Targeting mGlyR with nanobodies for depression

TL;DR

This study explores using nanobodies to target a glycine receptor linked to depression, showing promising antidepressant effects in mice.

Contribution

The paper introduces a novel nanobody-based immunotherapy targeting mGlyR for depression treatment.

Findings

Intranasal delivery of nanobodies produced rapid and lasting antidepressant effects in a mouse model.

The atomic structure of mGlyR bound to the nanobody was solved, revealing its mechanism of action.

Nanobodies inhibit mGlyR's regulation of G protein signaling, impacting neural circuitry.

Abstract

Development of therapies for neuropsychiatric conditions is one of the greatest challenges of modern medicine. Common limitations of traditional small molecule drugs include poor efficacy, off-target side effects and difficult druggability of many targets. In this study, we report a different approach deploying small engineered single domain antibodies, known as nanobodies, for the treatment of depression, a prevalent neuropsychiatric condition. We develop highly selective nanobodies for a recently discovered glycine receptor mGlyR crucially linked to pathophysiology of depression. Using a mouse model of stress-induced depression, we show that non-invasive intranasal delivery of nanobody produces rapid and lasting anti-depressant effect. We solve an atomic structure of mGlyR bound to nanobody and use a variety of cell-based approaches to reveal the mechanism of mGlyR modulation and its impact on neural circuitry. These findings support development of biologics for the treatment of intractable brain disorders.

This report describes a nanobody targeting glycine receptor mGlyR that inhibits its ability to regulate G protein signaling and produces anti-depressant effects in mice providing an immunotherapy approach to potentially treat depression.

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