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      BAX 335 hemophilia B gene therapy clinical trial results: potential impact of CpG sequences on gene expression

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          Abstract

          Gene therapy has the potential to maintain therapeutic blood clotting factor IX (FIX) levels in patients with hemophilia B by delivering a functional human F9 gene into liver cells. This phase 1/2, open-label dose-escalation study investigated BAX 335 (AskBio009, AAV8.sc-TTR-FIXR338Lopt), an adeno-associated virus serotype 8 (AAV8)–based FIX Padua gene therapy, in patients with hemophilia B. This report focuses on 12-month interim analyses of safety, pharmacokinetic variables, effects on FIX activity, and immune responses for dosed participants. Eight adult male participants (aged 20-69 years; range FIX activity, 0.5% to 2.0%) received 1 of 3 BAX 335 IV doses: 2.0 × 1011; 1.0 × 1012; or 3.0 × 1012 vector genomes/kg. Three (37.5%) participants had 4 serious adverse events, all considered unrelated to BAX 335. No serious adverse event led to death. No clinical thrombosis, inhibitors, or other FIX Padua–directed immunity was reported. FIX expression was measurable in 7 of 8 participants; peak FIX activity displayed dose dependence (32.0% to 58.5% in cohort 3). One participant achieved sustained therapeutic FIX activity of ∼20%, without bleeding or replacement therapy, for 4 years; in others, FIX activity was not sustained beyond 5 to 11 weeks. In contrast to some previous studies, corticosteroid treatment did not stabilize FIX activity loss. We hypothesize that the loss of transgene expression could have been caused by stimulation of innate immune responses, including CpG oligodeoxynucleotides introduced into the BAX 335 coding sequence by codon optimization. This trial was registered at www.clinicaltrials.gov as #NCT01687608.

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          A general framework for estimating the relative pathogenicity of human genetic variants

          Our capacity to sequence human genomes has exceeded our ability to interpret genetic variation. Current genomic annotations tend to exploit a single information type (e.g. conservation) and/or are restricted in scope (e.g. to missense changes). Here, we describe Combined Annotation Dependent Depletion (CADD), a framework that objectively integrates many diverse annotations into a single, quantitative score. We implement CADD as a support vector machine trained to differentiate 14.7 million high-frequency human derived alleles from 14.7 million simulated variants. We pre-compute “C-scores” for all 8.6 billion possible human single nucleotide variants and enable scoring of short insertions/deletions. C-scores correlate with allelic diversity, annotations of functionality, pathogenicity, disease severity, experimentally measured regulatory effects, and complex trait associations, and highly rank known pathogenic variants within individual genomes. The ability of CADD to prioritize functional, deleterious, and pathogenic variants across many functional categories, effect sizes and genetic architectures is unmatched by any current annotation.
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            Control of adaptive immunity by the innate immune system.

            Microbial infections are recognized by the innate immune system both to elicit immediate defense and to generate long-lasting adaptive immunity. To detect and respond to vastly different groups of pathogens, the innate immune system uses several recognition systems that rely on sensing common structural and functional features associated with different classes of microorganisms. These recognition systems determine microbial location, viability, replication and pathogenicity. Detection of these features by recognition pathways of the innate immune system is translated into different classes of effector responses though specialized populations of dendritic cells. Multiple mechanisms for the induction of immune responses are variations on a common design principle wherein the cells that sense infections produce one set of cytokines to induce lymphocytes to produce another set of cytokines, which in turn activate effector responses. Here we discuss these emerging principles of innate control of adaptive immunity.
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              Guidelines for the management of hemophilia.

              Hemophilia is a rare disorder that is complex to diagnose and to manage. These evidence-based guidelines offer practical recommendations on the diagnosis and general management of hemophilia, as well as the management of complications including musculoskeletal issues, inhibitors, and transfusion-transmitted infections. By compiling these guidelines, the World Federation of Hemophilia aims to assist healthcare providers seeking to initiate and/or maintain hemophilia care programs, encourage practice harmonization around the world and, where recommendations lack adequate evidence, stimulate appropriate studies. © 2012 Blackwell Publishing Ltd.
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                Author and article information

                Contributors
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                Journal
                Blood
                American Society of Hematology
                0006-4971
                1528-0020
                February 11 2021
                February 11 2021
                : 137
                : 6
                : 763-774
                Affiliations
                [1 ]BloodWorks Northwest, Seattle, WA;
                [2 ]Division of Hematology, University of Washington School of Medicine, Seattle, WA;
                [3 ]Icahn School of Medicine at Mount Sinai, New York, NY;
                [4 ]McGovern Medical School and Gulf States Hemophilia and Thrombophilia Center, University of Texas Health Science Center Houston Medical School, Houston, TX;
                [5 ]Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA;
                [6 ]Hemophilia and Thrombosis Treatment Center, University of California, San Diego, CA;
                [7 ]Asklepios BioPharmaceutical and Chatham Therapeutics, Chapel Hill, NC;
                [8 ]Gene Therapy Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC;
                [9 ]Baxalta Innovations GmbH, a member of the Takeda group of companies, Vienna, Austria; and
                [10 ]Baxalta US Inc., a member of the Takeda group of companies, Cambridge, MA
                Article
                10.1182/blood.2019004625
                33067633
                251eb56d-eba0-4fe6-8dd4-fbc3868ee6d5
                © 2021
                History

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