PTC-AADC Infusion Into Brain Shows Promise Against Symptoms

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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PTC-AADC eases symptoms in children/AADC News/medicine bottle labeled clinical trials illustration

Delivering the investigational gene therapy PTC-AADC to a specific part of the brain, called the putamen, was found to significantly and effectively lessen motor and non-motor symptoms in children with aromatic L-amino acid decarboxylase (AADC) deficiency, a review-like study highlights.

“Before this treatment, the children with AADC deficiency couldn’t lift their heads, but now some can sit and stand with help, and have even begun learning to talk,” Paul Wuh-Liang Hwu, MD, PhD, of the National Taiwan University Hospital and one of the study’s co-authors, said in a press release.

“The remarkable results published have been life-changing for the children we have treated,” Hwu said.

The study, “Gene therapy in the putamen for curing AADC deficiency and Parkinson’s disease,” was published in the form of a commentary in the journal EMBO Molecular Medicine, by scientists from PTC Therapeutics, the therapy’s developer.

“I am excited about what the success of this new approach means for the children and families living with AADC deficiency,” said Stuart W. Peltz, PhD, CEO of PTC Therapeutics.

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Focused on the benefits of putamen-delivered gene therapy in people with AADC deficiency and Parkinson’s disease, the study was authored by global experts in Taiwan, the U.S., France, Germany, and Japan. Some have been involved in trials testing such therapies.

AADC deficiency and Parkinson’s are two debilitating neurological disorders that involve motor impairment caused by low levels of a major neurotransmitter called dopamine. Neurotransmitters are chemical messengers used by nerve cells to communicate with each other.

The dopamine deficit in AADC deficiency is caused by mutations in the DDC gene, which result in low levels of AADC, an enzyme necessary for the production of dopamine and serotonin, another neurotransmitter. In Parkinson’s, the AADC enzyme levels decline with time due to the progressive loss of dopamine-producing nerve cells.

Low levels of both dopamine and serotonin in patients with AADC deficiency highly disrupt the communication between brain regions and between the brain and other parts of the body, beginning at an early age.

This leads to a number of symptoms with varying degrees of severity, such as developmental delays, intellectual disabilities, movement disorders, and muscle weakness. Oculogyric crises, in which spasms of the eye muscles cause the gaze to fix upward for minutes to hours, are another symptom of the rare disorder.

To date, there are no approved disease-modifying therapies for AADC deficiency. But PTC’s gene therapy PTC-AADC — currently under regulatory review by the European Medicines Agency — may become the first.

Notably, a final recommendation from the agency’s Committee for Medicinal Products for Human Use is expected by late this year. The committee’s recommendations usually are followed by the European Commission, which then makes a final approval decision.

A one-time treatment, PTC-AADC uses a modified and harmless adeno-associated virus (AAV2) to deliver a working version of the DDC gene to nerve cells. The therapy is delivered directly into the putamen through a surgical procedure.

The putamen, for its part, is directly impacted by the loss of dopamine production in the striatum, a brain region involved in motor function and rich in dopamine-producing nerve cells that connect with the putamen.

Besides its role in motor control, the putamen is thought to also be involved in non-motor functions such as language, emotional processing, and chronic pain.

All these features, along with the fact that the putamen is a large brain structure that can be more easily accessed through surgery — therefore resulting in fewer surgical complications, in most cases — make it a “prime target for gene therapy” aiming to restore dopamine levels, the researchers wrote.

Notably, previous studies of experimental gene therapies delivering the DDC gene to the putamen of Parkinson’s patients “served as a basis for developing the therapy against AADC deficiency,” they added.

To date, three clinical trials have evaluated the safety and effectiveness of PTC-AADC in a total of 20 children with the disorder. Two studies were conducted in Taiwan and involved 14 children, and one was conducted in Japan and included six children.

The doses used in these trials — 1.8 or 2 × 1011 vector genomes — were calculated based on those previously found to be effective in adults with Parkinson’s disease.

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Prior to treatment, most of these children were bedridden and had symptoms of severe disease, including involuntary muscle contractions, reduced range of motion, oculogyric crises, and emotional instability. Nearly all never developed muscle control, could not lift their heads, and were unable to move on their own, or talk.

After the gene therapy, every child showed significant improvements in motor function and emotional stability. Reductions in oculogyric crises also were found.

Some children gained good or partial head control, were able to sit and stand with support, and began to learn how to speak. One child who could walk with support prior to the therapy was able to run and ride a bicycle after it.

Imaging data also supported the presence of AADC activity and dopamine production in the putamen. Additionally, increased levels of dopamine and serotonin metabolites were detected in the fluid that surrounds the brain and spinal cord.

Both the surgical procedure and PTC-AADC were generally well-tolerated, with involuntary movements being the most common adverse events; these resolved within months. Fever also was reported in 16% of the children.

“These studies together demonstrate that the restoration of [dopamine] synthesis in the putamen via gene therapy using low doses of [PTC-AADC] is well tolerated, leads to sustained improvements in motor and nonmotor symptoms of AADC deficiency, and is overall beneficial for the patients,” the researchers wrote.

PTC Therapeutics noted that studies of its gene therapy date back more than a decade, with the first patient dosed in 2010. The positive results have continued in multiple trials, the company said.

“The data reported in this article show that the surgical approach of delivering our novel PTC-AADC gene therapy directly to the putamen robustly produces dopamine in the brain that results in sustained and substantial functional improvements in children with AADC deficiency,” Peltz said.

Several of the study’s authors are or were in some way affiliated with PTC.

Notably, a similar gene therapy approach that targets deeper brain areas in the midbrain also has been tested in a clinical trial (NCT02852213). This therapy showed promising results in seven children with AADC deficiency in a Phase 1 trial.