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Pharmaceutics
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Adeno-Associated Virus Vectors for Gene Therapy of Eye and Other...
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Adeno-Associated Virus Vectors for Gene Therapy of Eye and Other Diseases

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Gene and Cell Therapy".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 19071

Special Issue Editor

Prof. Dr. Stylianos Michalakis

E-Mail Website
Guest Editor
Department of Ophthalmology, University Hospital, LMU Munich, Mathildenstraße 8, 80336 Munich, Germany
Interests: gene therapy; retinal degeneration; inherited retinal disorders; adeno-associated virus vectors; preclinical testing; clinical trials; ATMP; viral vector manufacturing; CMC; vector engineering
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Recombinant adeno-associated virus (AAV) vectors have emerged as very promising gene therapy vectors and have been already used in more than 200 clinical trials across different indications with very good safety characteristics. This is reflected in the recent marketing authorization of Luxturna® and Zolgensma®, AAV vector-based therapies for RPE65-linked retinal dystrophy and SMN1-linked spinal muscular atrophy, respectively. While several protocols for efficient manufacturing of recombinant AAVs have been established in the past, some pharmaceutical aspects of the manufacturing still need to be further developed. The higher complexity of viral vectors with their combined protein and nucleic acid nature poses a higher burden on manufacturing than for comparison production of recombinant proteins or antibodies. Chemistry, manufacturing and controls (CMC) aspects for AAV vectors are constantly evolving and are an integral part of the core activities in any gene therapy campaign. Recently, CMC guidelines have been issued by regulatory authorities, industry, and academia are constantly working in improving manufacturing processes, analytics and quality control of AAV-based gene therapy products. This Special Issue of Pharmaceutics will focus on recent insights into the topic of "Adeno-Associated Virus Vectors for Gene Therapy of Eye and Other Diseases," including new insights into AAV production platforms, analytics, quality control, formulation and other pharmaceutical aspects of AAV vector manufacturing. Moreover, submissions dealing with the in vitro or in vivo application and characterization of AAV gene therapy products are also welcome. This includes but is not limited to preclinical proof of concept, validation or safety studies with AAV gene therapy products for ocular and non-ocular, rare disease or common disease indications.

Prof. Dr. Stylianos Michalakis
Guest Editor

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. Pharmaceutics 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 2900 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

  • Adeno-associated virus vector
  • AAV
  • gene therapy
  • manufacturing
  • analytics
  • formulation
  • CMC
  • ocular
  • retina
  • inherited retinal disorders

Published Papers (3 papers)

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Research

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19 pages, 5944 KiB  
Article
Comparison of Different Liquid Chromatography-Based Purification Strategies for Adeno-Associated Virus Vectors
by Ruth Rieser, Johanna Koch, Greta Faccioli, Klaus Richter, Tim Menzen, Martin Biel, Gerhard Winter and Stylianos Michalakis
Pharmaceutics 2021, 13(5), 748; https://doi.org/10.3390/pharmaceutics13050748 - 18 May 2021
Cited by 24 | Viewed by 6947
Abstract
Recombinant adeno-associated virus (rAAV) vectors have evolved as one of the most promising technologies for gene therapy due to their good safety profile, high transduction efficacy, and long-term gene expression in nondividing cells. rAAV-based gene therapy holds great promise for treating genetic disorders [...] Read more.
Recombinant adeno-associated virus (rAAV) vectors have evolved as one of the most promising technologies for gene therapy due to their good safety profile, high transduction efficacy, and long-term gene expression in nondividing cells. rAAV-based gene therapy holds great promise for treating genetic disorders like inherited blindness, muscular atrophy, or bleeding disorders. There is a high demand for efficient and scalable production and purification methods for rAAVs. This is particularly true for the downstream purification methods. The current standard methods are based on multiple steps of gradient ultracentrifugation, which allow for the purification and enrichment of full rAAV particles, but the scale up of this method is challenging. Here, we explored fast, scalable, and universal liquid chromatography-based strategies for the purification of rAAVs. In contrast to the hydrophobic interaction chromatography (HIC), where a substantial amount of AAV was lost, the cation exchange chromatography (CEX) was performed robustly for multiple tested serotypes and resulted in a mixture of full and empty rAAVs with a good purity profile. For the used affinity chromatography (AC), a serotype dependence was observed. Anion exchange chromatography (AEX) worked well for the AAV8 serotype and achieved high levels of purification and a baseline separation of full and empty rAAVs. Depending on the AAV serotype, a combination of CEX and AEX or AC and AEX is recommended and holds promise for future translational projects that require highly pure and full particle-enriched rAAVs. Full article
(This article belongs to the Special Issue Adeno-Associated Virus Vectors for Gene Therapy of Eye and Other Diseases)
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14 pages, 4172 KiB  
Article
Multiple-Monitor HPLC Assays for Rapid Process Development, In-Process Monitoring, and Validation of AAV Production and Purification
by Pete Gagnon, Blaz Goricar, Nina Mencin, Timotej Zvanut, Sebastijan Peljhan, Maja Leskovec and Ales Strancar
Pharmaceutics 2021, 13(1), 113; https://doi.org/10.3390/pharmaceutics13010113 - 17 Jan 2021
Cited by 20 | Viewed by 6084
Abstract
HPLC is established as a fast convenient analytical technology for characterizing the content of empty and full capsids in purified samples containing adeno-associated virus (AAV). UV-based monitoring unfortunately over-estimates the proportion of full capsids and offers little value for characterizing unpurified samples. The [...] Read more.
HPLC is established as a fast convenient analytical technology for characterizing the content of empty and full capsids in purified samples containing adeno-associated virus (AAV). UV-based monitoring unfortunately over-estimates the proportion of full capsids and offers little value for characterizing unpurified samples. The present study combines dual-wavelength UV monitoring with intrinsic fluorescence, extrinsic fluorescence, and light-scattering to extend the utility of HPLC for supporting development of therapeutic AAV-based drugs. Applications with anion exchange (AEC), cation exchange (CEC), and size exclusion chromatography (SEC) are presented. Intrinsic fluorescence increases sensitivity of AAV detection over UV and enables more objective estimation of empty and full capsid ratios by comparison of their respective peak areas. Light scattering enables identification of AAV capsids in complex samples, plus semiquantitative estimation of empty and full capsid ratios from relative peak areas of empty and full capsids. Extrinsic Picogreen fluorescence enables semiquantitative tracking of DNA with all HPLC methods at all stages of purification. It does not detect encapsidated DNA but reveals DNA associated principally with the exteriors of empty capsids. It also enables monitoring of host DNA contamination across chromatograms. These enhancements support many opportunities to improve characterization of raw materials and process intermediates, to accelerate process development, provide rapid in-process monitoring, and support process validation. Full article
(This article belongs to the Special Issue Adeno-Associated Virus Vectors for Gene Therapy of Eye and Other Diseases)
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Review

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16 pages, 10765 KiB  
Review
Next Step in Gene Delivery: Modern Approaches and Further Perspectives of AAV Tropism Modification
by Maxim A. Korneyenkov and Andrey A. Zamyatnin, Jr.
Pharmaceutics 2021, 13(5), 750; https://doi.org/10.3390/pharmaceutics13050750 - 19 May 2021
Cited by 30 | Viewed by 5200
Abstract
Today, adeno-associated virus (AAV) is an extremely popular choice for gene therapy delivery. The safety profile and simplicity of the genome organization are the decisive advantages which allow us to claim that AAV is currently among the most promising vectors. Several drugs based [...] Read more.
Today, adeno-associated virus (AAV) is an extremely popular choice for gene therapy delivery. The safety profile and simplicity of the genome organization are the decisive advantages which allow us to claim that AAV is currently among the most promising vectors. Several drugs based on AAV have been approved in the USA and Europe, but AAV serotypes’ unspecific tissue tropism is still a serious limitation. In recent decades, several techniques have been developed to overcome this barrier, such as the rational design, directed evolution and chemical conjugation of targeting molecules with a capsid. Today, all of the abovementioned approaches confer the possibility to produce AAV capsids with tailored tropism, but recent data indicate that a better understanding of AAV biology and the growth of structural data may theoretically constitute a rational approach to most effectively produce highly selective and targeted AAV capsids. However, while we are still far from this goal, other approaches are still in play, despite their drawbacks and limitations. Full article
(This article belongs to the Special Issue Adeno-Associated Virus Vectors for Gene Therapy of Eye and Other Diseases)
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