A CSF-Derived Therapy for Psychiatric Disorders

SHORT DESCRIPTION

A synthetic soluble ⍺2δ-1-Fc protein to restore brain function in schizophrenia and autism.

• Peter Penzes*
  • Northwestern University Feinberg School of Medicine, Department of Physiology
• Marc Dos Santos

NU Tech ID: NU 2023-196

IP STATUS

US Patent pending.

DEVELOPMENT STAGE

TRL-5 Proof-of-Concept in relevant environment: Demonstrated efficacy in neuronal cell cultures and in vivo mouse studies.

BACKGROUND

Synaptic abnormalities in neurons are believed to contribute to the development of psychiatric disorders, including schizophrenia. In the United States, schizophrenia and related psychotic disorders affect roughly 3.2–3.4 million adults, with around 100,000 people developing SCZ annually. Schizophrenia ranks among the top causes of disability globally and is associated with marked functional impairment, high rates of unemployment and homelessness, elevated suicide risk, and a reduction in life expectancy by 15–30 years compared with the general population. In SCZ, certain synaptic transmembrane proteins undergo shedding resulting in altered cerebrospinal fluid (CSF) composition, and these shed proteins may function as paracrine signals that influence neuronal activity. Current antipsychotic therapies primarily target the positive symptoms of SCZ, such as hallucinations, delusions, and altered movement kinetics, while few effectively address the negative symptoms, including reduced sociability and speech, or the cognitive symptoms, such as impaired working memory. There is a clear unmet need for therapies that can rebalance excitation and inhibition simultaneously to address these limitations.

ABSTRACT

Northwestern researchers have developed a recombinant form of the α2δ-1 protein to restore protein deficits observed in the CSF of schizophrenia patients. This protein modulates neuronal activity to rebalance excitation and inhibition, a hallmark dysfunction in many psychiatric disorders. In a mouse model of a chromosomal duplication syndrome associated with psychiatric disease, injection of the protein into the anterior cingulate cortex led to marked improvements in sociability, as well as enhanced novel object recognition. This protein-based therapeutic approach has the potential to complement existing antipsychotic medications, which primarily target positive symptoms, by specifically addressing negative and cognitive symptoms and expanding treatment options beyond traditional antipsychotic therapies.
 

APPLICATIONS

• Treatment of schizophrenia related to 16p11.2 duplication
• As a biomarker of therapeutic response
• Treatment of autism, bipolar disorder, ADHD, depression, and Rolandic epilepsy

ADVANTAGES

• Mimics endogenous protein activity without the adverse effects of synthetic drugs or gene delivery
• Enables more effective circuit-level modulation than conventional gene therapy
• Supports chemical modification to improve BBB permeability, efficacy, and stability
• Provides a therapeutic strategy for multiple disorders with shared features such as reduced sociability and inhibitory neuron dysfunction
• Uses soluble α2δ-1 as a biomarker to identify patients likely to respond to α2δ-1-fc treatment

PUBLICATIONS

• Dos Santos, M et al., Soluble Α2δ-1 Altered in Disease CSF Modulates Network Homeostasis and Rescues Deficits in a Neuropsychiatric Mouse Model. Neuron. Mar 19, 2026.

KEYWORDS

α2δ-1-Fc, neuropsychiatric, schizophrenia, autism, synaptic dysfunction, recombinant protein, therapeutic, psychiatry, psychiatric disorder