Terence R. Flotte, MD
Data demonstrating sustained protein expression five years after a single intramuscular injection of a gene-based therapy for the treatment of alpha-1 antitrypsin (AAT) deficiency also shows improvements in multiple indicators of AAT biological activity. The study appears in the June issue of Molecular Therapy. Applied Genetic Technologies Corporation (AGTC), a clinical stage biopharmaceutical company, developed the gene-based therapy evaluated in the study, which was led by Terence R. Flotte, MD, the Celia and Isaac Haidak Professor of Medical Education, executive deputy chancellor, provost and dean of the School of Medicine, and colleagues at UMass Medical School.
AAT deficiency is an inherited genetic defect that results in severe loss of lung function. The study describes five-year follow-up results of a one-time intramuscular injection of a recombinant adeno-associated virus (AAV)-AAT vector in patients with AAT deficiency who had participated in a Phase 2a trial and had not received subsequent AAT protein therapy.
Key findings from the study include:
“This is the first publication to demonstrate multi-year persistence of recombinant AAV expression in gene therapy trial participants without immune suppression or corticosteroid therapy,” Dr. Flotte said. “We also observed specific regulatory T-cell responses directed against AAV1 capsid proteins, and believe that these responses may help the immune system become tolerant to AAV1. This would be beneficial in enabling the development of AAV-based therapies for AAT deficiency that provide durable responses following a single administration and may also allow for repeat dosing regimens with potential to improve long-term outcomes for patients with AAT deficiency.”
The authors conclude that stable levels of serum AAT achieved in this study over five years may have beneficial clinical effects, despite being below the threshold of what is traditionally considered therapeutic. They hypothesize that continuous expression at a lower level may provide greater clinical benefit compared with levels that fluctuate drastically, as is observed with current AAT replacement therapy.
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