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Non-viral Gene Delivery: Hurdles and Promises
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Non-viral Gene Delivery: Hurdles and Promises

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Macromolecules".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 24367

Special Issue Editor

Dr. Thierry Bordet

E-Mail Website
Guest Editor
Eyevensys
Interests: gene therapy; retinal disorders; plasmid DNA; electrotransfection; nonclinical development; medical device

Special Issue Information

Dear Colleagues,

Gene-based medicines are part of the expanding new treatment options with already twenty marketed gene therapy and cell-based gene therapy products and over two thousand gene therapy clinical trials reported worldwide. While viral vectors proved to be efficient in delivering genes, non-viral gene delivery systems are considered with much interest to overcome some of the limitation encountered with viral vectors. Non-viral vectors are usually not immunogenic, have a better safety profile, a larger cargo capacity, and are more easily produced at large scale. However, the ability for nucleic acids to efficiently transduce cells is usually not effective unless complexed with other chemical molecules or physical methods applied to force its cellular entry and nuclear import.

This Special issue aims at providing the reader with most up-to-date knowledge on mechanisms involved in intracellular delivery of nucleic acid, the barriers to be overcome, and on recently developed non-viral gene delivery systems. Preclinical in vitro and in vivo proof-of-concept studies, nonclinical regulatory development studies, clinical trials and review articles as well are all welcome for consideration.

Dr. Thierry Bordet
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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 delivery
  • gene therapy
  • gene editing
  • nucleic acids
  • small and large DNA, oligonucleotides, ASO
  • RNA delivery, siRNA, mRNA, miRNA
  • delivery systems
  • nanoparticles, lipids, polymers
  • physical methods, electroporation, magnetofection
  • intracellular barriers, trafficking, nucleus entry
  • cancer, immunotherapy
  • vaccines
  • ocular
  • pulmonary
  • dermal
  • muscular
  • clinical trials

Published Papers (4 papers)

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Research

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20 pages, 2445 KiB  
Article
Generation of Recombinant Primary Human B Lymphocytes Using Non-Viral Vectors
by Daniel Keim, Katrin Gollner, Ulrich Gollner, Valérie Jérôme and Ruth Freitag
Int. J. Mol. Sci. 2021, 22(15), 8239; https://doi.org/10.3390/ijms22158239 - 30 Jul 2021
Cited by 3 | Viewed by 3002
Abstract
Although the development of gene delivery systems based on non-viral vectors is advancing, it remains a challenge to deliver plasmid DNA into human blood cells. The current “gold standard”, namely linear polyethyleneimine (l-PEI 25 kDa), in particular, is unable to produce transgene expression [...] Read more.
Although the development of gene delivery systems based on non-viral vectors is advancing, it remains a challenge to deliver plasmid DNA into human blood cells. The current “gold standard”, namely linear polyethyleneimine (l-PEI 25 kDa), in particular, is unable to produce transgene expression levels >5% in primary human B lymphocytes. Here, it is demonstrated that a well-defined 24-armed poly(2-dimethylamino) ethyl methacrylate (PDMAEMA, 755 kDa) nano-star is able to reproducibly elicit high transgene expression (40%) at sufficient residual viability (69%) in primary human B cells derived from tonsillar tissue. Moreover, our results indicate that the length of the mitogenic stimulation prior to transfection is an important parameter that must be established during the development of the transfection protocol. In our hands, four days of stimulation with rhCD40L post-thawing led to the best transfection results in terms of TE and cell survival. Most importantly, our data argue for an impact of the B cell subsets on the transfection outcomes, underlining that the complexity and heterogeneity of a given B cell population pre- and post-transfection is a critical parameter to consider in the multiparametric approach required for the implementation of the transfection protocol. Full article
(This article belongs to the Special Issue Non-viral Gene Delivery: Hurdles and Promises)
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Review

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18 pages, 1431 KiB  
Review
Nanotechnology-Based Strategies to Overcome Current Barriers in Gene Delivery
by Sofía Mirón-Barroso, Elena B. Domènech and Sonia Trigueros
Int. J. Mol. Sci. 2021, 22(16), 8537; https://doi.org/10.3390/ijms22168537 - 9 Aug 2021
Cited by 31 | Viewed by 6984
Abstract
Nanomaterials are currently being developed for the specific cell/tissue/organ delivery of genetic material. Nanomaterials are considered as non-viral vectors for gene therapy use. However, there are several requirements for developing a device small enough to become an efficient gene-delivery tool. Considering that the [...] Read more.
Nanomaterials are currently being developed for the specific cell/tissue/organ delivery of genetic material. Nanomaterials are considered as non-viral vectors for gene therapy use. However, there are several requirements for developing a device small enough to become an efficient gene-delivery tool. Considering that the non-viral vectors tested so far show very low efficiency of gene delivery, there is a need to develop nanotechnology-based strategies to overcome current barriers in gene delivery. Selected nanostructures can incorporate several genetic materials, such as plasmid DNA, mRNA, and siRNA. In the field of nanotechnologies, there are still some limitations yet to be resolved for their use as gene delivery systems, such as potential toxicity and low transfection efficiency. Undeniably, novel properties at the nanoscale are essential to overcome these limitations. In this paper, we will explore the latest advances in nanotechnology in the gene delivery field. Full article
(This article belongs to the Special Issue Non-viral Gene Delivery: Hurdles and Promises)
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23 pages, 7403 KiB  
Review
How Far Are Non-Viral Vectors to Come of Age and Reach Clinical Translation in Gene Therapy?
by Myriam Sainz-Ramos, Idoia Gallego, Ilia Villate-Beitia, Jon Zarate, Iván Maldonado, Gustavo Puras and Jose Luis Pedraz
Int. J. Mol. Sci. 2021, 22(14), 7545; https://doi.org/10.3390/ijms22147545 - 14 Jul 2021
Cited by 29 | Viewed by 5827
Abstract
Efficient delivery of genetic material into cells is a critical process to translate gene therapy into clinical practice. In this sense, the increased knowledge acquired during past years in the molecular biology and nanotechnology fields has contributed to the development of different kinds [...] Read more.
Efficient delivery of genetic material into cells is a critical process to translate gene therapy into clinical practice. In this sense, the increased knowledge acquired during past years in the molecular biology and nanotechnology fields has contributed to the development of different kinds of non-viral vector systems as a promising alternative to virus-based gene delivery counterparts. Consequently, the development of non-viral vectors has gained attention, and nowadays, gene delivery mediated by these systems is considered as the cornerstone of modern gene therapy due to relevant advantages such as low toxicity, poor immunogenicity and high packing capacity. However, despite these relevant advantages, non-viral vectors have been poorly translated into clinical success. This review addresses some critical issues that need to be considered for clinical practice application of non-viral vectors in mainstream medicine, such as efficiency, biocompatibility, long-lasting effect, route of administration, design of experimental condition or commercialization process. In addition, potential strategies for overcoming main hurdles are also addressed. Overall, this review aims to raise awareness among the scientific community and help researchers gain knowledge in the design of safe and efficient non-viral gene delivery systems for clinical applications to progress in the gene therapy field. Full article
(This article belongs to the Special Issue Non-viral Gene Delivery: Hurdles and Promises)
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30 pages, 5973 KiB  
Review
Recent Advances in Preclinical Research Using PAMAM Dendrimers for Cancer Gene Therapy
by Piotr Tarach and Anna Janaszewska
Int. J. Mol. Sci. 2021, 22(6), 2912; https://doi.org/10.3390/ijms22062912 - 13 Mar 2021
Cited by 57 | Viewed by 7770
Abstract
Carriers of genetic material are divided into vectors of viral and non-viral origin. Viral carriers are already successfully used in experimental gene therapies, but despite advantages such as their high transfection efficiency and the wide knowledge of their practical potential, the remaining disadvantages, [...] Read more.
Carriers of genetic material are divided into vectors of viral and non-viral origin. Viral carriers are already successfully used in experimental gene therapies, but despite advantages such as their high transfection efficiency and the wide knowledge of their practical potential, the remaining disadvantages, namely, their low capacity and complex manufacturing process, based on biological systems, are major limitations prior to their broad implementation in the clinical setting. The application of non-viral carriers in gene therapy is one of the available approaches. Poly(amidoamine) (PAMAM) dendrimers are repetitively branched, three-dimensional molecules, made of amide and amine subunits, possessing unique physiochemical properties. Surface and internal modifications improve their physicochemical properties, enabling the increase in cellular specificity and transfection efficiency and a reduction in cytotoxicity toward healthy cells. During the last 10 years of research on PAMAM dendrimers, three modification strategies have commonly been used: (1) surface modification with functional groups; (2) hybrid vector formation; (3) creation of supramolecular self-assemblies. This review describes and summarizes recent studies exploring the development of PAMAM dendrimers in anticancer gene therapies, evaluating the advantages and disadvantages of the modification approaches and the nanomedicine regulatory issues preventing their translation into the clinical setting, and highlighting important areas for further development and possible steps that seem promising in terms of development of PAMAM as a carrier of genetic material. Full article
(This article belongs to the Special Issue Non-viral Gene Delivery: Hurdles and Promises)
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