New Gene Therapy Offers Hope to Reverse Rare Genetic Disorder in Children

With gene editing and therapies steadily achieving success in the clinic, rare genetic disorders are ideal targets for clinical trials. In a new study, researchers reversed the deficiency of AADC, an enzyme essential for dopamine synthesis in the brain.

AADC (Aromatic L-amino acid decarboxylase) deficiency is a condition characterized by severe and long-term motor and learning defects in children, with less than 200 cases registered worldwide. Without AADC and related neurotransmitters, children lack muscle control, are unable to speak, and experience regular and long seizures.

In a new report published in Nature Communications, a team from UCSF and Ohio State University demonstrate a novel gene therapy to cure AADC deficiency. 

The Study

Deriving from clinical trials developed by senior author Krystof Bankiewicz’s team at Ohio State University, for Parkinson’s Disease, where AADC gene is delivered to specific brain regions, the authors identified two regions in the midbrain-substantia nigra and ventral tegmental area- where injection of AADC could restore the neuronal network and improve motor coordination.

This study was designed to test the safety and efficacy of in-fusion therapy in children and the ability of AADC to restore motor function. Unlike Parkinson’s disease where dopaminergic neurons degenerate, AADC deficiency in children retains the intact neuronal network of the motor neurons and lacks neurotransmitters to complete the circuit. Restoring neurotransmitter production can cause motor function gains. 

Positive Trial Outcomes

In a clinical trial with 7 patients, a viral vector with the AADC gene was slowly infused into the midbrain via a minor hole in the skull and monitored real-time by MRI. The authors measured AADC activity, dopamine levels, and improvement in clinical symptoms. Improvement in motor and social skills and disappearance of seizures were noted by all participants.

Some patients could learn to walk with support and speak, although with limited vocabulary. Caregivers noted remarkable improvements in mood, social skills, and a significant improvement in quality of life. Most participants tolerated the two-dose regimen with no major short-term and long-term side effects. 

After over two decades of extensive work in gene therapy, Bankiewicz said, “This work provides a framework for the treatment of other human nervous system genetic diseases. It’s our hope that this will be the first of many ultra-rare and other neurologic disorders that will be treated with gene therapy in a similar manner.” The team is gearing for similar clinical trials for Alzheimer’s disease and multiple system atrophy.

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Author

Sahana Shankar