Gene therapy outcomes in AADC deficiency best tracked by doctors
Study: Analysis of neurotransmitters not predictive of treatment response
Analysis of certain chemicals, known as neurotransmitters, in the cerebrospinal fluid (CSF) that bathes the brain and spinal cord does not predict clinical outcomes following gene therapy in children and adolescents with aromatic L-amino acid decarboxylase (AADC) deficiency.
That’s according to a recent study that analyzed CSF and clinical data in 30 children and adolescents treated with gene therapy.
“Current evidence suggests CSF metabolites do not overcome the predictive value of clinical observation on clinical outcomes and should be reserved for patients unresponsive to the therapy,” researchers wrote.
The study, “The value of CSF neurotransmitter monitoring in the outcome of gene therapy in aromatic amino acid decarboxylase (AADC) defect,” was published in Parkinsonism & Related Disorders.
One-time treatment utilizes a harmless virus
AADC deficiency is caused by mutations in the DDC gene, which result in absent or dysfunctional AADC, an enzyme that is crucial to produce neurotransmitters – chemicals nerve cells use to communicate – including dopamine and serotonin. The disease can lead to symptoms such as developmental delays, movement disorders, and autonomic dysfunction, which is a dysregulation of involuntary bodily processes, including heart and respiratory rate.
The recent approval of the gene therapy Kebilidi (eladocagene exuparvovec) has improved the natural history of the disease. The one-time treatment utilizes a harmless virus, known as adeno-associated virus serotype 2 (AAV2), to deliver a healthy copy of the DDC gene directly into the brain through a minimally invasive neurosurgical procedure.
In this study, researchers investigated the utility of measuring disease biomarkers in the CSF to monitor the effects of treatment on neurotransmitters.
The researchers analyzed the clinical data of 30 people with AADC deficiency, in whom gene therapy was delivered to the putamen (23 patients) or the substantia nigra. These regions normally have the highest levels of AADC activity and dopamine, a neurotransmitter crucial for motor control.
Participants had a mean age of 6.6 years at the time of treatment (ranging from 1.7 to 19 years), with CSF evaluation performed before and at least six months after gene therapy delivery surgery, in conjunction with clinical evaluation.
Following treatment, all patients demonstrated improvements in motor and neurodevelopmental function.
HVA levels significantly increased after treatment in most participants
The researchers assessed the levels of CSF metabolites, specifically those of dopamine (homovanillic acid, or HVA), serotonin (5-hydroxyindoleacetic acid, or 5-HIAA), and levodopa (3-O-methyldopa, or 3-OMD), a precursor of dopamine. These metabolites are used to represent the levels of these neurotransmitters and are reliable biomarkers for the diagnosis of AADC deficiency.
HVA levels significantly increased after treatment in most participants with available data.
Although HVA levels were not associated with patients’ clinical improvement, having better motor performance before treatment was associated with a higher increase in HVA levels after treatment. This effect was independent of the amount of time between the treatment and the CSF analysis.
According to the current preliminary data, monitoring post-treatment [neurotransmitter] metabolites in CSF does not seem superior to clinical observation as an outcome measure.
Contrary to HVA, 5-HIAA levels were not affected by treatment, and 3-OMD levels remained increased.
Regarding the delivery strategy, there was a significantly higher increase in HVA levels when gene therapy was administered to the substantia nigra compared to when it was administered to the putamen.
“According to the current preliminary data, monitoring post-treatment [neurotransmitter] metabolites in CSF does not seem superior to clinical observation as an outcome measure,” the researchers wrote, adding that “this procedure might be reserved for patients who do not show the expected clinical improvement following gene therapy.”
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