Disease severity varies widely in LOPD gene therapy screening

Researchers were assessing adults with LOPD for eligibility in a clinical trial

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

Share this article:

Share article via email
This illustration shows a gene therapy counselor in a chair listening to an oversized DNA strand reclining on a couch.

Disease severity varied widely among adults with late-onset Pompe disease who underwent screening to assess their eligibility to participate in a gene therapy clinical trial, a study reports.

Elevated levels of antibodies against the viral delivery vector were one of the exclusion criteria, suggesting that future studies may use immunosuppressive therapy to deplete these antibodies and allow more individuals with Pompe to participate, the researchers noted.

“Screening data for a LOPD gene therapy trial provide insight into important considerations for enrollment criteria,” they wrote in the study, “Screening data from 19 patients with late-onset Pompe disease for a phase I clinical trial of AAV8 vector-mediated gene therapy,” published in the journal JIMD Reports.

Recommended Reading
An illustration of a strand of DNA highlights its double-helix structure.

Gene therapy shows promise in mouse model of Pompe

The GAA gene carries instructions for acid-alpha-glucosidase (GAA), an enzyme that breaks down a complex sugar molecule called glycogen. People with Pompe disease harbor mutations in the GAA gene, leading to reduced or complete loss of GAA activity. This results in a toxic buildup of glycogen in cells, especially muscle cells, which triggers the onset of symptoms.

Enzyme replacement therapy (ERT) is currently the standard treatment for Pompe, in which patients receive a lab-made version of the GAA enzyme. Still, many patients develop antibodies against the lab-made GAA, limiting its effectiveness, and in many cases patients continue to experience persistent muscle symptoms.

ACTUS-101 (AAV2/8-LSPhGAA) is an investigational gene therapy for Pompe disease. It uses a harmless adeno-associated virus (AAV8) to deliver a functional version of the GAA gene to the liver to promote the production of the GAA enzyme.

The gene therapy is currently being tested in a Phase 1/2 open-label trial (NCT03533673) at Duke University in North Carolina. Sponsored by Asklepios Biopharmaceutical, acquired by Bayer, the study has enrolled seven adults with confirmed LOPD.

Potential participants underwent a screening process to determine whether they met the trial’s eligibility criteria. This included the ability to walk at least 100 meters (about 110 yards) on the six-minute walking test (assistive devices permitted), being treated with ERT for at least two years before screening, and lung function below the expected normal range.

Researchers describe screening process

In this report, researchers at Duke described the screening process used for the Phase 1/2 trial (NCT03285126), which included 19 adults. All individuals carried a well-described GAA mutation associated with LOPD, called c.-32-13T>G, in one gene copy as well as another GAA mutation in the second gene copy (one from each parent).

Blood tests identified eight individuals without detectable pre-existing antibodies against the AAV8 virus delivery vector, while six participants were weakly positive for these antibodies and could be considered for enrollment.

“Neutralizing antibodies against AAV8 inhibit transduction of the liver and are a critical laboratory assay in determining who is more likely to experience a clinical benefit from an AAV gene therapy trial,” the team wrote.

Higher levels of these antibodies, which were found in five (26%) of the screened patients, “raises the need to consider future studies with immunosuppressive therapy, or other strategies, to deplete anti-AAV antibodies in individuals with Pompe disease to make AAV vector-mediated gene therapy available to them,” they added.

The distance walked in six minutes varied significantly between patients, ranging from 24% to 91% of the expected distance. The average distance was 60 meters (about 65 yards).

Upright FVC percent predicted, the measure of lung function, also varied considerably, ranging from 35% to 91% predicted, with an average of 66%.

‘Significant variability’ in disease severity

“It is clear that the participants screened had significant variability in clinical severity,” the researchers wrote. They suggested this may be due to the second GAA mutation, age, and/or the presence of antibodies against previous ERT.

All but one of the participants had normal levels of alanine aminotransferase (ALT), a marker for liver injury. Gamma-glutamyl transferase (GGT), a marker for hepatitis, or liver inflammation, was normal in all patients except for another patient. Creatine kinase, a marker for muscle damage, also was normal in all participants.

Researchers noted that markers for liver injury, such as ALT, may be elevated due to muscle damage in Pompe disease, “which could complicate the use of ALT as a marker of AAV-related hepatitis to indicate the need for immunosuppression.” They added that prior ERT normalized ALT levels for patients undergoing screening in this study, “therefore monitoring for hepatitis will be possible in a phase I clinical trial of gene therapy.”

“This paper highlights lessons learned from the screening data for a phase I clinical trial of AAV-mediated gene therapy collected from 19 individuals with LOPD,” the authors wrote.

“Determining the best parameters to measure efficacy of intervention and overcoming immune phenomena,” they added, “are problems that are broadly relevant as AAV vector-mediated gene therapy will likely be developed as a new therapeutic modality for multiple inborn errors of metabolism.”