Metabolic biomarkers for targeted treatment of schizophrenia and related disorders

This technology is a set of metabolite profiles for identifying disruptions in the brain glutamate metabolic cycle that can enable more targeted treatment of schizophrenia and related psychotic disorders.

Unmet Need: Effective detection of brain glutamate metabolic pathway disruption

In early-stage schizophrenia, excess glutamate levels in the hippocampus drive hyperactivity and atrophy. The enzyme responsible for the glutamate elevation can be identified through changes in the metabolites of the glutamate metabolic cycle: glutamine, glutamate, and GABA. Identifying which enzyme has altered activity in early-stage schizophrenia will allow for more targeted treatments of schizophrenia and improve the effectiveness of clinical trials. However, current methods for non-invasive measurements of metabolite concentrations in the brain rely on 1H-magnetic resonance spectroscopy (1H-MRS), which struggles to distinguish glutamine from glutamate at low magnetic field (3 tesla) and faces a lack of magnetic field uniformity at higher magnetic field (7 tesla) due to hippocampus’s proximity to tissue, air, and bone.

The Technology: Brain metabolites indicative of glutaminase1 hyperactivity in schizophrenia

This technology utilizes metabolite profiles consisting of glutamate, glutamine, and GABA to pinpoint glutamate metabolic cycle disruptions in the brain. These metabolite profiles are obtained from deep learning deconvolution of 3 tesla 1H-MRS measurements. One profile that consists of increases in glutamate and GABA but not glutamine concentration is observed in the hippocampus of patients with early-stage schizophrenia or related psychotic disorders. This indicates hyperactivity of glutaminase (GLS1), the enzyme that converts glutamine to glutamate, as the driver of glutamate increase. As glutamate accounts for most of the convoluted glutamate-glutamine 1H-MRS measurement, the combination of this peak and GABA elevation is sufficient to act as a biomarker for GLS1 hyperactivity and to distinguish between patients and control.

This technology has been validated with 3 tesla 1H-MRS measurements of the hippocampus of patients with early-stage schizophrenia or related psychotic disorders and controls.

Applications:

• Biomarkers for glutaminase hyperactivity
• Early detection or targeted therapy of schizophrenia and related psychotic disorders
• Enrollment or target engagement biomarker for brain disorder clinical trials targeting enzymes in the glutamate metabolic cycle
• Assessment of the efficacy of glutaminase inhibitors
• Metabolic imaging of cancer cells
• Research tool for studying glutamate metabolic cycle in healthy brain, Alzheimer’s disorder, Parkinson’s disease, neurodegeneration, schizophrenia, epilepsy, psychotic disorders, and cancer
• Identification of glutamate metabolic cycle enzyme targets in brain disorders

Advantages:

• Compatible with brain tissues that are difficult to image with 1H-MRS
• Compatible with the more cost-effective and time-efficient 3 tesla 1H-MRS
• Enables targeted clinical trials for more effective and less costly assessment of drugs
• Non-invasive

Lead Inventor:

Scott Small, M.D.

Related Publications:

Tech Ventures Reference:

• IR CU21216

• Licensing Contact: Jerry Kokoshka