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Microorganisms
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Adeno-Associated Virus Biology and AAV Vector-Mediated Gene Therapy
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Adeno-Associated Virus Biology and AAV Vector-Mediated Gene Therapy

A special issue of Microorganisms (ISSN 2076-2607). This special issue belongs to the section "Virology".

Deadline for manuscript submissions: closed (31 March 2024) | Viewed by 6491

Special Issue Editors

Dr. Magalie Penaud-Budloo

E-Mail Website
Guest Editor
Freelance Consultant, Nantes, France
Interests: gene therapy; AAV; virology; molecular biology; high-throughput sequencing; epigenetics
Dr. Virginie Pichard

E-Mail Website
Guest Editor
Translational Research in Gene Therapy, INSERM UMR 1089, CHU de Nantes, Nantes Université, F-44200 Nantes, France
Interests: gene transfer; viral vectors; AAV; in vivo model; Immune response; liver gene therapy

Special Issue Information

Dear Colleagues,

Following their successful use as vectors in gene therapy clinical trials, adeno-associated viruses (AAV) have increased in popularity and have become emblematic viruses of the Parvovirinae subfamily. However, grey areas remain in the wild-type AAV life cycle. Whereas AAV was disclosed to the scientific community in 1964, novel coding sequences and proteins were only recently discovered, such as the MAAP (membrane-associated accessory protein) identified by Church’s group 4 years ago. Additional knowledge on fundamental biology has a potential impact on AAV vector production, purification and efficiency. In this regard, the assembly-activating protein (AAP) described in 2010 shed new light on the capsid assembly mechanism, leading to a rethinking of Cap ORF molecular design for the generation of AAV variants. This Special Issue of Microorganisms invites submissions of manuscripts that address AAV biology and vectorology. Scientific findings must be relevant to recombinant AAV-mediated gene therapy. Original research articles and reviews are welcome. Research areas may include (but are not limited to) the following: genomics, epigenetics, vector design and quality control studies. We look forward to receiving your contributions.

Dr. Magalie Penaud-Budloo
Dr. Virginie Pichard
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Microorganisms is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • gene therapy
  • adeno-associated virus
  • recombinant AAV
  • natural capsid variants
  • vector design
  • production methods
  • analytics
  • epigenetics
  • evolutionary biology

Published Papers (3 papers)

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Research

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16 pages, 3940 KiB  
Article
A Comprehensive Study of the Effects by Sequence Truncation within Inverted Terminal Repeats (ITRs) on the Productivity, Genome Packaging, and Potency of AAV Vectors
by Yinxing Chen, Shiliang Hu, William Lee, Noel Walsh, Kayla Iozza, Neil Huang, Gregory Preston, Lauren M. Drouin, Nannan Jia, June Deng, Matthias Hebben and Jing Liao
Microorganisms 2024, 12(2), 310; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms12020310 - 01 Feb 2024
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Abstract
One of the primary challenges in working with adeno-associated virus (AAV) lies in the inherent instability of its inverted terminal repeats (ITRs), which play vital roles in AAV replication, encapsidation, and genome integration. ITRs contain a high GC content and palindromic structure, which [...] Read more.
One of the primary challenges in working with adeno-associated virus (AAV) lies in the inherent instability of its inverted terminal repeats (ITRs), which play vital roles in AAV replication, encapsidation, and genome integration. ITRs contain a high GC content and palindromic structure, which occasionally results in truncations and mutations during plasmid amplification in bacterial cells. However, there is no thorough study on how these alterations in ITRs impact the ultimate AAV vector characteristics. To close this gap, we designed ITRs with common variations, including a single B, C, or D region deletion at one end, and dual deletions at both ends of the vector genome. These engineered ITR-carrying plasmids were utilized to generate AAV vectors in HEK293 cells. The crude and purified AAV samples were collected and analyzed for yield, capsid DNA-filled percentage, potency, and ITR integrity. The results show that a single deletion had minor impact on AAV productivity, packaging efficiency, and in vivo potency. However, deletions on both ends, except A, showed significant negative effects on the above characteristics. Our work revealed the role of ITR regions, A, B, C, and D for AAV production and DNA replication, and proposes a new strategy for the quality control of ITR-bearing plasmids and final AAV products. Full article
(This article belongs to the Special Issue Adeno-Associated Virus Biology and AAV Vector-Mediated Gene Therapy)
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Review

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24 pages, 2454 KiB  
Review
Development of Stable Packaging and Producer Cell Lines for the Production of AAV Vectors
by Otto-Wilhelm Merten
Microorganisms 2024, 12(2), 384; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms12020384 - 13 Feb 2024
Viewed by 1814
Abstract
Today, recombinant adeno-associated virus (rAAV) vectors represent the vector systems which are mostly used for in vivo gene therapy for the treatment of rare and less-rare diseases. Although most of the past developments have been performed by using a transfection-based method and more [...] Read more.
Today, recombinant adeno-associated virus (rAAV) vectors represent the vector systems which are mostly used for in vivo gene therapy for the treatment of rare and less-rare diseases. Although most of the past developments have been performed by using a transfection-based method and more than half of the authorized rAAV-based treatments are based on transfection process, the tendency is towards the use of stable inducible packaging and producer cell lines because their use is much more straightforward and leads in parallel to reduction in the overall manufacturing costs. This article presents the development of HeLa cell-based packaging/producer cell lines up to their use for large-scale rAAV vector production, the more recent development of HEK293-based packaging and producer cell lines, as well as of packaging cell lines based on the use of Sf9 cells. The production features are presented in brief (where available), including vector titer, specific productivity, and full-to-empty particle ratio. Full article
(This article belongs to the Special Issue Adeno-Associated Virus Biology and AAV Vector-Mediated Gene Therapy)
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21 pages, 2033 KiB  
Review
AAV Immunotoxicity: Implications in Anti-HBV Gene Therapy
by Ridhwaanah Jacobs, Makafui Dennis Dogbey, Njabulo Mnyandu, Keila Neves, Stefan Barth, Patrick Arbuthnot and Mohube Betty Maepa
Microorganisms 2023, 11(12), 2985; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms11122985 - 14 Dec 2023
Viewed by 1361
Abstract
Hepatitis B virus (HBV) has afflicted humankind for decades and there is still no treatment that can clear the infection. The development of recombinant adeno-associated virus (rAAV)-based gene therapy for HBV infection has become important in recent years and research has made exciting [...] Read more.
Hepatitis B virus (HBV) has afflicted humankind for decades and there is still no treatment that can clear the infection. The development of recombinant adeno-associated virus (rAAV)-based gene therapy for HBV infection has become important in recent years and research has made exciting leaps. Initial studies, mainly using mouse models, showed that rAAVs are non-toxic and induce minimal immune responses. However, several later studies demonstrated rAAV toxicity, which is inextricably associated with immunogenicity. This is a major setback for the progression of rAAV-based therapies toward clinical application. Research aimed at understanding the mechanisms behind rAAV immunity and toxicity has contributed significantly to the inception of approaches to overcoming these challenges. The target tissue, the features of the vector, and the vector dose are some of the determinants of AAV toxicity, with the latter being associated with the most severe adverse events. This review discusses our current understanding of rAAV immunogenicity, toxicity, and approaches to overcoming these hurdles. How this information and current knowledge about HBV biology and immunity can be harnessed in the efforts to design safe and effective anti-HBV rAAVs is discussed. Full article
(This article belongs to the Special Issue Adeno-Associated Virus Biology and AAV Vector-Mediated Gene Therapy)
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