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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 dopaminergic neurons in the midbrain, ”Was 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 movements of the hands and feet.
One of the characteristic symptoms of the disease is seizure-like episodes called oculogyric crises, in which spasms of the eye muscles cause the gaze to gaze upward for minutes to hours. Anxiety and emotional outbursts often accompany these episodes.
“Remarkably, these episodes are the first symptom to go away after gene therapy surgery, and they never come back,” Krystof Bankiewicz, MD, PhD, of Ohio State University College of Medicine, said in an academic press release.
Bankiewicz and his colleagues at several other institutions conducted a clinical trial (NCT02852213) to test the safety and effectiveness of using a harmless virus to provide a healthy copy of the AADC gene directly in the brain of patients.
In particular, the researchers targeted two regions of the midbrain – the substantia nigra pars compacta and the ventral tegmental area – which contain dopamine-producing neurons with intact nerve projections in AADC patients. The approach differs from that of PTC-AADC gene therapy from PTC Therapeutics, 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).
“Really what we’re doing is putting a different code into the cell,” said James Elder, MD, one of the researchers involved in the study. “And we watch it all happen live. So we continually repeat the MRI and we can see the infusion flourish in the desired nucleus.
The main objectives of the study were to assess the safety of the treatment and to document the evidence of restored AADC activity. Secondary goals included assessment of changes in motor function and other symptoms.
Four girls and three boys aged 4 to 9 participated 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 has been shown to be generally safe and well tolerated in children. The oculogyric seizures “completely stopped” 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 with which motor symptoms improved varied widely among individuals, six of the children regained normal head control and four were able to sit without support one year after surgery.
Three were able to reach and type after a year and one was able to pronounce 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.
“Administration of the midbrain gene in children with AADC deficiency is feasible and safe, and leads to clinical improvements in symptoms and motor function,” the researchers concluded, noting that “greater improvement was obviously not associated with one or the other. [higher dose] or with a younger age in this small group of subjects.
Participants also experienced fewer sleep disturbances and feeding 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 neurological and other disorders that are similarly treated with gene therapy.”