PTC-AADC Gene Therapy Safe, Showing Promise for Children

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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Using PTC-AADC gene therapy in children with aromatic l-amino acid decarboxylase (AADC) deficiency was found to be relatively safe and led to improvements in motor function, cognitive abilities, and breathing, a review of six clinical trials found.

The therapy also showed benefits in feeding, mood, and sleep among boys and girls with the genetic and neurometabolic disease.

The review study, “Gene Therapy in Movement Disorders: A Systematic Review of Ongoing and Completed Clinical Trials,” was published in the journal Frontiers in Neurology.

Gene therapy to treat AADC deficiency aims to restore the function of the defective DDC gene, which carries instructions for the AADC enzyme. A lack of this enzyme leads to lower levels of the nerve cell signaling molecules (neurotransmitters) dopamine and serotonin, causing a range of disease symptoms.

Such therapy also is being investigated in various other movement disorders, including Parkinson’s and Huntington’s diseases, and two conditions similar to Parkinson’s, called multiple system atrophy (MSA) and supranuclear palsy (PSP).

Now, investigators based at the Ohio State University Wexner Medical Center sought to provide an overview of published and ongoing clinical trials in movement disorders using gene therapy. To do so, the team searched medical databases and reviewed relevant literature.

Eligible studies in the database Pubmed were analyzed, along with a website, called, that reports on such trials. Gene therapy-related search terms were used, and no restrictions were applied to age, gender, ethnicity, follow-up, disease duration or severity.

The search identified four published studies on AADC deficiency and two ongoing clinical trials. The analysis focused on changes in motor function, cognition, and autonomic nerve functions — regulation of bodily functions that act primarily unconsciously, such as breathing. Safety and tolerability also were assessed, with particular attention given to identifying adverse effects (AEs) of the therapy.

The four published studies included two Phase 1/2 open-label trials, one Phase 1 open-label trial, and one compassionate use study. All investigated PTC Therapeutics‘ gene therapy candidate PTC-AADC, which is currently under review by the European Medicines Agency.

Altogether, the studies included 14 boys and 13 girls, with a mean age ranging from 4.3 to 10.8 years. The children received the AADC gene using a modified, harmless adenovirus vector (AAV2) infused into the brain. Follow-up ranged from nine months to just over three years (38 months).

All patients reported improvements in motor outcomes, as measured by the Alberta Infant Motor Score, the Peabody Developmental Motor Scores-2, or the Gross Motor Function Measure-88. Younger participants given the PTC-AADC therapy trended toward greater improvement.

Breathing and swallowing improved, uncontrolled muscle contractions (dystonia) resolved, and oculogyric crisis — the involuntary upward deviation or darting of the eyes — decreased in frequency or severity to varying degrees.

All these symptoms “are disease manifestations that have a high impact on quality of life as reported by caregivers of children with AADC deficiency,” the team wrote.

Cognitive scores also improved for all patients, particularly in those with mild to moderate disease at the study’s onset.

Available imaging data showed increased dopamine in regions correlating with infusion areas up to two years after follow-up. Analysis also demonstrated increased dopamine metabolites, but the degree of change in serotonin metabolites and the dopamine precursor levodopa varied significantly between patients both before and after treatment.

Improvements in feeding, mood, sleep, and autonomic functions also were reported by most caregivers.

Regarding safety, three serious AEs were reported, including one bleeding related to the surgical procedure, one very high fever, and one transient increase in breathing pauses. Two deaths due to flu-related brain inflammation and another unknown cause were considered unrelated to treatment.

All participants experienced short involuntary, irregular muscle movements weeks to months after surgery to varying degrees, and most were managed with medication adjustments.

The two ongoing trials include a Phase 1/2 study (NCT01395641), with 10 children older than age 2, and a Phase 2 trial (NCT02926066) involving 12 patients ages 2 to 6. These studies also are investigating PTC-AADC gene therapy. Primary outcomes include motor scales and neurotransmitter metabolite profiles in the cerebrospinal fluid surrounding the spinal cord and brain.

In addition to safety, pharmacological profiles will be assessed, as well as changes in radioactive dopamine precursor following gene transfer.

“Gene therapy studies have demonstrated to be relative [safe] in four AADC deficiency trials aimed at restoring [dopamine and serotonin] synthesis by constitutively enhancing AADC enzymatic capacity following a single infusion of AAV2-AADC,” the investigators wrote.