Upstaza (PTC-AADC)

Upstaza (eladocagene exuparvovec), formerly called PTC-AADC, is an experimental treatment for aromatic L-amino acid decarboxylase (AADC) deficiency. Agilis Biotherapeutics, which initially developed the treatment, was acquired by PTC Therapeutics, which is continuing its development.

What is AADC deficiency?

AADC deficiency is a rare disease caused by mutations in a gene called DDC that provides the instructions necessary to make an enzyme called AADC. This enzyme is part of the biochemical pathway that produces neurotransmitters, or cell signaling molecules, such as dopamine and serotonin, which are vital to communication between nerve cells.

Without enough AADC enzyme, the brain cannot make enough serotonin and dopamine. This leads to physical and mental developmental delays from a young age; children with this disease have muscle weakness and muscle stiffness or spasms.

How does Upstaza work?

Upstaza is a gene therapy, meaning it contains a virus, modified so it cannot cause disease, to transmit a healthy copy of the DDC gene to nerve cells. The cells use the gene to make functional AADC enzymes, with a goal of increasing the amount of AADC enzyme available.

Doctors administer the gene therapy via a surgical procedure that introduces the virus to an area of the brain called the putamen, which normally provides most of the dopamine that the brain requires.

Because this treatment is still experimental, there are questions that researchers must answer before it can move to the clinic. For example:

  • How old do patients need to be to receive the treatment successfully?
  • If patients receive the treatment at a young age, can it counter or prevent the symptoms of AADC deficiency?
  • Is a single administration of the virus sufficient to treat AADC deficiency, or will patients need multiple administrations over their lifetime?

Upstaza in clinical trials

A Phase 1/2 clinical trial (NCT01395641) tested the safety and efficacy of Upstaza, then known as PTC-AADC, in treating AADC deficiency. Ten patients older than 24 months took part. Researchers injected PTC-AADC into the brains of the patients, who were assessed at baseline (prior to surgery) and three, six, nine, and 12 months after surgery.

Trial results were published in The Lancet Child & Adolescent Health in December 2017. All patients tolerated the surgery and treatment well. The trial met its primary objectives with improvements seen in the peabody developmental motor scales (PDMS-2, a measure of motor development in children). Throughout the study, 31 treatment-related adverse events occurred, one of which was severe. No treatment-related adverse events led to hospital admission or death.

A Phase 2 clinical trial (NCT02926066) was built upon the previous trial and assessed the safety and efficacy of an increased dosage of the viral treatment in 10 patients. The primary outcome measure was motor developmental milestones as assessed by PDMS-2. The researchers also recorded adverse events and assessed patients for two years following treatment.

The researchers collated the results of the trial with five years’ worth of data from the Phase 1/2 trial. The findings were published in the journal Neurology in April 2019, and showed clinically meaningful improvements in the patients in the PDMS-2 total score and single-item motor developmental milestones versus natural history controls. All patients had sustained dopamine production. No new safety concerns were present five years post-treatment.

Researchers also presented preliminary results from three clinical trials at the 48th Annual Meeting of the Child Neurology Society in October 2019. All given the gene therapy had fewer oculogyric crises (involuntary upward eye movement, which is a characteristic symptom of AADC deficiency). Treated patients also improved their ability to sit, walk, and talk. Benefits lasted for up to five years after treatment.

Based on these and other findings, PTC plans to seek approval for Upstaza in the U.S. and Europe.


Last updated: May 25, 2022


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