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Gene therapy significantly improved motor functions and quality of life in children with aromatic L-amino acid decarboxylase (AADC) deficiency in a recent phase 1 clinical trial.
The healthy copy of AADC The gene the children received corrected the seizure-like episodes associated with the disorder and, in many cases, allowed the children to develop normal head control, sit independently and walk with support. .
The study, “Gene therapy for aromatic L-amino acid decarboxylase deficiency by MRI-guided direct delivery of AAV2-AADC to midbrain dopaminergic neuronswas published in the journal Nature Communication.
Without the AADC enzyme, the body cannot produce dopamine and serotonin, two molecules that serve as messengers between nerve cells. This disrupts communication between the brain and other parts of the body, hampering normal development and causing symptoms such as weak muscles and uncontrollable hand and foot movements.
One of the hallmark symptoms of the disorder are seizure-like episodes called oculogyric crises, during which spasms of the eye muscles cause the gaze to fixate upwards for minutes to hours. Anxiety and emotional outbursts often accompany these episodes.
“Remarkably, these episodes are the first symptom to disappear after gene therapy surgery, and they never return,” said Krystof Bankiewicz, MD, PhD, of The Ohio State University College of Medicine, in a university press release. .
Bankiewicz and his colleagues at several other institutions conducted a clinical trial (NCT02852213) to test the safety and efficacy of using a harmless virus to deliver a healthy copy of the AADC gene directly into the patient’s brain.
In particular, the researchers targeted two regions of the midbrain – the substantia nigra pars compacta and the ventral tegmental area – that contain dopamine-producing neurons with intact nerve projections in AADC patients. The approach differs from PTC Therapeutics’ PTC-AADC gene therapy, which targets a different region called the putamen.
The researchers performed minor surgery on the participants to slowly infuse the therapy, while monitoring the spread of the infusion in the brain via real-time magnetic resonance imaging (MRI).
“What we’re really doing is introducing a different code into the cell,” said James Elder, MD, one of the researchers involved in the study. “And we watch everything happen live. So we continuously repeat the MRI and we can see the infusion blossom into the desired core.
The main objectives of the study were to assess the safety of the treatment and to document the evidence for restored AADC activity. Secondary objectives included assessment of changes in motor function and other symptoms.
Four girls and three boys aged 4 to 9 took part in the study. Three patients received a lower dose of 8.3 × 1011vector genomes (vg)/mL, while the others received a higher dose (2.6 × 1012vg/mL).
The treatment was found to be generally safe and well tolerated in children. The oculogyric crises “completely ceased” in six of the seven children within three months of treatment and did not return during the two-year follow-up period. The remaining patient had fewer episodes and with significantly reduced severity compared to before surgery.
Although the speed of improvement in motor symptoms varied greatly between individuals, six of the children regained normal head control and four were able to sit without support one year after the operation.
Three were able to reach and grasp after a year and one was able to say about 50 words.
Two children – aged 8 and 6 at the start of the study – were able to walk with trunk support one year after treatment and walk with two-handed support at 18 months. One of them began to take independent measurements 2.5 years after treatment.
“Gene delivery to the midbrain in children with AADC deficiency is feasible and safe, and leads to clinical improvements in symptoms and motor function,” the researchers concluded, noting that an “improvement more important was obviously associated with neither. [higher dose] or with a younger age in this small group of subjects.
Participants also experienced fewer sleep disturbances and eating difficulties, and caregivers reported lasting improvements in mood.
“This work provides a framework for the treatment of other genetic diseases of the human nervous system,” Bankiewicz said. “We hope this will be the first of many ultra-rare and other neurological disorders that will be treated with gene therapy in the same way.”