The data, “Combination of a Novel Chimeric AAV Capsid and Potency Enhanced FIX Variant for Hemophilia B Gene Therapy,” were presented recently at the World Federation of Hemophilia Virtual Summit.
Hemophilia B is caused by lack of, or defective, FIX, a blood clotting protein, owing to mutations in the F9 gene. The idea behind gene therapy for hemophilia B is to deliver a non-mutated copy of the gene to patients’ cells to enable production of functional FIX. Engineered adeno-associated viruses (AAVs) are a common type of virus used for gene therapies, due to their safety and efficiency in introducing genes into cells.
Of particular interest is a gene version called the Padua variant, which provides instructions for making a FIX protein with abnormally high activity. A high-activity protein is an advantage in gene therapy because it allows for lower viral doses to achieve the same effect.
CB 2679d-GT delivers a different version of the F9 gene that was modified by researchers at Catalyst to create a highly active protein. The potential treatment uses a novel viral capsid, or outer shell, to enable greater FIX production in liver cells, resulting in less liver damage, lower manufacturing costs, and reduced ability of inducing an immune response compared to other approaches.
The new data include a direct comparison between CB 2679d-GT and the Padua variant in a mouse model of hemophilia B. Relative to the same dose of the Padua variant, CB 2679d-GT provided a fourfold reduction in blood loss and an eight times decrease in bleeding time.
Experiments in mice also showed that CB 2679d-GT could increase levels of FIX consistently for 18 weeks.
In primates, CB 2679d-GT had a superior response to pre-existing neutralizing antibodies compared to a different viral capsid, known as LK03. Neutralizing antibodies may block viruses from delivering genes into cells, rendering treatments ineffective.
Also in primates, CB 2679d-GT was well-tolerated, and increased FIX levels to between 25–50% above pre-treatment levels for at least six weeks.
“The preclinical data from our constructs demonstrated a strong dose response and improved reduction in bleeding relative to the Padua variant,” Nassim Usman, PhD, president and CEO of Catalyst, said in a press release. “The enhanced FIX activity and reduced viral dose may offer advantages over current AAV-based gene therapies in clinical development.”
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