Gene therapy shows promise in children with devastating genetic disease

Children with a devastating genetic disease characterized by severe motor disability and developmental delay have seen sometimes dramatic improvements in a gene therapy trial launched at UCSF 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, especially dopamine, which makes them unable to speak, eat or hold their heads. Six of the children were treated at UCSF and one at Ohio State Wexner Medical Center.

The children in the study experienced improved motor function, better moods, and longer sleep, and were able to interact more fully with their parents and siblings. The oculogyric crisis, a feature of the disorder involving involuntary upward gaze that can last for hours and may be accompanied by seizure-like episodes, ceased in all but one of the patients. The results appear on July 12, 2021 in Nature Communications.

Only 135 children worldwide lack the enzyme AADC, the disease affecting more people of Asian descent.

The trial borrowed gene delivery techniques used to treat Parkinson’s disease, developed by lead author Krystof Bankiewicz, MD, PhD, of the Department of Neurological Surgery at UCSF and the Weil Institute for Neurosciences, and the Ohio State University Department of Neurological Surgery. Both conditions are associated with deficiencies in AADC, which converts levodopa into dopamine, a neurotransmitter involved in movement, mood, learning, and concentration.

Viral vector, real-time MRI imaging, key to success

By 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 magnetic resonance imaging to allow the neurosurgeon to map the target region and plan the insertion and perfusion of the cannula.

Children with primary AADC deficiency do not have a working copy of the gene, but we assumed their true neural pathway was intact. It’s different from Parkinson’s disease, where the neurons that make dopamine degenerate. “

Nalin Gupta, MD, PhD, Co-First Author, UCSF Department of Neurological Surgery and Principal Investigator in Surgery

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

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

Doctors who follow patients with AADC deficiency agree that it is generally treated with limited success in managing symptoms, such as with drugs used for Parkinson’s disease to increase dopamine, melatonin for blood disorders. sleep and benzodiazepines to relieve oculogyric crisis.

After gene administration, PET imaging demonstrated increased brain AADC activity and screening for cerebrospinal fluid neurotransmitter metabolites showed elevated concentrations, the researchers noted.

At the start of the study, only two of the seven children had partial head control, only one could reach or grab, and none were able to sit independently. Six of the seven were described as irritable and all but one suffered from insomnia. Their basic motor skill scores were all in the severe impairment range. Symptoms improved after surgery, starting with an oculogyric crisis.

“Remarkably, these episodes were the first to go and they never came back,” Bankiewicz said. “Over the following months, many patients experienced life-changing improvements. Not only did they start laughing and their mood improved, some were able to start talking and even walking.”

New goals achieved by sitting, walking, eating, talking

All patients experienced recognizable gains in motor function, manifested in increased tone and better control of the head and trunk, as well as deliberate limb movements. Head control was achieved by six of the seven children by month 12 and four were able to sit independently at that time. Additionally, at 12 months, three patients could reach and grip and two were able to walk with trunk support. Two and a half years after surgery, a patient began to take independent measures. One patient was able to speak using a vocabulary of around 50 single words at 12 months and a second was able to communicate with an assistive device between 12 and 18 months after giving birth to the gene.

Significant improvements have been reported by parents and caregivers in sleep and mood, as well as in feeding difficulties, such as vomiting and upper airway obstruction due to profuse mucus and fluid secretions. congestion. The procedure was well tolerated with no short- or long-term side effects, but one child died seven months after the surgery. The patient appeared to be in good health and the cause of death is “most likely due to the underlying primary disease,” the researchers said.

The study follows the Parkinson’s disease trial, which also showed positive results with increased durations of well-controlled symptoms. Bankiewicz’s team will launch two new gene therapy trials, using the same surgical techniques and the same viral vector, for early-onset Alzheimer’s disease and for multisystem atrophy, a rare neurodegenerative disease. Both trials will take place at Ohio State University and begin next month.