Gene Therapy Offers Hope for Children with Rare, Incurable Disorder

Children with a devastating genetic disorder characterized by severe motor disability and developmental delay have experienced sometimes dramatic improvements in a gene therapy trial launched at UC San Francisco Benioff Children’s Hospitals. The trial includes seven children aged 4 to 9 born with deficiency of AADC, an enzyme involved in the synthesis of neurotransmitters, particularly dopamine, that leaves them unable to speak, feed themselves or hold up their head. Six of the children were treated at UCSF and one at Ohio State Wexner Medical Center.

Children in the study experienced improved motor function, better mood, and longer sleep, and were able to interact more fully with their parents and siblings. Oculogyric crisis, a hallmark of the disorder involving involuntary upward fixed gaze that may last for hours and may be accompanied by seizure-like episodes, ceased in all but one patient. Just 135 children worldwide are known to be missing the AADC enzyme, with the condition affecting more people of Asian descent.

The trial borrowed from gene delivery techniques used to treat Parkinson’s disease, pioneered by senior author Krystof Bankiewicz, MD, PhD, of the UCSF Department of Neurological Surgery and the Weill Institute for Neurosciences, and of the Department of Neurological Surgery at Ohio State University. Both conditions are associated with deficiencies of AADC, which converts levodopa into dopamine, a neurotransmitter involved in movement, mood, learning and concentration. In treating both conditions, Bankiewicz developed a viral vector containing the AADC gene. The vector is infused into the brain via a small hole in the skull, using real-time MR imaging to enable the neurosurgeon to map the target region and plan canula insertion and infusion.

Children with primary AADC deficiency lack a functional copy of the gene, but we had presumed that their actual neuronal pathway was intact,” said co-first author Nalin Gupta, MD, PhD, of the UCSF Department of Neurological Surgery and the surgical principal investigator. “This is unlike Parkinson’s disease, where the neurons that produce dopamine undergo degeneration.

While the Parkinson’s trial focused on the putamen, a part of the brain that plays a key role in this degeneration, Gupta said the AADC gene therapy trial targeted neurons in the substantia nigra and ventral tegmental area of the brainstem, sites that may have more therapeutic benefits.

The approach for treating AADC deficiency is much more straightforward than it is for Parkinson’s,” said Bankiewicz. “In AADC deficiency, the wiring of the brain is normal, it’s just the neurons don’t know how to produce dopamine because they lack AADC.”

Results appear in Nature Communications.

Source: https://www.ucsf.edu/