Gene therapy helps children with AADC deficiency gain movement skills
Study finds early treatment may lead to greater improvements
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One-time treatment with Kebilidi (eladocagene exuparvovec-tneq) helped children with aromatic L-amino acid decarboxylase (AADC) deficiency gain new motor abilities within about a year, according to data from an ongoing clinical trial.
The findings come from a Phase 2 clinical trial (NCT04903288) testing Kebilidi in 13 children with severe AADC deficiency and significant motor delays. Treatment also improved muscle tone and developmental measures, including cognitive and language scores, with brain scans showing changes consistent with the therapy’s intended effect.
Younger children showed the strongest improvements
The fastest and most pronounced improvements were seen in children who were under 2 years old at the time of treatment. The researchers noted these findings highlight “the importance of increasing disease awareness among general pediatricians and the need for early and prompt diagnoses.”
Trial results were published in the study, “Pharmacodynamics, Efficacy, and Safety of Intraputaminal Eladocagene Exuparvovec Administered to Pediatric Patients With Aromatic L-Amino Acid Decarboxylase Deficiency Using an MR-Compatible Cannula: 48 Weeks of Follow-Up,” in the Journal of Inherited Metabolic Disease.
AADC deficiency is caused by mutations in the DDC gene. This gene encodes an enzyme called AADC, which the brain needs to make key chemical messengers — including dopamine and serotonin — that nerve cells use to communicate with each other and with the rest of the body. Without enough of these messengers, children develop serious neurological symptoms.
Kebilidi is a one-time gene therapy that uses a modified, harmless virus to deliver a healthy copy of the DDC gene to nerve cells. Administered directly into the brain, the therapy is designed to restore AADC enzyme production, which may help restore production of key brain chemicals such as dopamine and serotonin and improve symptoms of the disease.
One-year data from the Phase 2 study supported the therapy’s accelerated approval in the U.S. to treat people with AADC deficiency. Kebilidi is also approved in the U.K. and the European Union for patients ages 18 months and older with severe AADC deficiency, where it’s sold under the name Upstaza.
Trial evaluates one-time gene therapy in children
Called GT-002, the trial enrolled 13 children around ages 1 to 10 with AADC deficiency. Each child received a single Kebilidi treatment, delivered directly to the brain using a device called the SmartFlow MR-compatible cannula, and continued standard-of-care as needed. While the ongoing study will assess Kebilidi’s safety and efficacy over five years, the researchers here report results from a 48-week follow-up (nearly one year).
Before the trial began, all 13 patients had severe delays in motor development, as assessed by the Peabody Developmental Motor Scales-Second Edition (PDMS-2). One child had partial head control, and one could sit with assistance.
Of the 12 patients who reached 48 weeks post-treatment, many showed meaningful gains in physical ability. Nine patients achieved full head control; four sat without assistance; two stood with support; and two walked independently to a toy.
Two of the youngest participants, both under 24 months old at the time of treatment, were able to walk backward using a normal stride, which was the “highest achieved motor milestone recorded in this study,” the team wrote. In fact, these two children showed the fastest and most pronounced improvements in motor development.
Two other patients reached partial head control alone after about a year, while another did not achieve any motor milestones by week 48 but was later able to fully control head movement and sit with assistance after about 1.8 years of follow-up.
Motor and developmental scores improved after treatment
PDMS-2 scores for motor development reflected these gains. The mean score across all patients increased sixfold, improving from 14.5 at the start of the study to 84.1 at week 48. At the same time, mean scores on the combined Bayley-III assessment, which includes measures of cognitive and language development, also improved, rising from 29.5 to 47.1. Weight gains were also noted.
“As was observed for motor development, patients who were younger at gene therapy administration appeared to show the fastest and most pronounced improvements in Bayley-III combined score,” the team noted.
At the outset, all 13 patients had hypotonia, or abnormally low muscle tone. By week 48, two patients showed no hypotonia, while the proportion of those with severe hypotonia dropped from about 69% to just over 8%.
All patients initially showed signs of reduced dopamine production, as indicated by reduced levels of homovanillic acid (HVA), a dopamine metabolite, in cerebrospinal fluid (the fluid surrounding the brain and spinal cord). By week eight, HVA levels more than doubled from 22.5 to 53.9 nanomoles/L and remained elevated at week 48 (55.3 nanomoles/L in nine patients).
Brain imaging confirms increased dopamine activity
A separate imaging measure assessed uptake of radio-labeled L-DOPA, a dopamine precursor, providing an indication of dopamine production in the brain. Before treatment, uptake in the putamen (a brain region involved in movement) was minimal in all 13 patients. Imaging data showed a 271% increase in mean uptake at week eight and a 296% increase by week 48, indicating increased dopamine production. These changes were clearly visible on PET scan images.
During the same period, the proportion of patients taking standard-of-care medications decreased from about 67% at week 8 to 22% at week 48.
The most common side effects were fever (85%), involuntary movements known as dyskinesia (77%), and diarrhea (62%). Two serious adverse events, both dyskinesia in one patient, were considered related to Kebilidi. One patient also experienced two severe seizures that were not considered related to treatment. There were no withdrawals from the study, no deaths, and no cerebrospinal fluid (CSF) leaks were reported or detected on imaging. Additionally, while patients developed antibodies to the therapy, no harmful immune responses were observed.
“This study provides further evidence of the clinically meaningful benefits of [Kebilidi] in children with AADC deficiency and its potential to significantly improve patient outcomes,” the researchers wrote. These data also suggest that “the response to [Kebilidi] may be greater when treatment is received at a younger age, perhaps owing to the worsening of complications associated with this disease over time.”
