Probe That Acts as PET Scan Tracer May Give Glimpse into Gene Therapy’s Effects on Brain

A radioactive probe that might enable imaging tools to effectively monitor what a gene therapy is doing in the brain — important in treating diseases like multiple sclerosis with such a therapy — has been developed at Stanford University.

The probe is a kind of radiotracer used successfully in this study with PET imaging of the brain. It can cross the natural barrier, called the brain-blood barrier, that protects the central nervous system (CNS), making it a potentially useful tool in tracing the effects of a gene therapy in patients whose disease affects the central nervous system, like MS, Parkinson’s and Alzheimer’s.

This work is described in the study “A Novel Positron Emission Tomography Reporter Gene/Reporter Probe for the Central Nervous System,” presented at the SNMMI 2018 Annual Meeting recently held in Philadelphia.

Interest is growing in gene therapies as a treatment approach for diseases of the CNS, supported by better delivery vehicles and the identification of attractive therapeutic targets. But the development of gene therapies for these diseases has been limited by the lack of imaging techniques to monitor effectiveness.

The new probe, which the Stanford researchers identified as ¹⁸F-DASA-23 and refer to as a “reporter probe,” may be that needed piece.

It was designed to target the pyruvate kinase M2 (PKM2) protein in the CNS, which is often deregulated in cancer and in MS lesions, and is present in very low levels in healthy brains.

Studies in mice revealed that the probe could effectively cross the blood-brain-barrier and target brain cells that were specifically changed, using a gene therapy approach, to have higher amounts of PKM2.

With use of positron emission tomography (PET) imaging, the researchers were able to visualize the mice brains and track the progressively increasing levels of PKM2 over time.

“It is challenging to find a reporter gene and imaging agent that can be used in all areas of the brain with a high signal-to-background ratio,” Thomas Haywood, PhD, researcher at the department of radiology at Stanford University and the study’s lead author, said in a press release. “This allows us to monitor reporter gene expression and ultimately therapeutic gene expression for gene therapy in all regions of the brain.”

These positive preclinical results suggest that PKM2 may have the potential to be developed into a PET reporter gene system to monitor the CNS.

The imaging tracer is currently undergoing the first-in-human Phase 1 trial (NCT03539731) at Stanford to test its potential to detect early therapeutic response in healthy volunteers and brain cancer patients.

“Having a reporter gene/reporter probe system that allows monitoring of all areas of the brain opens the door to more accurate and less invasive imaging of the brain and of gene therapies used to tackle diseases of the brain,” Haywood concluded.