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Gene therapy restores missing enzyme in rare childhood disease

Thirty months after gene therapy, a 10-year-old girl who hadn’t been able to sit independently was able to walk with support. Bankiewicz lab, Nature Communications

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder that leads to near absent levels of the brain chemicals serotonin and dopamine. These neurotransmitters are critical for movement, behavior, and sleep. AADC deficiency develops in infancy and causes severe developmental disability, motor problems that affect walking and speech, mood issues, and sleep disturbances. Approximately 135 cases have been reported worldwide.

Children with AADC deficiency are at risk of death at a young age from disease complications. There are no effective therapies. Drug treatments to increase dopamine levels have provided little benefit.

Mutations in the DDC gene cause AADC deficiency. Gene therapy to replace this gene was previously tested in Taiwan and Japan with mixed results.

In a new study, a research team led by Dr. Krystof Bankiewicz of the University of California, San Francisco and Ohio State University delivered gene therapy into different regions of the brain. They packaged the gene in an adeno-associated virus for delivery into brain cells. There, it would provide instructions for making AADC. Restoring the enzyme would potentially improve production of dopamine and serotonin.

The work was supported by NIH’s National Institute of Neurological Disorders and Stroke (NINDS). Results appeared in Nature Communications on July 16, 2021.

Seven children, ages 4 to 9, received infusions of the DDC gene into two specific regions of the midbrain. The researchers used magnetic resonance imaging to guide the placement of the gene therapy. The children received one of two dose levels.

The team then evaluated how well the therapy had worked. Scans revealed production of dopamine in the deep brain structures involved in motor control three and 24 months after surgery. Levels of a dopamine metabolite, resulting from dopamine breakdown, significantly increased in the spinal fluid.

The therapy also improved the children’s symptoms. Abnormal upward movement of the eyes called oculogyric crises, a hallmark of the disease, completely went away in 6 of 7 participants. In some, improvement was seen as early as nine days after treatment.

All of the children showed improvements in movement and motor function. Twelve months after surgery, 6 of 7 subjects gained normal head control and 4 of 7 could sit independently. Two subjects could walk with support 18 months after receiving the gene therapy. Parents of a majority of the participants also reported improvements in their children’s sleep and mood.

Overall, the gene therapy was well tolerated by all the participants, and no adverse side effects were reported. One of the children died unexpectedly seven months after the surgery, but the cause of death was determined to be due to the underlying disease.

“Gene therapy is a potentially revolutionary therapeutic approach for many human diseases,” Bankiewicz says. “Although this was an early phase clinical trial, our results suggest that gene delivery in children with AADC deficiency is safe and can lead to clinical improvements.”