New Gene Therapy Technique To Cure Brain Disorders

Ruzanna Harutyunyan's picture

To treat neurodegenerative diseases such as Alzheimer's, UCSF researchers have developed a new strategy for delivering gene therapy to the brain cells that stand to benefit most.

Gene therapy to treat degenerative brain disorders is still regarded as a promising approach, and is again being tested in experimental clinical trials.

It is difficult to get drugs that are large molecules, such as proteins, into the brain. Gene therapy puts genes into brain cells, so they can make their own therapeutic proteins. But then, there is still the problem of delivering the genes. Many drug developers continue to choose a common virus, called adeno-associated virus, as the gene delivery vehicle. But the brain poses special challenges for drug delivery.

The favored approach has been to inject the gene therapy drug through several cannulae — kind of like very long, extremely thin straws — threaded through holes drilled in the skull and guided into place with fancy imaging equipment. Despite all that special effort, it remains difficult to control where the drug goes, and how far it goes toward reaching targeted cells.

Now a team at UCSF led by neuroscientist Dr. Krystof Bankiewicz has developed a way to get nerve cells themselves to help disperse gene therapy to targeted cells.


In research reported in the online edition of the Proceedings of the National Academy of Sciences, Bankiewicz and colleagues injected adeno-associated virus bearing either therapeutic or marker genes into specific cells within a brain structure called the thalamus, situated below the cerebral cortex. Neurons in the thalamus make specific connections to cells in the cortex through branching processes called axons.

Bankiewicz's research team found that gene therapy delivered to cells in the thalamus could be made to spread efficiently through axons to all cortical regions, where it made the gene-encoded proteins.

"For the first time, specific regions of the cortex can be supplied with therapeutic agents by targeting defined regions of the thalamus," Bankiewicz says. "Critical and widespread cortical regions can be reached through each individual cannula, using this new approach."

The technique is called convection-enhanced delivery. The fluid containing the gene therapy is injected under pressure, delivered in pulses. The pulsation acts a pump to deliver the therapy over greater distances.

"This procedure can now be performed under the direct guidance and control of interventional MRI, to assure precise delivery of the viral vector," Bankiewicz says.

"Translational experiments now are in progress to evaluate the potential of this unique gene delivery technology for the treatment of cortical dementias such as Alzheimer's disease and lysosomal storage disorders in children."