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Eyedrops that Probe the Brain

Gene probes deployed in eyedrops show brain damage in MRIs of mice.
April 4, 2008

By dosing mice with eyedrops containing gene probes that then travel to the brain, Harvard researchers are using magnetic resonance imaging to observe the brains of living animals. The method could allow doctors to directly diagnose problems such as tumors, viral infections, and head injury, without the need for a brain biopsy. It could also be useful in monitoring patients and perhaps even targeting drug treatment to affected areas of the brain.

Eye on the brain: Gene probes administered to mice via eyedrops traveled into the brain, allowing researchers to image brain damage in living animals.

The gene probe technique, reported in the latest issue of the Federation of American Societies for Experimental Biology Journal, allows MRI scans that show gliosis, the process in which glial cells in the brain form a fibrous network as a defense against damage. This scarring occurs in disorders such as Alzheimer’s disease and Parkinson’s disease and as a consequence of brain tumors and serious brain injury.

The work is “really a good start,” says Monique Stins, a visiting scientist at Johns Hopkins Medical Institutions, who was not involved in the research. However, she adds, “It’s still far from the bedside. The safety of all these kinds of probes still has to be assessed.”

In earlier studies, radiologist Philip Liu and his colleagues at Harvard Medical School injected the probes directly into the brains of animals. Now they’ve incorporated them into eyedrops.

To create the gene targeting probe, Liu and his colleagues hitched a common MRI probe to a DNA sequence complementary to the mRNA of a protein found in glial cells. They tested the probe in mice in which the blood-brain barrier–which regulates the movement of substances from the blood to the brain–had been breached. The barrier is compromised in many neurological disorders, including stroke, multiple sclerosis, and viral infections, although the process is not yet well understood.

Liu and his colleagues are not sure how the probes penetrated the brain, but they believe it may have been via the lymphatic system, which includes vessels in the eyes. Fluid from the lymphatic system merges with blood in the vascular system, and if the blood-brain barrier is compromised, Liu says, probes could travel from the eye to the brain.

After treating the mice with eyedrops, the team performed MRI scans on the live animals to produce images of gliosis in their brains. Such scans could be a valuable indicator of brain injury or a neurological disorder, Liu says, and they could be performed regularly to monitor a patient’s progress.

They could also help doctors better treat patients with brain disorders or injuries, Liu says. Although gliosis performs a valuable function by isolating damaged tissue, it also hinders the brain’s repair mechanisms. “If we know gliosis is happening,” Liu says, gliosis inhibitors could be administered “to allow more time for repair.” The probes could also be used to deliver drugs directly to damaged regions of the brain, he adds.

“In theory, it’s a great concept,” says Ahmet Hoke, an associate professor of neurology and neuroscience, also at Johns Hopkins. However Hoke, who was not involved in the work, wants to see more proof that the probe is specific to gliosis.

Like Hoke, Ausim Azizi, a professor of neurology at Temple University School of Medicine, has doubts about the specificity of the probe, but he says the technique has the potential to be a useful diagnostic tool, because it could distinguish between gliomas–brain tumors that involve glial cells–and other types of tumors. However, Azizi wonders if the eyedrop method will be able to deliver enough probes to the human brain to be helpful in diagnosis.

Because the technique took advantage of breaches in the blood-brain barrier created in mice using fairly harsh techniques such as brain punctures, oxygen starvation, and electric shock, Stins says, “it remains to be seen to what extent breaches in the blood-brain barrier in human diseases will be enough to deliver this gene probe with the specificity they claim they have. They’ve got their work cut out for them.”

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