Experts urge new guidelines for gene therapy in AADC deficiency

Aim is safe application for patients and outcome follow-up

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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In this gene therapy illustration, a strand of DNA is shown on a couch while a therapist sits on a chair nearby.

A group of international experts in aromatic L-amino acid decarboxylase (AADC) deficiency and similar neurologic conditions have developed guidelines for the safe application of gene therapy in AADC patients, and for needed outcome follow-up.

The new recommendations come within a year of approvals in the European Union and the U.K. of Upstaza (eladocagene exuparvovec), a one-time gene therapy for AADC deficiency. Its developer, PTC Therapeutics, plans to ask for an approval in the U.S. in coming months.

“Due to lack of data on long-term outcomes and the comparative efficacy of alternative … procedures … a structured follow-up plan and systematic documentation of outcomes in a suitable, industry-independent registry study are necessary,” the researchers wrote in a study outlining their proposal.

The study, “Gene therapy for aromatic L-amino acid decarboxylase deficiency: requirements for safe application and knowledge-generating follow-up,” was published in the Journal of Inherited Metabolic Disease. The recommendations were created by members of the International Working Group on Neurotransmitter-related Disorders (iNTD).

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AADC deficiency is an ultra-rare disease caused by mutations in the DDC gene, which lead to low levels of the AADC enzyme or the production of a faulty enzyme.

Without proper AADC function, the production of major nerve signaling molecules in the brain, such as dopamine and serotonin, is deficient, impairing nerve cell function. This leads to physical and mental developmental delays starting from a young age.

Gene therapy for AADC deficiency aims to replace the defective DDC gene with a healthy copy, which is expected to restore AADC production and normalize dopamine and serotonin levels.

PTC Therapeutics’ Upstaza is a gene therapy that delivers a working DDC copy directly into the brain. It’s been shown to provide developmental benefits for up to 10 years post-dosing in clinical trials.

The therapy was approved in the U.K. last fall for adults and children with AADC deficiency. Just months earlier, it had been approved in the EU for patients ages 18 months and older with the ultra-rare disorder. In the U.S., it remains an experimental treatment.

A similar gene therapy that targets deeper areas in the brain also is being tested in a U.S-based Phase 1 clinical trial (NCT02852213).  To date, it has shown positive results, improving both motor function and quality of life.

While these therapies are promising, “it must be kept in mind that not all aspects regarding safety and efficacy are yet known given the relatively small number of patients treated to date,” the researchers wrote.

“Due to the challenges expected to arise following the approval of [Upstaza],” the researchers wrote, selected members of the iNTD with experience caring for AADC patients developed recommendations “regarding the requirements for safe application and knowledge-generating follow-up of patients who have received AADC gene therapy.”

Several of the experts have previously received speaker and research honorarium from PTC.

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The first steps for monitoring gene therapy in AADC deficiency

As a first step, the experts say, the decision to recommend gene therapy to an AADC deficiency patient must be made by a pediatrician with several years of experience specializing in neurological conditions and rare movement disorders.

The AADC diagnosis must be confirmed by a genetic analysis that detects DDC mutations or evidence of either deficient AADC activity in the bloodstream or an abnormal neurotransmitter profile in the fluid that surrounds the brain and spinal cord.

Newly-diagnosed patients should be offered an appointment at the treatment center within four weeks, or about one month, to be provided information about the disease and available therapies. Upstaza now is the only therapy targeting the disease’s underlying cause.

Because severe symptoms may not occur until an older age, all diagnosed infants should receive appropriate medication, according to guidelines. Those with mild to moderate disease severity may respond to drug treatment, the experts noted.

For patients with more severe disease, early treatment may provide some developmental benefits before gene therapy, and continuation of medication should be decided case by case based on clinical outcomes.

Based on the healthcare system specific to each country, covering the cost of gene therapy should be discussed. If needed, an application to cover costs can be submitted to an insurance company.

An inpatient screening visit, 15-30 days before gene therapy surgery, will assess the patient’s medical history, physical characteristics, and motor and developmental status. Lab tests also will be reviewed, as will be imaging scans, vaccination status, and the potential for social counseling.

Patients should be enrolled in the iNTD Registry Study “to document the treatment and the follow up of the patients in an industry independent approach,” the experts wrote.

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To ensure the patient’s stability, an inpatient admission should be completed at least 24 hours in advance of surgery. During this time, the patient’s legal guardian/caregiver will be informed about anesthesiology, the surgical procedure, and any blood sampling.

During surgery, the treatment is infused into the brain using MRI guidance. In the case of Upstaza, the therapy is administered to the putamen or substantia nigra, two areas that provide most of the dopamine in the brain. MRI scans during and after surgery will be used to detect signs of complications, such as bleeding or a lack of oxygen.

After treatment, patients will be transferred to intensive care to be monitored for any signs of neurological problems that may indicate complications for at least three days. At this point, a team of neuropediatricians, neurosurgeons, and other specialists will determine the duration of inpatient monitoring and outpatient follow-up.

Temporary involuntary muscle movements, known as dyskinesia, can be expected for 2-6 weeks after surgery, due to the preexisting higher-than-normal sensitivity to dopamine in the brain of AADC deficiency patients. With worsening dyskinesias, previous medication must be gradually reduced, and the need for more intensive care may be necessary.

[These guidelines] should be reviewed and updated at regular intervals, and collection of patients’ data in an industry-independent international registry will help understand patients’ courses after gene therapy.

Patients should regularly return to the treatment center for the first two years to monitor for side effects and clinical progress. While follow-up can occur through a local physician closer to home, the researchers noted that this would ideally be in addition to the treatment center.

Finally, long-term follow-up after gene therapy should be required at least once a year for 15 years to monitor symptoms, overall developmental progress, and any delayed complications that may arise.

“Gene therapy for [AADC deficiency] is likely to continue to evolve, considering ongoing clinical trials to investigate [deeper brain] gene delivery, and the potential for future therapeutic approaches that aim to address both dopamine and serotonin deficiency,” the researchers wrote.

This consensus statement “should be reviewed and updated at regular intervals, and collection of patients’ data in an industry-independent international registry will help understand patients’ courses after gene therapy,” they added.