Gene therapy shows benefits despite limited brain coverage

Kebilidi (eladocagene exuparvovec-tneq), an approved gene therapy delivered directly to the brain to treat AADC deficiency, led to clinical benefits even when only a small portion of the targeted brain region was reached by the treatment, according to a small study in France.

Clinical benefits were seen across all patients, including motor gains, and no serious adverse events were reported. Oculogyric crises — episodes in which the eyes involuntarily roll upward — also became less frequent or less severe in most patients.

The study, “Gene Therapy for Amino Acid Decarboxylase Deficiency: Clinical and Imaging Outcomes in a French Cohort,” was published in the journal Movement Disorders.

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AADC deficiency disrupts dopamine, serotonin production

AADC deficiency is a rare genetic disorder caused by mutations in the DDC gene, which provides instructions to make the enzyme AADC. As a result of these mutations, the enzyme is faulty or absent, leading to reduced production of dopamine and serotonin, two chemical messengers needed for movement, sleep, and other nervous system functions.

Kebilidi, sold by PTC Therapeutics and branded as Upstaza in Europe and the U.K., is an approved gene therapy that delivers a healthy copy of the DDC gene to brain cells in the putamen, a brain region involved in movement control. The goal is to restore local AADC enzyme activity and dopamine production.

Although the therapy’s clinical benefit has been established in clinical trials, it remains unclear how the extent of gene therapy delivery in the brain, changes seen on dopamine-related imaging, and clinical recovery are related.

To better understand these relationships, a team led by researchers at Montpellier University Hospital in France followed six people with AADC deficiency — five males and one female, with a mean age of 9.7 years — who received the gene therapy between December 2020 and January 2024. They were followed for a mean of two years.

All had severe disease and insufficient responses to medications. The treatment involved delivering the gene therapy directly into the putamen on both sides of the brain.

Researchers assessed several outcomes, including motor function, adaptive behavior, comfort, oculogyric crises, dyskinesias (involuntary movements), and safety. They also used MRI scans to see how much of the putamen was reached by the treatment. In addition, they used 18F-DOPA PET imaging to track changes in AADC enzyme activity and dopamine-related activity in the putamen over time.

Before surgery, patients had very low motor function scores. Improvements were modest after three months but became more evident with longer follow-up.

Across the group, the mean gain in the Gross Motor Function Measure-88 (GMFM-88) was 6.7 points at the final follow-up. The GMFM-88 is a standardized test that assesses motor abilities such as lying, rolling, sitting, crawling, standing, walking, running, and jumping, with higher scores indicating better motor function. Before gene therapy treatment, gross motor function was severely impaired, with a mean GMFM-88 score of 3.3 points.

Two patients achieved clinically meaningful responses, exceeding a seven-point improvement threshold reported in previous literature.

Motor gains emerge over longer follow-up

Major motor milestones were reported after treatment: four of the six patients recovered partial head control, which had been absent before treatment. The same four patients showed improved hand or manual function, including active hand use, object grasping, independent finger movement, or handling objects with both hands.

One patient achieved unassisted tripod sitting at 5.5 months, while another walked with support using a mobile standing frame at 32 months.

Within a year of gene therapy, five of the six patients had less frequent and less severe oculogyric crises. Two eventually became free of the episodes, one after 18 months and the other after 5.5 months.

Behavioral improvements were seen across the cohort from the first follow-up visit. Sleep problems that were present before treatment resolved in all but one patient, who developed new sleep problems related to dyskinesias after surgery.

All six patients developed dyskinesias within the first month after surgery. Their severity varied, with symptoms peaking between one and six months after treatment.

The dyskinesias either resolved or became less severe within six to 18 months. No serious adverse events were reported.

The imaging findings suggested that these temporary dyskinesias could be related to an early increase in AADC enzyme activity after gene therapy. PET scans showed a marked rise in 18F-DOPA uptake in the putamen after one month, followed by a sharp decline at three months. Uptake then gradually recovered and stabilized from 12 months onward.

Clinical recovery did not depend on full putamen coverage

One of the study’s main goals was to determine whether greater putamen coverage by the gene therapy infusion predicted better outcomes.

The researchers found that clinical recovery did not correlate with the volume of the putamen covered by the gene therapy. MRI and metabolic imaging measures also did not correlate with clinical or biochemical outcomes.

Instead, the findings suggested that the gene therapy may only need to reach a critical threshold of dopamine production to trigger broader brain network changes and functional recovery, rather than requiring complete coverage of the putamen.

Despite the small number of patients, these findings “align with the established efficacy and safety of [Kebilidi],” the researchers wrote.

The researchers added that therapeutic efficacy seems “to depend on reaching a critical threshold of dopamine production rather than on exhaustive anatomical coverage of the putamen.”