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 Addressing the big business of fake science(Elsevier, 2022) Frederickson, Robert M.; Herzog, Roland W.; Pediatrics, School of MedicineItem Adeno-Associated Virus 8 and 9 Myofibre Type/Size Tropism Profiling Reveals Therapeutic Effect of Microdystrophin in Canines(Wiley, 2025) Burke, Matthew J.; Blatt, Braiden M.; Teixeira, James A.; Pérez-López, Dennis O.; Yue, Yongping; Pan, Xiufang; Hakim, Chady H.; Yao, Gang; Herzog, Roland W.; Duan, Dongsheng; Pediatrics, School of MedicineBackground: Adeno-associated virus (AAV) 8 and 9 are in clinical trials for treating neuromuscular diseases such as Duchenne muscular dystrophy (DMD). Muscle consists of myofibres of different types and sizes. However, little is known about the fibre type and fibre size tropism of AAV in large mammals. Methods: We evaluated fibre type- and size-specific transduction properties of AAV8 and AAV9 in 17 dogs that received systemic gene transfer (dose 1.94 ± 0.52 × 1014 vg/kg; injected at 2.86 ± 0.30 months; harvested at 20.79 ± 3.30 months). For AAV8, two DMD dogs and three carrier dogs received an alkaline phosphatase (AP) reporter vector, and five DMD dogs received a four-repeat microdystrophin (uDys) vector. For AAV9, one normal and one DMD dog received the AP vector, and five DMD dogs received a five-repeat uDys vector. Association between AAV transduction and the fibre type/size was studied in three muscles that showed mosaic transgene expression, including the biceps femoris, teres major and latissimus dorsi. Results: Transgene expression was detected in 30%-45% of myofibres. In the AP reporter vector-injected dogs, neither AAV8 nor AAV9 showed a statistically significant fibre type preference. Interestingly, AP expression was enriched in smaller fibres. In uDys-treated DMD dogs, slow and fast myofibres were equally transduced. Notably, uDys-expressing myofibres were significantly larger than uDys-negative myofibres irrespective of the AAV serotype (p < 0.0001). In AAV8 uDys vector-injected dogs, the mini-Feret diameter was 15%, 16% and 23% larger in uDys-positive slow, fast and hybrid fibres, respectively; the cross-sectional area was 30%, 34% and 46% larger in uDys-positive slow, fast and hybrid fibres, respectively. In AAV9 uDys vector-injected dogs, the mini-Feret diameter was 12%, 13% and 25% larger in uDys-positive slow, fast and hybrid fibres, respectively; the cross-sectional area was 25%, 28% and 59% larger in uDys-positive slow, fast and hybrid fibres, respectively. Conclusions: Our studies suggest that AAV8 and AAV9 transduce fast and slow myofibres at equivalent efficiency. Importantly, uDys therapy effectively prevented dystrophic myofibre atrophy. Our study provides important insight into systemic muscle AAV delivery in large mammals and supports further development of uDys gene therapy for DMD.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 Medicine