Direct Delivery of Gene Therapy to Midbrain Areas Improved Symptoms of Rare Metabolic Brain Disease 

Results of a clinical trial (NCT02852213) published in Nature Communications show that direct intracranial injection of gene therapy to midbrain regions improved symptoms of aromatic L-amino acid decarboxylase (AADC) deficiency in 7 children. 

All 7 children had fewer hours per week and lower severity of oculogyric crises. All had gains in motor milestones manifested by increased tone, improved trunk control, and more purposeful limb movements. Within 6 to 12 months, 6 attained head control, and 3 could reach and grasp. The ability to walk with support was gained by 2 of the children (age 6 and 9 at baseline), and 1 was able to take independent steps 2.5 years after the procedure. Improvements in nonmotor symptoms were also observed. No treatment-related serious adverse events occurred, although 1 child died during the study.

The children (age 4 to 9 years at baseline) were given intraoperative intracranial injections of the AADC gene on an adeno-associated virus type 2 (AAV-2) vector. Injections were to the substantia nigra pars compacta and the ventral tegmental area in the midbrain. Delivery of the gene therapy is monitored and adjusted during the procedure to insure deliver to those specific brain regions. Fluorodopa positron emission tomography (F-DOPA PET) and analysis of cerebrospinal fluid metabolites were used to confirm AADC enzymatic activity over a 2-year period. 

“Really, what we're doing is introducing a different code to the cell,” said James B. Elder, MD, director of neurosurgical oncology, Ohio State Wexner Medical Center Neurological Institute, “and we're watching the whole thing happen live. We continuously repeat the MRI and we can see the infusion blossom within the desired nucleus.” 

AADC deficiency results in the inability to synthesize dopamine and serotonin, causing lifelong motor and nonmotor symptoms, including hypokinesia, oculogyric crises, sleep disorders, and mood disturbances. Levodopa treatment is ineffective because with no AADC, these individuals cannot convert levodopa to dopamine.