosts mGlu2 receptor activity and another that binds without activating it. This design increased the molecule's potency and duration at its target site. Nanobodies, originally found in camelids, are approximately one-tenth the size of conventional antibodies, making them easier to produce and more likely to cross biological barriers.
When injected into the abdomen of mice, DN13-DN1 successfully crossed the blood-brain barrier and reached key brain regions including the cortex and hippocampus, areas rich in mGlu2 receptors. Remarkably, the nanobody remained in the brain for at least seven days after a single injection, despite only 0.1% of the administered dose crossing into the brain.
Therapeutic Efficacy in Disease Models
The team tested DN13-DN1 in two mouse models with reduced NMDA receptor function: one caused by early-life exposure to phencyclidine and a genetic model (GluN1-KD) that mimics a rare human disorder. Both models exhibit cognitive and sensory deficits similar to those seen in people with schizophrenia.
DN13-DN1 demonstrated significant improvements in memory tasks including novel object recognition and the Y-maze test. The nanobody also enhanced sensorimotor gating, a process often impaired in schizophrenia patients. These therapeutic effects lasted at least one week, substantially longer than the standard mGlu2/3 drug LY379268, which loses effectiveness within 24 hours.
Importantly, DN13-DN1 showed no effects in healthy mice and did not alter overall activity levels or mGlu2 expression. A larger antibody version (DN13-Fc) failed to improve behavior or reach the brain, highlighting the critical importance of the nanobody's compact size for brain penetration.
Safety and Dosing Considerations
Repeated low-dose injections over several weeks produced sustained improvements with no signs of toxicity. The nanobody's allosteric mechanism preserves natural patterns of receptor activity, only boosting mGlu2 activity when the natural ligand is present, which may reduce side effects such as overstimulation.
DN13-DN1 avoids the off-target effects commonly seen with hydrophobic drugs, making it a strong candidate for further development not only for schizophrenia but for other brain conditions involving glutamate signaling.
Clinical Translation Challenges
Before clinical use, several hurdles must be addressed. The nanobody will need to be "humanized" to prevent immune reactions, and long-term safety must be thoroughly evaluated. Researchers must also determine optimal dosing strategies and delivery routes, including intravenous, subcutaneous, or intranasal administration.
The findings could help revive interest in mGlu2 as a therapeutic target. DN13-DN1 sidesteps problems encountered in previous failed trials by acting specifically on mGlu2 homodimers and maintaining effectiveness even when receptor expression is low, as occurs in GRIN disorders.
As the authors noted, "Our study opens new routes for the clinical management of brain diseases with nanobody-based immunotherapies using low-frequency, peripheral administration." This approach could complement recent advances like Cobenfy, the first FDA-approved schizophrenia drug targeting cholinergic rather than dopamine receptors, signaling a broader shift toward more targeted psychiatric treatments.
