Rational Engineering and Preclinical Evaluation of Neddylation and SUMOylation Site Modified Adeno-Associated Virus Vectors in Murine Models of Hemophilia B and Leber Congenital Amaurosis

Human Gene Therapy, Ahead of Print.
Source: Human Gene Therapy - Category: Genetics & Stem Cells Authors: Source Type: research

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We report the generation of an AAV transgene cassette containing the hyperfunctional hFIX-E456H variant showing improved binding to platelets, with a comparison to wild-type hFIX (hFIX-WT) and hFIX-R384L variant (Padua) transgenes, containing F9 truncated-intron 1 (I1). In vitro specific activity was increased by 3.2- and 4.2-fold with hFIX-E456H and hFIX-R384L variants compared with hFIX-WT, using chromogenic assay, and by 7-and 8.6-fold with hFIX-E456H and hFIX-R384L variants compared with hFIX-WT, using one-stage assay. The transgenes were packaged into single-stranded AAV2/8 vectors that were tail vein injected at 5&th...
Source: Thrombosis and Haemostasis - Category: Hematology Authors: Tags: Thromb Haemost Source Type: research
Many genetic diseases, including hemophilia, require long-term therapeutic effects. Despite the initial success of liver-directed adeno-associated virus (AAV) gene therapy for hemophilia in clinical trials, long-term sustained therapeutic effects have yet to be seen. One explanation for the gradual decline of efficacy over time is that the nonintegrating AAV vector genome could be lost during cell division during hepatocyte turnover, albeit at a slow pace in adults. Readministering the same vector is challenging as a result of the AAV-neutralizing antibodies elicited by the initial treatment. Here, we investigated the use ...
Source: Blood - Category: Hematology Authors: Tags: Thrombosis and Hemostasis, Gene Therapy Source Type: research
Semin Thromb Hemost DOI: 10.1055/s-0039-1688445Hemophilia is a monogenic disease with robust clinicolaboratory correlations of severity. These attributes coupled with the availability of experimental animal models have made it an attractive model for gene therapy. The road from animal models to human clinical studies has heralded significant successes, but major issues concerning a previous immunity against adeno-associated virus and transgene optimization remain to be fully resolved. Despite significant advances in gene therapy application, many questions remain pertaining to its use in specific populations such as those ...
Source: Seminars in Thrombosis and Hemostasis - Category: Hematology Authors: Tags: Review Article Source Type: research
Reena Goswami1, Gayatri Subramanian2, Liliya Silayeva1, Isabelle Newkirk1, Deborah Doctor1, Karan Chawla2, Saurabh Chattopadhyay2, Dhyan Chandra3, Nageswararao Chilukuri1 and Venkaiah Betapudi1,4* 1Neuroscience Branch, Research Division, United States Army Medical Research Institute of Chemical Defense, Aberdeen, MD, United States 2Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States 3Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States 4Department of Physiology and Biophysics, Case Western Reserve University, Clev...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Abstract Genetic diseases affecting proteins and cells composing the blood may be treated by gene therapy using gene addition or gene editing methods. Protein deficiencies (e.g. hemophilia) are being approached using in vivo gene delivery by adeno-associated virus (AAV) vectors for therapeutic gene addition or gene editing. Blood cell diseases (e.g. sickle cell disease) are being approached using ex vivo gene addition or gene editing to treat isolated blood-forming hematopoietic stem cells or T cells that are then re-transplanted. In recent years, there has been much progress, and gene therapy is now routinely pro...
Source: Current Opinion in Biotechnology - Category: Biotechnology Authors: Tags: Curr Opin Biotechnol Source Type: research
Conclusions: Current treatments have reduced life-threatening bleeds, chronic joint disease and disability; however, people with haemophilia B continue to have significantly decreased quality of life. This study has shown a single infusion of low dose FLT180a leads to FIX levels of>40%, greatly reducing the risk of spontaneous or traumatic bleeds and raises the prospect of achieving a functional cure by normalising FIX levels with a higher dose. This will reduce the risk of life-threatening bleeds following trauma and surgery, transform quality of life and thus represents a major therapeutic advance for people with haem...
Source: Blood - Category: Hematology Authors: Tags: 322. Disorders of Coagulation or Fibrinolysis: Hemophilia: Emerging Therapies Source Type: research
Introduction: AMT-060 consists of an adeno-associated virus serotype 5 (AAV5) vector containing a codon-optimized wildtype human factor IX (FIX) gene under control of a liver-specific promoter. We have previously reported on the safety and efficacy of AMT-060 gene therapy at 2 dose levels in adults with moderate-severe or severe hemophilia B with up to 1-year follow-up. Here we present longer-term follow-up data on reductions in annualized bleed rates and FIX consumption up to 2.5 years post-treatment.Methods: Multi-national, open-label, dose-escalating study in participants (pts) with FIX activity ≤2 % of normal, and a...
Source: Blood - Category: Hematology Authors: Tags: 801. Gene Therapy and Transfer: Poster II Source Type: research
CONCLUSIONS: Gene therapy has the potential to fundamentally alter the management of hemophilia. This educational activity identified clear deficits about - and attitudes toward - gene therapy among healthcare providers who currently care for patients with hemophilia. Furthermore, the great majority of healthcare providers lacked confidence in their understanding of gene therapy for hemophilia A. These findings will be used to inform the development of educational programs and to prepare providers for anticipated changes to the hemophilia treatment landscape.DisclosuresPasi: Catalyst Bio: Honoraria; Octapharma: Honoraria; ...
Source: Blood - Category: Hematology Authors: Tags: 801. Gene Therapy and Transfer: Poster II Source Type: research
Factor IX (FIX) Padua (R338L) has been described as a game changer for hemophilia B (HB) gene therapy. The ~8-fold increased specific activity compared to wild-type FIX (FIX WT) in aPTT-based clotting assay has recently allowed for a lowering of adeno-associated virus (AAV) vector dose compared to earlier gene therapy trials using FIX WT, while still achieving sustained near-curative FIX activity levels. The lowered AAV vector dose mitigated the vector dose-dependent hepatotoxicity, which had remained a major safety and efficacy limitation for AAV gene therapy. To date, at least 2 pivotal phase III gene therapy trials for ...
Source: Blood - Category: Hematology Authors: Tags: 801. Gene Therapy and Transfer: Poster II Source Type: research
Conclusions: The results from this ongoing international epidemiology study demonstrate that the prevalence of preexisting cell-mediated immunity to AAV8 resulting from natural exposure to wild-type AAV is approximately 1 in 4 adult males with severe hemophilia A or B. Furthermore, there appears to be a correlation between cell-mediated and humoral immune responses, as two thirds of patients with positive AAV8-specific ELISPOT results also tested positive for AAV8 NAbs. Understanding the relationship between cell-mediated and humoral immunity and how it may affect an individual's response to AAV-based gene therapy will be ...
Source: Blood - Category: Hematology Authors: Tags: 801. Gene Therapy and Transfer Source Type: research
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