Treatment with AGIL-AADC gene therapy induces sustained improvements in motor, cognitive, and language measures in children with aromatic L-amino acid decarboxylase (AADC) deficiency for up to five years, researchers report.
Their work, “AGIL-AADC Gene Therapy Results in Sustained Improvements in Motor and Developmental Milestones Over 5 Years in Children With AADC Deficiency,” was presented in a poster at the 2019 American Academy of Neurology (AAN) Annual Meeting in Philadelphia.
The AADC enzyme is involved in the production of several brain chemical messengers, such as dopamine and serotonin. The lack of such enzyme alters brain development, causing severe mental and motor disturbances in affected children, with most of them being unable to speak or stand.
Researchers from the National Taiwan University Hospital set up to assess clinical outcomes in AADC children treated with PTC Therapeutics‘ AGIL-AADC, a recombinant adeno-associated viral (AAV) vector carrying the gene for the human aromatic L-amino acid decarboxylase protein.
At the AAN meeting, investigators presented two-year post-treatment data of 18 AADC patients, and five-year post-treatment data for eight of those patients. One patient died 11 months after the gene therapy; the death was deemed unrelated to treatment.
Patients were ages 21 months to 8.5 years and had been included in two single-arm, open-label clinical studies — AADC-1601 (NCT02926066), a trial in which patients were enrolled under individual compassionate use consents, and AADC-010 (NCT01395641).
In a single session, the therapy was bilaterally administered (total dose, 1.8×1011 vector genomes) into the patient’s putamen — a large structure in the brain filled with dopamine receptors and involved in movement control.
The research team then used clinical scales to evaluate the patients’ motor control, cognition, and language. The study’s primary goal was achievement of motor developmental milestones on the Peabody Developmental Motor Scale, Second Edition (PDMS-2).
Scientists also evaluated dopamine production using a non-invasive imaging technique known as positron-emission tomography (PET), which enables the visualization of dopamine synthesis in the body via a radioactive tracer called F-DOPA.
Results were compared to a group of 82 untreated AADC patients who were followed over time. These patients had “no or very limited developmental milestones,” failing to achieve full head control, and lacking the ability to sit, stand, or walk.
After AGIL-AADC administration, all patients showed sustained dopamine production, and their motor skill abilities significantly improved compared to the control group.
At two years, eight patients (44%) had achieved full head control, six (35%) were able to sit unassisted, and three (17%) could stand without support. Among the eight patients followed for five or more years, four (50%) had full head control, four (50%) could sit unassisted, and two (25%) could stand without support.
Among the five patients who could stand without support, two were able to walk with a wheeled walker, and one is now able to walk multiple steps without any assistance.
The children’s cognition and speech abilities were also better after gene therapy administration. But in all measures, earlier treatment meant more significant benefits, said poster presenter Brian E. Pfister, MD, MBA, executive director, MSL lead at PTC Therapeutics.
Importantly, no new safety issues were observed over the five-year follow-up, with all serious adverse events being consistent with the disease state and considered unrelated to AGIL-AADC treatment.
“In children with AADC deficiency, AGIL-AADC gene therapy achieved clinically meaningful, sustained improvements in motor, cognitive, and language milestones for up to five years, with no new safety signals identified,” researchers stated.