Gene Therapy for Hemophilia A (GO-8 Trial)
Recruiting in Palo Alto (17 mi)
+3 other locations
Age: 18+
Sex: Male
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Waitlist Available
Sponsor: University College, London
No Placebo Group
Trial Summary
What is the purpose of this trial?This trial tests a gene therapy that uses a harmless virus to deliver a healthy gene to adults with severe haemophilia A. The goal is to help their bodies produce a missing blood-clotting protein, potentially curing their condition. Gene therapy for hemophilia has been explored for many years, with several programs in advanced stages.
Do I need to stop my current medications for the trial?
The trial protocol does not specify if you need to stop your current medications. However, you cannot have used investigational therapy for hemophilia within 30 days before enrollment, and you cannot be on antiviral therapy for hepatitis B or C. It's best to discuss your specific medications with the trial team.
What data supports the idea that Gene Therapy for Hemophilia A is an effective treatment?
The available research shows that Gene Therapy for Hemophilia A, specifically using the AAV8 vector, is highly effective. In a study with hemophilia A mice, AAV8 achieved 100% correction of the blood clotting issue, regardless of how it was administered. This suggests that the therapy can fully restore the necessary blood clotting factor. Compared to traditional treatments, which require frequent and costly infusions, gene therapy offers a promising alternative by potentially providing a long-term solution with fewer treatments.
12345What safety data is available for the gene therapy treatment for Hemophilia A?
The safety data for the gene therapy treatment using AAV8 vectors in Hemophilia A shows promising results. Studies have demonstrated long-term efficacy and safety in both mice and dogs, with therapeutic levels of Factor VIII achieved without antibody formation or other toxicities for more than 3 years. In rhesus macaques, AAV8 vectors were well tolerated with only mild liver-related histopathology and transient elevations in transaminases. These findings support the safety of AAV8-based gene therapy for Hemophilia A.
23678Is the treatment AAV2/8-HLP-FVIII-V3 a promising treatment for Hemophilia A?
Yes, AAV2/8-HLP-FVIII-V3 is a promising treatment for Hemophilia A. Research shows that using AAV8, a type of virus used to deliver the gene therapy, can fully correct the blood clotting issue in mice with Hemophilia A. This suggests that the treatment could potentially reduce the need for expensive and frequent protein replacement therapies, making it a more accessible and long-term solution for patients.
2391011Eligibility Criteria
Adult males over 18 with severe Hemophilia A, who have used hFVIII concentrates for more than 50 days and suffer from frequent bleeding or joint damage due to bleeding. Participants must be able to follow the trial procedures for five years and use barrier contraception post-treatment until semen tests confirm safety.Inclusion Criteria
I am a man over 18 with severe hemophilia A due to low-risk gene mutations.
I have a severe bleeding disorder with frequent bleeding episodes or joint damage due to bleeding.
I have been treated with hFVIII for over 50 days.
Exclusion Criteria
My liver tests show higher than normal levels.
My health limits my daily activities significantly.
I have severe haemophilia A with specific genetic changes.
I do not have uncontrolled heart failure or unstable chest pain.
I have had tuberculosis, fungal disease, or another long-term infection.
I do not have uncontrolled glaucoma, diabetes, or high blood pressure.
My liver ultrasound showed a possible cancer sign.
I have active hepatitis B or C, or I am on antiviral therapy for it.
Participant Groups
The GO-8 study is testing a gene therapy called AAV2/8-HLP-FVIII-V3 in men with severe Hemophilia A. It aims to evaluate how safe and effective this treatment is over time.
1Treatment groups
Experimental Treatment
Group I: Treatment ArmExperimental Treatment1 Intervention
Treatment with AAV2/8-HLP-FVIII-V3
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
St. Luke'S Regional Medical Center, LtdBoise, ID
St Jude's Children's Research HospitalMemphis, TN
University of KentuckyLexington, KY
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Who is running the clinical trial?
University College, LondonLead Sponsor
Medical Research CouncilCollaborator
References
FIX It in One Go: Enhanced Factor IX Gene Therapy for Hemophilia B. [2019]A phase 1/2 clinical trial of AAV-mediated gene therapy in patients with hemophilia B using an enhanced specific activity factor IX (FIX) transgene reports sustained levels of FIX levels, leading to the near elimination of bleeding for more than a year and without serious adverse side effects. These results are the best outcome to date for hemophilia gene therapy.
Total correction of hemophilia A mice with canine FVIII using an AAV 8 serotype. [2021]Despite the popularity of adeno-associated virus 2 (AAV2) as a vehicle for gene transfer, its efficacy for liver-directed gene therapy in hemophilia A or B has been suboptimal. Here we evaluated AAV serotypes 2, 5, 7, and 8 in gene therapy of factor VIII (FVIII) deficiency in a hemophilia A mouse model and found that AAV8 was superior to the other 3 serotypes. We expressed canine B domain-deleted FVIII cDNA either in a single vector or in 2 separate AAV vectors containing the heavy- and light-chain cDNAs. We also evaluated AAV8 against AAV2 in intraportal and tail vein injections. AAV8 gave 100% correction of plasma FVIII activity irrespective of the vector type or route of administration.
The treatment of hemophilia A: from protein replacement to AAV-mediated gene therapy. [2012]Factor VIII (FVIII) is an essential component in blood coagulation, a deficiency of which causes the serious bleeding disorder hemophilia A. Recently, with the development of purification level and recombinant techniques, protein replacement treatment to hemophiliacs is relatively safe and can prolong their life expectancy. However, because of the possibility of unknown contaminants in plasma-derived FVIII and recombinant FVIII, and high cost for hemophiliacs to use these products, gene therapy for hemophilia A is an attractive alternative to protein replacement therapy. Thus far, the adeno-associated virus (AAV) is a promising vector for gene therapy. Further improvement of the virus for clinical application depends on better understanding of the molecular structure and fate of the vector genome. It is likely that hemophilia will be the first genetic disease to be cured by somatic cell gene therapy.
Adenovirus-associated antibodies in UK cohort of hemophilia patients: A seroprevalence study of the presence of adenovirus-associated virus vector-serotypes AAV5 and AAV8 neutralizing activity and antibodies in patients with hemophilia A. [2023]Current treatment for severe hemophilia A is replacement of deficient factor. Although replacement therapy has improved life expectancy and quality, limitations include frequent infusions and high costs. Gene therapy is a potential alternative that utilizes an adeno-associated virus (AAV) vector containing the human genetic code for factor 8 (FVIII) that transduces the liver, enabling endogenous production of FVIII. Individuals with preexisting immunity to AAV serotypes may be less likely to benefit from this treatment.
Bioengineered coagulation factor VIII enables long-term correction of murine hemophilia A following liver-directed adeno-associated viral vector delivery. [2020]Clinical data support the feasibility and safety of adeno-associated viral (AAV) vectors in gene therapy applications. Despite several clinical trials of AAV-based gene transfer for hemophilia B, a unique set of obstacles impede the development of a similar approach for hemophilia A. These include (i) the size of the factor VIII (fVIII) transgene, (ii) humoral immune responses to fVIII, (iii) inefficient biosynthesis of human fVIII, and (iv) AAV vector immunity. Through bioengineering approaches, a novel fVIII molecule, designated ET3, was developed and shown to improve biosynthetic efficiency 10- to 100-fold. In this study, the utility of ET3 was assessed in the context of liver-directed, AAV-mediated gene transfer into hemophilia A mice. Due to the large size of the expression cassette, AAV-ET3 genomes packaged into viral particles as partial genome fragments. Despite this potential limitation, a single peripheral vein administration of AAV-ET3 into immune-competent hemophilia A mice resulted in correction of the fVIII deficiency at lower vector doses than previously reported for similarly oversized AAV-fVIII vectors. Therefore, ET3 appears to improve vector potency and mitigate at least one of the critical barriers to AAV-based clinical gene therapy for hemophilia A.
Multiyear therapeutic benefit of AAV serotypes 2, 6, and 8 delivering factor VIII to hemophilia A mice and dogs. [2022]Hemophilia A, a deficiency of functional coagulation factor VIII (FVIII), is treated via protein replacement therapy. Restoring 1% to 5% of normal blood FVIII activity prevents spontaneous bleeding, making the disease an attractive gene therapy target. Previously, we have demonstrated short-term activity of a liver-specific AAV2 vector expressing canine B-domain-deleted FVIII (cFVIII) in a hemophilia canine model. Here, we report the long-term efficacy and safety of AAV-cFVIII vectors of serotypes 2, 5, 6, and 8 in both hemophilia A mice and dogs. AAV6-cFVIII and AAV8-cFVIII restored physiologic levels of plasma FVIII activity in hemophilia A mice. The improved efficacy is attributed to more efficient gene transfer in liver compared with AAV2 and AAV5. However, supraphysiologic cFVIII levels correlated with the formation of cFVIII-neutralizing antibodies in these mice. Of importance, hemophilia A dogs that received AAV2-cFVIII, AAV6-cFVIII, and AAV8-cFVIII have persistently expressed therapeutic levels of FVIII, without antibody formation or other toxicities, for more than 3 years. However, liver transduction efficiencies are similar between AAV2, AAV6, and AAV8 serotypes in hemophilia A dogs, in contrast to mice. In summary, this is the first report demonstrating multiyear therapeutic efficacy and safety of multiple AAV-cFVIII vectors in hemophilia A dogs and provides the basis for human clinical studies.
Non-Clinical Study Examining AAV8.TBG.hLDLR Vector-Associated Toxicity in Chow-Fed Wild-Type and LDLR+/- Rhesus Macaques. [2018]Vectors based on adeno-associated virus serotype 8 (AAV8) have been evaluated in several clinical trials of gene therapy for hemophilia B with encouraging results. In preparation for a Phase 1 clinical trial of AAV8 gene therapy for the treatment of homozygous familial hypercholesterolemia (HoFH), the safety of the clinical candidate vector, AAV8.TBG.hLDLR, was evaluated in wild-type rhesus macaques and macaques heterozygous for a nonsense mutation in the low-density lipoprotein receptor (LDLR) gene (LDLR+/-). Intravenous infusion of 1.25 × 1013 GC/kg of AAV8.TBG.hLDLR expressing the human version of LDLR was well tolerated and associated with only mild histopathology that was restricted to the liver and sporadic, low-level, and transient elevations in transaminases. Some animals developed T cells to both capsid and the hLDLR transgene, although these adaptive immune responses were most evident at the early time points from peripheral blood and in mononuclear cells derived from the liver. This toxicology study supports the safety of AAV8.TBG.hLDLR for evaluation in HoFH patients, and provides some context for evaluating previously conducted clinical trials of AAV8 in patients with hemophilia.
Adeno-associated virus-mediated expression of activated factor V (FVa) for hemophilia phenotypic correction. [2022]Adeno-associated virus (AAV) gene therapy has been successfully applied in hemophilia patients excluding patients with inhibitors. During the coagulation pathway, activated factor V (FVa) functions downstream as a cofactor of activated factor X (FXa) to amplify thrombin generation. We hypothesize that the expression of FVa via gene therapy can improve hemostasis of both factor IX and FVIII deficiencies, regardless of clotting factor inhibitor. A human FVa (hFVa) expression cassette was constructed, and AAV8 vectors encoding hFVa (AAV8/TTR-hFVa) were intravenously administrated into mice with hemophilia A and B with or without FVIII inhibitors. Hemostasis, including hFVa level, activated partial thromboplastin time (aPTT), tail clip, and the saphenous vein bleeding assay (SVBA), was evaluated. In hemophilia B mice, a dose of 4 × 1013 vg/kg AAV8/TTR-hFVa vectors achieved a complete phenotypic correction over 28 weeks. In hemophilia A mice, hemostasis improvement was also achieved, regardless of FVIII inhibitor development. In vivo hemostasis efficacy was confirmed by tail clip and SVBA. Interestingly, while minimal shortening of aPTT was observed at a lower dose of AAV8 vectors, hemostasis improvement was still achieved via in vivo bleeding assays. Collectively, FVa-based AAV gene therapy shows promise for hemostasis correction in hemophilia, regardless of inhibitor development and no potential risk for thrombosis.
Advancements in gene transfer-based therapy for hemophilia A. [2021]Gene therapy has promised clinical benefit to those suffering with hemophilia A, but this benefit has not yet been realized. However, during the past two decades, basic and applied gene therapy research has progressed and the goal of gene therapy for hemophilia A is once again in our sights. The hemophilia A patient population suffers from a disease that requires invasive, lifelong management, is exorbitantly expensive to treat, has geographically limited treatment access and can become untreatable due to immune reactions to the treatment product. Subsequent to the cloning of the factor VIII gene and cDNA in the early 1980s, academic and commercial research laboratories began to pursue gene transfer-based therapies to supplement or supplant the available protein replacement therapy. However, to date, clinical trials for gene therapy of hemophilia A have been unsuccessful. Three trials have been conducted with each having tested a different gene-transfer strategy and each demonstrating that there is a considerable barrier to achieving sustained expression of therapeutic amounts of factor VIII. Recent progress has been made in gene-transfer technology and, relevant to hemophilia A, towards increasing the biosynthetic efficiency of factor VIII. These advances are now being combined to develop novel strategies to treat and possibly cure hemophilia A.
Adenovirus-mediated factor VIII gene expression results in attenuated anti-factor VIII-specific immunity in hemophilia A mice compared with factor VIII protein infusion. [2012]Hemophilia A patients are typically treated by factor VIII (FVIII) protein replacement, an expensive therapy that induces FVIII-specific inhibitors in approximately 30% of patients with severe hemophilia. FVIII gene therapy has the potential to improve the current treatment protocols. In this report, we used a hemophilia A mouse model to compare the humoral and cellular immune responses between an E1/E2a/E3-deficient adenovirus expressing human FVIII directed by a liver-specific albumin promoter and purified recombinant FVIII protein infusion. Adenovirus-mediated FVIII expression did not elicit detectable CD4+ or CD8+ T cell responses and induced a weak antibody immune response to FVIII. In contrast, FVIII protein administration resulted in a potent anti-FVIII antibody response and moderate CD4+ T cell response. Furthermore, hemophiliac mice preimmunized with FVIII protein infusion to induce anti-FVIII immunity, and subsequently treated by adenovirus-mediated FVIII gene therapy, expressed therapeutic levels of FVIII despite the presence of low levels of anti-FVIII antibodies. No FVIII was detected in the plasma of mice with intermediate or high antibody levels, although anti-FVIII antibody levels in some vector-treated animals declined. The data support the hypothesis that liver-specific gene therapy-mediated expression of FVIII may be less immunogenic than traditional protein replacement therapy.
Comparison of platelet-derived and plasma factor VIII efficacy using a novel native whole blood thrombin generation assay. [2023]We have recently developed a successful gene therapy approach for hemophilia A in which factor VIII (FVIII) expression is targeted to platelets by the αIIb promoter. Levels of platelet-expressed FVIII (2bF8) achieved by gene therapy may vary between individuals due to differences in ex vivo transduction and gene expression efficiency. Accurate assays to evaluate 2bF8 efficacy are desirable.