Midbrain Gene Therapy Improved Symptoms, Motor Function in Rare Genetic Disease

By Marilynn Larkin

July 21, 2021

NEW YORK (Reuters Health) - Gene therapy delivered to the midbrain was safe and led to symptom and motor function improvement in children with a rare genetic disorder characterized by deficiencies in dopamine and serotonin synthesis.

The disorder, aromatic L-amino acid decarboxylase (AADC) deficiency, presents in early infancy and causes severe developmental disability and lifelong motor, behavioral, and autonomic symptoms including oculogyric crises (OGC), sleep disorders, and mood disturbances, according to Dr. Krystof Bankiewicz of the University of California, San Francisco and Ohio State University and colleagues.

"I developed the same gene therapy for Parkinson's disease (PD), and based on that experience used it in kids with AADC deficiency," Dr. Bankiewicz told Reuters Health by email. "I was surprised by magnitude of change in older kids. We assumed that beyond a certain age the brain lost plasticity and improvement would be limited. That was not the case."

In a study Dr. Bankiewicz is running in Europe, responses have been seen in youngsters 16 and older; the oldest responder was a 26-year-old man, he said. "In the 26-year-old, there was a very significant response, but it took more time."

As reported in Nature Communications, the team delivered a viral vector expressing AADC (AAV2-hAADC) to the midbrain of seven children ages 4-9 with AADC deficiency.

Specifically, participants underwent convection-enhanced delivery of AAV2-hAADC to the bilateral substantia nigra (SN) and ventral tegmental area (VTA). The total infusion volume was 80 microliters per hemisphere in two dose cohorts: three children received 1.3 x 1011 vector genomes and four received 4.2 x 1011 vg.

The team found that direct bilateral infusion of AAV2-hAADC was safe, well-tolerated and achieved the target coverage of 98% of the SN and 70% of the VTA.

Dopamine metabolism increased in all children and FDOPA uptake was enhanced within the midbrain and the striatum.

In six of the seven children, OGC resolved completely by month 3 post-surgery.

Twelve months after surgery, six of the children had gained normal head control and four could sit independently. At 18 months, two could walk with two-hand support.

One child died suddenly at home without any preceding illness, seven months after surgery. The cause of death was unknown, and deemed to be most likely attributable to the underlying disease.

The authors state, "The durability of AADC transduction for children with AADC deficiency is unclear, but clinical data from subjects with PD (>4 years) and pre-clinical data from non-human primates (>8 years) suggest that long-term and possibly life-long expression persists."

Dr. Bankiewicz added, "Mono-genetic disease of the brain can be treated by gene therapy with significant clinical outcomes, provided that delivery of the treatment - site and the method - are correct."

Dr. Darryl Vivo, professor of neurology and of pediatrics at Columbia University Irving Medical Center in New York City, commented on the study in an email to Reuters Health. "Our experience with spinal muscular atrophy and glucose transporter type 1 deficiency syndrome are two examples of genetic diseases that need to be treated early in post-natal life to achieve best outcomes."

"AADC deficiency may be an example of functional recovery even when treatment is delayed until later in life," he said. "The structural integrity of the developing brain appears to be relatively preserved, despite neurotransmitter depletion. Restoration of function, as in this study, allowed for remarkable developmental gains as the neurotransmitter was repleted. The investigators should be congratulated for conducting this informative research study."

SOURCE: https://go.nature.com/2VQ64Se Nature Communications, online July 12, 2021.