Gene therapy delivered to the brain shows promise in children with rare neurodegenerative disease

Scientists from Ohio State University have developed a novel method for delivering gene therapy to specific regions of the brain. Now, they have evidence from a small clinical trial in children that the treatment could address a rare, inherited neurodegenerative disease. And they believe their technique could eventually be used to treat more common brain diseases, like Alzheimer’s and Parkinson’s.

The Ohio State team developed the gene therapy to treat aromatic L-amino acid decarboxylase (AADC) deficiency, which hampers the body’s ability to make dopamine and serotonin and results in developmental delays and a range of motor and behavioral symptoms. The gene therapy uses a viral vector to carry DNA-expressing AADC to the brain.

In seven children with AADC deficiency, the gene therapy boosted the metabolism of dopamine, the researchers reported in Nature Communications. Within three months, six of the children were no longer experiencing oculogyric crises (OGC), which are eye spasms that commonly occur in children with the disorder. After a year, six of the participants had normal head control, the researchers said.

During the trial, the Ohio State team delivered the gene therapy directly to the midbrain, monitoring the spread of the DNA in real time using MRI imaging. They reported “dramatic improvements” in several symptoms beyond OGC, including sleep disturbances and irritable mood, according to the paper. Improvements in motor function took longer to emerge, they wrote, but were markedly better than what would normally be “expected to occur in the natural course of AADC deficiency for patients in this age range (4–9 years) who have severe motor impairment.”

The ability to deliver gene therapy directly to the brain—and monitor its effects with advanced imaging—could enhance efforts to treat a range of neurodegenerative disorders, said Krystof Bankiewicz, M.D., Ph.D., neurological surgery professor at the Ohio State College of Medicine, in a statement.

In fact, a handful of companies are working toward that goal. They include Lexeo Therapeutics, which is developing a gene therapy to deliver the APOE2 gene into the central nervous system in the hopes that it will slow the development of Alzheimer’s in people with two copies of the the high-risk APOE4 variant.

Another company examining brain-delivered gene therapy is VectorY, which recently raised $38 million to advance its work. VectorY is using viruses to carry genes into the brain that can encode therapeutic antibodies. It is using the newly raised funding to complete preclinical work on therapies for amyotrophic lateral sclerosis and Alzheimer’s.

Based on the success of their early-stage trial in AADC deficiency, the Ohio State researchers are planning clinical trials of their brain-delivered gene therapy in other incurable, debilitating diseases, they said.

“The gene therapy approach described here represents many years of careful work to develop and to understand” effective ways to deliver gene therapy to the brain, they wrote in the study. “This work provides a framework for the treatment of other human CNS genetic diseases, and iterative refinement of the individual components of this approach will facilitate broader application.”