Lower-dose gene therapy effective in severe hemophilia A: Study
Single dose of GS001 safely boosts Factor VIII levels for 3 years
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A single infusion of the experimental gene therapy GS001 safely increased the levels of factor VIII (FVIII) — the missing clotting protein in hemophilia A — for almost three years, effectively reducing bleeds and the need for replacement therapies at doses much lower than those used in currently approved gene therapies for the bleeding disorder.
Those findings come from a Phase 1 pilot study (NCT04728841) that evaluated the safety, tolerability, and biological activity of GS001 at one of two doses in 12 men with severe hemophilia A. Because gene therapy may trigger immune responses that hinder treatment effectiveness, participants received immunosuppressive medications before treatment.
“GS001 infusion was safe and well-tolerated, achieving a significant increase in factor VIII level,” the researchers wrote. They added that preventive treatment to suppress “induced immune responses” may enhance treatment effectiveness “without increasing the risk of infection.”
The study, “Phase 1 pilot study for hemophilia-A: AAV8 vector with prophylactic tacrolimus-glucocorticoid achieves therapeutic FVIII activity,” was published in Signal Transduction and Targeted Therapy.
Hemophilia A is caused by mutations in the F8 gene that lead to a deficiency of FVIII. Without enough working FVIII, blood doesn’t clot properly, leading to unusually easy and prolonged bleeding episodes.
Challenges of gene therapy
Standard hemophilia treatment involves preventive (prophylactic) factor replacement therapy, in which a healthy version of the missing protein is infused regularly into the bloodstream to normalize its levels and prevent bleeds.
Gene therapy has been shown to be effective at reducing bleeding episodes and the need for frequent factor replacement therapy infusions. This type of therapy uses a harmless adeno-associated virus (AAV) to deliver a working copy of the missing gene directly to liver cells, enabling them to produce the clotting protein on their own.
However, immune responses against the viral delivery system or against liver cells that have taken up the therapeutic gene can significantly reduce the therapy’s effectiveness. In hemophilia A, maintaining stable, long-term FVIII production has also proven difficult, likely due to the relatively large size of the F8 gene and the complexity of the FVIII protein.
To address these challenges, researchers in China developed GS001, a gene therapy that uses an engineered AVV8 viral vector to deliver a shortened but functional version of the F8 gene, thereby enhancing gene activity and stability in liver cells.
The Phase 1 study was conducted to assess the safety and effectiveness of two doses of GS001 in men with severe hemophilia A. All 12 participants, with a mean age of 27.7, were enrolled between March 2021 and May 2023 at a single hospital in China. Nine were receiving preventive FVIII treatment before enrollment, while three were being treated on demand when bleeding occurred.
The therapy was given as a single infusion at 2 trillion vector genomes per kilogram of body weight (vg/kg) in six participants and 4 trillion vg/kg in the remaining six. Both doses are much lower than those used in approved hemophilia A gene therapies.
One week before treatment, participants received preventive immunosuppressive therapy with prednisone, with tacrolimus added to three participants in the lower-dose group and to all in the higher-dose group.
Median follow-up was 156 weeks (about 3 years) in the lower-dose group and 110.5 weeks (just over 2 years) in the higher-dose group.
FVIII levels increased within the first week and peaked about five to seven weeks after treatment. In the lower-dose group, all participants maintained FVIII levels at least consistent with moderate hemophilia after nearly three years. In the higher-dose group, after about two years, all participants maintained FVIII levels at least consistent with mild hemophilia.
Clinical outcomes also improved. In both groups, the number of bleeding episodes per year dropped sharply, and annual FVIII use decreased substantially. None of the participants in the higher-dose group required on-demand FVIII treatment for bleeding events during follow-up.
Further analyses suggested that prednisone combined with tacrolimus was more effective than prednisone alone at suppressing immune responses that could limit the therapy’s effectiveness. Tacrolimus was found to strongly suppress the activity of a specific subset of immune T-cells mostly responsible for attacking liver cells carrying the therapeutic gene.
In the lower-dose group, participants who received prednisone together with tacrolimus showed faster increases in FVIII levels during the first week after treatment and maintained higher FVIII levels over time than those who received prednisone alone.
The therapy was generally well tolerated in both dose groups. The most common treatment-related side effects were temporary increases in liver enzyme levels, which resolved with monitoring or short-term treatment and did not lead to treatment discontinuation. No serious side effects attributed to prednisone or tacrolimus were reported.
“GS001 demonstrates favorable efficacy and tolerability” in people with severe hemophilia A, the researchers wrote. The long-term durability of FVIII production beyond two years continues to be monitored in participants in the higher-dose group, they said.
