Review
Biotechnology & Applied Microbiology
Sha Sha, Andrew J. Maloney, Georgios Katsikis, Tam N. T. Nguyen, Caleb Neufeld, Jacqueline Wolfrum, Paul W. Barone, Stacy L. Springs, Scott R. Manalis, Anthony J. Sinskey, Richard D. Braatz
Summary: The article focuses on analyzing the bottlenecks in rAAV production during cell culture, comparing differences between wild-type and recombinant systems, and proposing future directions for improvement.
BIOTECHNOLOGY ADVANCES
(2021)
Article
Multidisciplinary Sciences
Mathieu Colomb-Delsuc, Roman Raim, Christian Fiedler, Stefan Reuberger, Johannes Lengler, Rickard Nordstrom, Martin Ryner, Ioana Mihaela Folea, Barbara Kraus, Juan A. Hernandez Bort, Ida-Maria Sintorn
Summary: Although there have been significant developments in the field of gene therapy vectors, only a small number of drugs have been approved for market use. Therefore, the need for characterization methods to validate the drug development process is crucial. This study proposes an analytical method based on CryoTEM to determine the percentage of filled particles in an rAAV sample, which correlates with the potency of the drug.
Article
Nanoscience & Nanotechnology
Alicja Bienkowska-Tokarczyk, Maciej Malecki
Summary: Recombinant adeno-associated virus vectors (rAAV) are valuable as gene therapy vectors due to their nanometer size and biological characteristics. A mosaic vector, rAAV/DJ/CAG, showed efficient gene delivery to melanoma cells metastasized to the lungs, with transduction being temperature dependent. High temperatures and UV light had the most detrimental impact on transduction efficiency.
JOURNAL OF BIOMEDICAL NANOTECHNOLOGY
(2021)
Article
Biotechnology & Applied Microbiology
Min Lu, Zion Lee, Yu-Chieh Lin, Ibrahim Irfanullah, Wen Cai, Wei-Shou Hu
Summary: A synthetic biology approach was used to establish stable cell lines for recombinant adeno-associated virus (rAAV) production. Productivity of the cell lines was improved by reducing gene of interest expression, optimizing induction profiles, and alleviating capsid protein degradation, bringing it close to traditional multiple plasmid transfection.
BIOTECHNOLOGY AND BIOENGINEERING
(2023)
Review
Medicine, Research & Experimental
Andreas L. Gimpel, Georgios Katsikis, Sha Sha, Andrew John Maloney, Moo Sun Hong, Tam N. T. Nguyen, Jacqueline Wolfrum, Stacy L. Springs, Anthony J. Sinskey, Scott R. Manalis, Paul W. Barone, Richard D. Braatz
Summary: The article introduces analytical methods for rAAV quality attributes, emphasizing the importance of rapid, high-throughput methods, which are not yet widely used in academic and industrial practice, and have limited supporting data.
MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT
(2021)
Review
Biochemistry & Molecular Biology
Lyubava Belova, Alexander Lavrov, Svetlana Smirnikhina
Summary: Cellular 3D structures, such as organoids, are important for biomedical research. However, there are challenges in delivering transgenes to these structures. This review explores ways to improve the efficiency of transgene delivery.
Review
Oncology
Motahareh Arjomandnejad, Ishani Dasgupta, Terence R. Flotte, Allison M. Keeler
Summary: Recombinant adeno-associated viruses (AAVs) have shown promise as gene delivery vehicles, but immune responses against the AAV vector and transgene have limited their widespread application. Factors such as vector design, dose, and route of administration influence the immunogenicity of AAVs. Innate immune sensing and subsequent adaptive immune response contribute to the specific reactions against AAV vectors. This review discusses the challenges and potential strategies to mitigate immune responses, thereby enhancing the therapeutic potential of AAV gene therapy.
Article
Integrative & Complementary Medicine
Yi-lin Xie, Ji-yao Wang, Yun He, Xiao-min Yu, Qing-yun Zheng, Chen Ling, Xi-lin Feng, Li-qing Zhu
Summary: The use of melittin significantly enhances transgene expression mediated by recombinant adeno-associated virus serotype 2 vectors (rAAV2) both in vitro and in vivo. Pre-incubation of rAAV2 vectors with melittin greatly improves their transduction efficiency in HEK293 and Huh7 cells. This research expands the pharmacological potential of melittin and provides a new strategy to enhance gene therapy using rAAV vectors.
JOURNAL OF INTEGRATIVE MEDICINE-JIM
(2023)
Review
Biochemistry & Molecular Biology
Leyao Li, Lakshmy Vasan, Bryan Kartono, Kevan Clifford, Ahmadreza Attarpour, Raghav Sharma, Matthew Mandrozos, Ain Kim, Wenda Zhao, Ari Belotserkovsky, Claire Verkuyl, Gerold Schmitt-Ulms
Summary: This review introduces the use of recombinant adeno-associated virus (rAAV) vectors in the treatment of neurodegenerative diseases, highlighting recent research advancements and challenges. It provides a reference for newcomers to the field and directs researchers struggling to keep up with the literature towards important studies. The review covers early milestones, current clinical trials, gene editing applications, and payload elements of rAAV vectors, as well as discusses the risks and mitigation strategies associated with off-target effects and immunogenicity.
Article
Biochemical Research Methods
Aurelien Jacob, Laurie Brun, Paloma Jimenez Gil, Lucie Menard, Mohammed Bouzelha, Frederic Broucque, Aline Roblin, Luk H. Vandenberghe, Oumeya Adjali, Cecile Robin, Achille Francois, Veronique Blouin, Magalie Penaud-Budloo, Eduard Ayuso
Summary: Manufacturing viral vectors for gene delivery is challenging, with a scalable baculovirus-insect cell platform being used for producing rAAV vectors. A faster and safer method based on homologous recombination (HR) has been investigated to avoid technical constraints and safety concerns associated with the Tn7 transposition method. The HR system offers increased stability and avoids undesirable bacterial genes, ensuring the generation of safer rAAV biotherapeutic products.
BIOTECHNOLOGY JOURNAL
(2021)
Article
Medicine, Research & Experimental
Takayuki Onishi, Michika Nonaka, Takahiro Maruno, Yuki Yamaguchi, Mitsuko Fukuhara, Tetsuo Torisu, Masaharu Maeda, Susan Abbatiello, Anisha Haris, Keith Richardson, Kevin Giles, Steve Preece, Noriko Yamano-Adachi, Takeshi Omasa, Susumu Uchiyama
Summary: This study provides the first comprehensive characterization of low- and high-density rAAV serotype 2 particles, revealing differences in capsid composition. Additionally, the researchers were able to generate highly functional rAAV by single amino acid replacement, resulting in increased transduction efficacy.
MOLECULAR THERAPY METHODS & CLINICAL DEVELOPMENT
(2023)
Article
Biochemistry & Molecular Biology
Sylvia Fong, Bridget Yates, Choong-Ryoul Sihn, Aras N. Mattis, Nina Mitchell, Su Liu, Chris B. Russell, Benjamin Kim, Adebayo Lawal, Savita Rangarajan, Will Lester, Stuart Bunting, Glenn F. Pierce, K. John Pasi, Wing Yen Wong
Summary: Factor VIII gene transfer using valoctocogene roxaparvovec (AAV5-hFVIII-SQ) through a single intravenous infusion has shown clinical benefits lasting 5 years in patients with severe hemophilia A. This study investigated the molecular mechanisms underlying the sustained expression of AAV5-hFVIII-SQ-derived FVIII in the liver. The results demonstrated persistent episomal vector structures and provided insights into potential mechanisms mediating interindividual variability in transgene expression.
Article
Engineering, Chemical
Abhiram Arunkumar, Nripen Singh
Summary: This study quantitatively investigated the ultrafiltration behavior of AAVs using different membrane molecular weight cut-off and operating conditions, showing that these factors can impact the flux and transmission of AAV. The study found that a 100 kDa ultrafiltration membrane can act as a completely retentive membrane or as significantly permeable to AAV serotypes depending on the operating conditions.
JOURNAL OF MEMBRANE SCIENCE
(2021)
Article
Medicine, Research & Experimental
Alexander Michels, Annika M. Frank, Dorothee M. Guenther, Mehryad Mataei, Kathleen Borner, Dirk Grimm, Jessica Hartmann, Christian J. Buchholz
Summary: This study successfully improved gene delivery efficiency to CD8+ mouse lymphocytes using mCD8-LV, based on DARPin binding to murine CD8. The results suggest a potential application of DARPins in AAV vectors for targeted gene therapy.
MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT
(2021)
Article
Computer Science, Software Engineering
Mukul Sati, Jarek Rossignac
Summary: The article introduces definitions and closed-form expressions for Valley Average of Directions (VAD) and Valley Average of Lines (VAL) in 3D space, with L being independent of the input order and having specific properties.
COMPUTER-AIDED DESIGN
(2021)
Article
Biochemistry & Molecular Biology
Ling Yin, Geoffrey D. Keeler, Yuanhui Zhang, Brad E. Hoffman, Chen Ling, Keyun Qing, Arun Srivastava
Summary: In vitro, AAV3-miR-26a and scAAV3-miR-122 vectors show moderate growth inhibition of Huh7 cells, with an additive effect when co-transduced. In vivo, the combination of these vectors leads to significant growth inhibition of Huh-derived human liver tumors in a mouse xenograft model.
Article
Biochemistry & Molecular Biology
Janine A. Gilkes, Benjamin L. Judkins, Brontie N. Herrera, Ronald J. Mandel, Sanford L. Boye, Shannon E. Boye, Arun Srivastava, Coy D. Heldermon
Summary: The study evaluated two intracranially administered adeno-associated virus serotype 8 variants for potential treatment of MPS IIIB, with one variant (double Y-F + T-V) showing better efficacy. The IC6 method resulted in the widest biodistribution within the brain, indicating enhanced utility of the capsid modified AAV8 variant for therapeutic purposes.
Article
Biotechnology & Applied Microbiology
Min Li, Yuxiao Tang, Dongyao Wang, Xiaofeng Zhai, Hui Shen, Chen Zhong, Man Yao, Aiguo Jin, Zhengjun Zhou, Shaolai Zhou, Jia Fan, Chang-quan Ling, Chen Ling
Summary: This study elucidated the mechanisms of iron's enhancement activity on HCC metastasis and identified SPNS2 as a potential therapeutic target for preventing HCC pulmonary metastasis.
Article
Integrative & Complementary Medicine
Shufang Liang, Yong Zou, Jingdong Gao, Xiaolin Liu, Wanfu Lin, Zifei Yin, Juan Du, Ya'ni Zhang, Qunwei Chen, Shu Li, Binbin Cheng, Changquan Ling
EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE
(2022)
Article
Virology
Hubert D. -J Daniel, Sanjay Kumar, Rajesh Kannangai, J. Farzana, Joseph N. Joel, Aby Abraham, Kavitha M. Lakshmi, Mavis Agbandje-McKenna, Kirsten E. Coleman, Arun Srivastava, Alok Srivastava, Asha M. Abraham
Summary: Gene therapy using AAV vector is a promising treatment option for monogenetic disorders, but the presence of pre-existing anti-AAV antibodies poses a challenge. In this study, the prevalence of these antibodies in Indian hemophilia A patients was examined, revealing a high prevalence and an age-related increase in anti-AAV antibodies.
JOURNAL OF MEDICAL VIROLOGY
(2022)
Article
Microbiology
Jakob Shoti, Keyun Qing, Arun Srivastava
Summary: Recombinant MV serotype vectors and their variants are being used in clinical trials for gene therapy for hemophilia. However, traditional liver-directed AAV gene therapy does not work in children with hemophilia. This study describes the development of an optimized human Factor IX gene expression cassette for potential gene therapy for hemophilia in children.
FRONTIERS IN MICROBIOLOGY
(2022)
Article
Integrative & Complementary Medicine
Yi-lin Xie, Ji-yao Wang, Yun He, Xiao-min Yu, Qing-yun Zheng, Chen Ling, Xi-lin Feng, Li-qing Zhu
Summary: The use of melittin significantly enhances transgene expression mediated by recombinant adeno-associated virus serotype 2 vectors (rAAV2) both in vitro and in vivo. Pre-incubation of rAAV2 vectors with melittin greatly improves their transduction efficiency in HEK293 and Huh7 cells. This research expands the pharmacological potential of melittin and provides a new strategy to enhance gene therapy using rAAV vectors.
JOURNAL OF INTEGRATIVE MEDICINE-JIM
(2023)
Review
Pharmacology & Pharmacy
Man Yao, Shufang Liang, Binbin Cheng
Summary: Hepatocellular carcinoma (HCC) is typically associated with chronic liver inflammation and cirrhosis. Exosomes, nanometer-sized membrane vesicles, play a crucial role in the initiation and progression of HCC. They mediate cell-cell communication and regulate the tumor microenvironment by carrying proteins, DNAs, and various forms of RNA. Studies have shown that exosomes are involved in the communication between HCC cells and stromal cells, and they influence tumor proliferation, metastasis, immune evasion, and immunotherapy. Furthermore, exosomes can be utilized for the diagnosis and treatment of HCC, serving as biomarkers for early detection and drug delivery vehicles. Chinese herbal medicine, commonly used in HCC prevention and treatment in China, may regulate the release of exosomes and exosomes-mediated intercellular communication. This review summarizes the role of exosomes in HCC initiation, progression, and treatment, as well as the potential value of Traditional Chinese medicine in exosomes-mediated biological behaviors of HCC.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Medicine, Research & Experimental
Karina Krotova, Hisae Kuoch (Yoshitomi), Colin Caine, George Aslanidi
Summary: This study further elucidated the mechanism of a novel AAV-based vaccine, which inhibits tumor growth by optimizing AAV vectors and gene expression. The vaccine induced cellular and humoral antigen-specific immune responses and the temporal expression of antigen coincided with T cell infiltration. Our data demonstrated the superior protective immune response of optimized AAV6-TRP1 compared to other self-antigens.
MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT
(2023)
Biographical-Item
Biotechnology & Applied Microbiology
Kenneth I. I. Berns, Barry J. J. Byrne, Terence R. R. Flotte, R. Jude Samulski, Arun Srivastava
HUMAN GENE THERAPY
(2023)
Article
Medicine, Research & Experimental
Xiao Tian, Qingyun Zheng, Jinyan Xie, Qinlinglan Zhou, Letong Liang, Guotong Xu, Hongyan Chen, Chen Ling, Daru Lu
Summary: The Mfrp and Ctrp5 genes are transcribed as a bicistronic unit, and dysregulation of either gene is associated with retinal degeneration in RPE cells. A microRNA-based negative feedback loop involving miR-149-3p binding to the 30UTR of Mfrp gene was identified, which helps maintain normal expression levels of the bicistronic transcript.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2023)
Article
Biochemistry & Molecular Biology
Hisae Kuoch, Karina Krotova, Melanie L. Graham, Mark L. Brantly, George Aslanidi
Summary: Accurate assessment of AAV-specific pre-existing humoral immunity is crucial for effective use of clinical gene therapy. This study presents a method that applies equivalent infection conditions to each AAV serotype and validates it through evaluating neutralizing antibody titers in human donors, dogs, and non-human primates. The method allows for rapid and accurate evaluation of neutralizing titers for individual subjects, aiding clinical enrollment and the selection of the most suitable AAV serotype for each patient.
Article
Oncology
Wentao Jia, Jiaying Yuan, Binbin Cheng, Changquan Ling
Summary: This review discusses the potential mechanism of tumor-derived exosome (TDE)-mediated premetastatic niche (PMN) formation as a means of organotropic metastasis. Traditional Chinese medicine (TCM) has been successful in preventing and treating tumor metastasis, but the underlying mechanisms are still unclear. The review explores PMN formation through TDE biogenesis, cargo sorting, and alterations in recipient cells, which are crucial for metastatic outgrowth. It also examines the metastasis-preventive effects of TCM, which target the physicochemical materials and functional mediators of TDE biogenesis, regulate cargo sorting machinery and secretory molecules in TDEs, and target the TDE-recipient cells involved in PMN formation.
Article
Integrative & Complementary Medicine
Bing-jie Guo, Yi Ruan, Ya-jing Wang, Chu-lan Xiao, Zhi-peng Zhong, Bin-bin Cheng, Juan Du, Bai Li, Wei Gu, Zi-fei Yin
Summary: This study investigated the mechanism of Jiedu Recipe (JR) in hepatocellular carcinoma (HCC) treatment. The results showed that JR inhibits the proliferation, migration and invasion of HCC cells under hypoxia by blocking the Wnt/β-catenin pathway and reducing the expression of tumor stem cells.
JOURNAL OF INTEGRATIVE MEDICINE-JIM
(2023)
Letter
Medicine, General & Internal
Madhusudana G. Sanal, Arun Srivastava, Margareth C. Ozelo, Wing Y. Wong
Summary: This study reports the results of a gene therapy trial for severe hemophilia A. The low transduction efficiency of AAV5 vector and the stress response in hepatocytes may contribute to the decline in factor VIII levels.
NEW ENGLAND JOURNAL OF MEDICINE
(2022)