GT-AADC (formerly AGIL-AADC) is an experimental treatment for aromatic L-amino acid decarboxylase (AADC) deficiency. Originally developed by Agilis Biotherapeutics, the treatment is now being developed by PTC Therapeutics after its acquirement of Agilis Biotherapeutics.
What is AADC deficiency?
AADC deficiency is a rare disease caused by mutations in a gene called DDC. This gene provides the instructions necessary for nerve cells 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, not enough serotonin and dopamine are made in the brain. 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 GT-AADC work?
GT-AADC is a gene therapy — it contains a virus (modified so it cannot cause disease) to transmit a healthy copy of the DDC gene into nerve cells. The gene is used by the cells to make functional AADC enzyme, with the goal of increasing the amount of AADC enzyme available and countering the deficiency caused by the disease.
The gene therapy must be administered via 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 must be answered before it can be used in the clinic. For example:
- How old do patients need to be to receive the treatment successfully?
- If the treatment is supplied 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 multiple administrations be required over a patient’s lifetime?
GT-AADC in clinical trials
A Phase 1/2 clinical trial (NCT01395641) tested the safety and efficacy of GT-AADC in treating AADC deficiency. Ten patients older than 24 months were enrolled. They were treated with GT-AADC injected into the brain. The patients were assessed at baseline (prior to surgery) and three, six, nine, and 12 months after surgery. They were also assessed a further six and 12 months after treatment.
The results of the trial were published in The Lancet Child & Adolescent Health. All patients tolerated the surgery and treatment well. They also all met the primary endpoint: an improvement in the Peabody developmental motor scales (PDMS-2, a measure of motor development in children). Throughout the study, 31 treatment-related adverse events occurred, only 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. An increased dosage of the viral treatment was used, and safety and efficacy were assessed for the treatment in 10 patients. The primary outcome measure was motor developmental milestones as assessed by PDMS-2; adverse events were also recorded. Patients were assessed for two years following treatment.
The results of the trial were collated with five years’ worth of data from the Phase 1/2 trial and published in the journal Neurology. Clinically meaningful improvements were observed in the PDMS-2 total score and single-item motor developmental milestones versus natural history controls. All patients had sustained dopamine production. All adverse events reported were associated with the disease; no new safety concerns were raised five years post-treatment.
A Phase 1 clinical trial (NCT02852213) is currently recruiting children with AADC deficiency in San Francisco to assess the safety and efficacy of GT-AADC. Six patients will receive the treatment as an injection into the brain. Over the two years following treatment, adverse events will be recorded. Motor function improvement will be assessed by gross motor function measures (GMFM-88).
Last updated: Sept. 19, 2019.
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