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Principal Investigator: Roland W. Herzog
Organization: INDIANA UNIVERSITY INDIANAPOLIS
Fiscal Year: 2024
Award: $2,492,072
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY ABSTRACT
Gene therapy for the X-linked bleeding disorder hemophilia holds much promise to accomplish a lasting cure.
Four clinical trials utilizing adeno-associated viral (AAV) gene transfer to the livers of males with severe
hemophilia are currently being investigated in multiple Phase III clinical trials. Hemophilia A (deficiency in factor
VIII, FVIII), the more common form of the disease (~80% of patients), has traditionally been more difficult to treat
by gene therapy because FVIII is a large molecule and not efficiently expressed and secreted. Nonetheless,
initial results demonstrated complete correction of the disease. However, FVIII levels declined substantially over
time, raising worrying questions about durability, and patients also experienced prolonged mild hepatotoxicity
despite steroid drug treatment during the first year of gene therapy. Multiple recent observations raise serious
questions about the safety of hepatic gene therapy for hemophilia A. These urgently need to be addressed so
that this promising approach can be safely applied to patients and to achieve sustained correction. For instance,
the reasons for hepatotoxicity and for the decline in FVIII expression are unclear, highlighting critical gaps in our
knowledge of the interactions between the vector and hepatocytes and between the FVIII expression and
hepatocytes, as well as the role of the immune system in long-term outcome. There is also renewed concern
about insertional mutagenesis. We will address these basic and mechanistic questions related to the biology of
AAV and FVIII. The central hypothesis of this proposal is that multiple interconnected features of AAV and FVIII
biology limit durability of therapeutic expression and pose serious safety concerns. Further, we postulate that
unraveling these mechanisms will allow for design of vectors and protocols that minimize these problems, thus
resulting in lasting therapy and enhanced safety. The program combines expertise in FVIII biology, cellular stress
responses, immunology, and AAV vector biology and is structured into 3 scientific Projects, an administrative
Core and 2 scientific Cores. Project 1 (Kaufman) seeks to overcome FVIII protein misfolding and cell toxicity.
Project 2 (Xiao) will uncover the mechanisms that lead to formation of subgenomic AAV vector particles that
form during vector production through nuclease and recombination activities. Project 3 (Herzog) will define the
mechanisms of innate and adaptive immune responses to AAV-FVIII gene transfer. The objectives of the three
projects will be supported by an administrative core (Core A), a core that provides human hepatocytes for in vitro
and in vivo studies (Core B), and a core that performs development and molecular analysis of AAV vectors (Core
C). Overall, this project applies the expertise of the individual investigators towards addressing major
unanswered questions in FVIII biology, gene therapy for hemophilia, liver-directed gene transfer, and molecular
and immunobiology of AAV vectors.
Terms: <Address><Antihemophilic Factor><Attention><Basic Research><Basic Science><Biology><Birth><Blood Coagulation Disorders><Blood Coagulation Factor><Blood Coagulation Factor VIII><Cell Body><Cells><Cellular Stress><Cellular Stress Response><Clinical Research><Clinical Study><Clinical Trials><Coagulation Disorder><Coagulation Factor VIII><Coagulation Factor VIII, Procoagulant Component><Coagulation Factor VIIIc><Coagulation Factors><Coagulopathy><Commercial Sectors><Communities><DNA><DNA Recombination><DNA Therapy><DXS1253E><Deoxyribonucleic Acid><Development><Disease><Disorder><Dose><Drug Therapy><ER stress><Elements><Event><F8 gene><F8 protein><F8B><F8C><FVIII><Factor VIII><Factor VIII Deficiency><Factor VIII F8B><Factor VIIIF8B><Food and Drug Administration><Gene Transfer><Gene Transfer Clinical><Generations><Genetic Intervention><Genetic Recombination><Genome><Goals><Grant><HEMA gene><Hemophilia><Hemophilia A><Hepatic><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Hepatotoxic effect><Hepatotoxicity><Human><Human Biology><Immune><Immune Tolerance><Immune response><Immune system><Immunes><Immunobiology><Immunologic Tolerance><Immunological response><Immunology><Immunophysiology><In Vitro><Individual><Innate Immune Response><Insertional Mutagenesis><Investigation><Investigators><Knowledge><Link><Liver><Liver Cells><Liver Toxicity><Modern Man><Molecular><Molecular Analysis><Molecular Virology><Normal Range><Normal Values><Outcome><Parturition><Patients><Pharmacotherapy><Phase 3 Clinical Trials><Phase III Clinical Trials><Position><Positioning Attribute><Probability><Procoagulant Component><Production><Proteins><Protocol><Protocols documentation><Recombination><Research Personnel><Researchers><Role><Safety><Steroid Compound><Steroids><Structure><Testing><Therapeutic><Thromboplastinogen><Time><Toxic effect><Toxic effect on liver cells><Toxicities><Transfer Factor><Transgenes><Translations><USFDA><United States Food and Drug Administration><Variant><Variation><Viral><Viral Genes><Viral Vector><aberrant protein folding><abnormal protein folding><adaptive immune response><amyloid assembly><amyloid formation><antihemophilic factor A><bleeding disorder><cell stress><clotting disorder><clotting factor><complex Blood-coagulation factor VIII><design><designing><developmental><drug treatment><endoplasmic reticulum stress><experience><gene repair therapy><gene therapy><gene-based therapy><genetic therapy><genomic therapy><hepatic body system><hepatic organ system><hepatic toxicity><hepatoxicity><host response><immune system response><immune system tolerance><immune unresponsiveness><immunological paralysis><immunoresponse><improved><in vivo><innate immune mechanisms><male><mouse model><murine model><nuclease><particle><pathologic protein folding><phase III protocol><platelet cofactor I><programs><protein misfolding><response><social role><thromboplastinogen A><transgene><translation><vector><vector genome>