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Browsing by Author "Herzog, Roland W."
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Item A novel class of self-complementary AAV vectors with multiple advantages based on cceAAV lacking mutant ITR(Elsevier, 2024-02-03) Zhang, Junping; Frabutt, Dylan A.; Chrzanowski, Matthew; Li, Ning; Miller, Lohra M.; Tian, Jiahe; Mulcrone, Patrick L.; Lam, Anh K.; Draper, Benjamin E.; Jarrold, Martin F.; Herzog, Roland W.; Xiao, Weidong; Pediatrics, School of MedicineSelf-complementary AAV vectors (scAAV) use a mutant inverted terminal repeat (mITR) for efficient packaging of complementary stranded DNA, enabling rapid transgene expression. However, inefficient resolution at the mITR leads to the packaging of monomeric or subgenomic AAV genomes. These noncanonical particles reduce transgene expression and may affect the safety of gene transfer. To address these issues, we have developed a novel class of scAAV vectors called covalently closed-end double-stranded AAV (cceAAV) that eliminate the mITR resolution step during production. Instead of using a mutant ITR, we used a 56-bp recognition sequence of protelomerase (TelN) to covalently join the top and bottom strands, allowing the vector to be generated with just a single ITR. To produce cceAAV vectors, the vector plasmid is initially digested with TelN, purified, and then subjected to a standard triple-plasmid transfection protocol followed by traditional AAV vector purification procedures. Such cceAAV vectors demonstrate yields comparable to scAAV vectors. Notably, we observed enhanced transgene expression as compared to traditional scAAV vectors. The treatment of mice with hemophilia B with cceAAV-FIX resulted in significantly enhanced long-term FIX expression. The cceAAV vectors hold several advantages over scAAV vectors, potentially leading to the development of improved human gene therapy drugs.Item AAV and hepatitis: Cause or coincidence?(Elsevier, 2022) de Jong, Ype P.; Herzog, Roland W.; Pediatrics, School of MedicineItem AAV Immunogenicity: New Answers Create New Questions(Elsevier, 2018-11-07) Shirley, Jamie L.; Herzog, Roland W.; Pediatrics, School of MedicineComment on Exposure to wild-type AAV drives distinct capsid immunity profiles in humans. [J Clin Invest. 2018]Item Adding recombinant AAVs to the cancer therapeutics mix(Elsevier, 2022-10-02) Mulcrone, Patrick L.; Herzog, Roland W.; Xiao, Weidong; Pediatrics, School of MedicineGene therapy is a powerful biological tool that is reshaping therapeutic landscapes for several diseases. Researchers are using both non-viral and viral-based gene therapy methods with success in the lab and the clinic. In the cancer biology field, gene therapies are expanding treatment options and the possibility of favorable outcomes for patients. While cellular immunotherapies and oncolytic virotherapies have paved the way in cancer treatments based on genetic engineering, recombinant adeno-associated virus (rAAV), a viral-based module, is also emerging as a potential cancer therapeutic through its malleability, specificity, and broad application to common as well as rare tumor types, tumor microenvironments, and metastatic disease. A wide range of AAV serotypes, promoters, and transgenes have been successful at reducing tumor growth and burden in preclinical studies, suggesting more groundbreaking advances using rAAVs in cancer are on the horizon.Item An Annis Mirabilis for the Molecular Therapy Journal Family(Elsevier, 2021) Frederickson, Robert M.; Herzog, Roland W.; Pediatrics, School of MedicineItem ASGCT 2021: Time to celebrate and expand(Elsevier, 2021) Herzog, Roland W.; Frederickson, Robert; Pediatrics, School of MedicineItem ASGCT 2022 – Bigger than Ever(Elsevier, 2022) Herzog, Roland W.; Pediatrics, School of MedicineItem ASGCT 2023—Gene therapy is becoming medicine(Elsevier, 2023) Herzog, Roland W.; Bricker-Anthony, Courtney; Pediatrics, School of MedicineItem ASGCT Meeting Showcases Fast-Paced Development of Gene and Cell Therapy Technologies(Elsevier, 2020-07-08) Herzog, Roland W.; Frederickson, Robert M.; Pediatrics, School of MedicineItem B cell focused transient immune suppression protocol for efficient AAV readministration to the liver(Elsevier, 2024-02-20) Rana, Jyoti; Herzog, Roland W.; Muñoz-Melero, Maite; Yamada, Kentaro; Kumar, Sandeep R. P.; Lam, Anh K.; Markusic, David M.; Duan, Dongsheng; Terhorst, Cox; Byrne, Barry J.; Corti, Manuela; Biswas, Moanaro; Pediatrics, School of MedicineAdeno-associated virus (AAV) vectors are used for correcting multiple genetic disorders. Although the goal is to achieve lifelong correction with a single vector administration, the ability to redose would enable the extension of therapy in cases in which initial gene transfer is insufficient to achieve a lasting cure, episomal vector forms are lost in growing organs of pediatric patients, or transgene expression is diminished over time. However, AAV typically induces potent and long-lasting neutralizing antibodies (NAbs) against capsid that prevents re-administration. To prevent NAb formation in hepatic AAV8 gene transfer, we developed a transient B cell-targeting protocol using a combination of monoclonal Ab therapy against CD20 (for B cell depletion) and BAFF (to slow B cell repopulation). Initiation of immunosuppression before (rather than at the time of) vector administration and prolonged anti-BAFF treatment prevented immune responses against the transgene product and abrogated prolonged IgM formation. As a result, vector re-administration after immune reconstitution was highly effective. Interestingly, re-administration before the immune system had fully recovered achieved further elevated levels of transgene expression. Finally, this immunosuppression protocol reduced Ig-mediated AAV uptake by immune cell types with implications to reduce the risk of immunotoxicities in human gene therapy with AAV.