Repairing the Brain: Gene Therapy

Björklund, Tomas

doi:10.3233/jpd-181485

Cited by 4 publications

(5 citation statements)

References 70 publications

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“…Previously commented limiting factors, along with the need to use appropriate vehicles that are able to deliver efficiently the genetic material, justify the hard path of brain gene therapy to reach clinical practice. In fact, although many phase I clinical trials have been reported; only a few have reached phase II [154]. However, with the new emerging technologies applied to gene therapy, the cure of brain diseases might look like a reasonable option in the near future [155].…”

Section: General Conceptsmentioning

confidence: 99%

“…However, with the new emerging technologies applied to gene therapy, the cure of brain diseases might look like a reasonable option in the near future [155]. One of the most promising approaches is to explore the use of non-viral vectors as gene delivery systems due to their safer profile, easy production capacity, and lower cost when compared to their viral vector counterparts [154].…”

Section: General Conceptsmentioning

confidence: 99%

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Niosome-Based Approach for In Situ Gene Delivery to Retina and Brain Cortex as Immune-Privileged Tissues

et al. 2020

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Non-viral vectors have emerged as a promising alternative to viral gene delivery systems due to their safer profile. Among non-viral vectors, recently, niosomes have shown favorable properties for gene delivery, including low toxicity, high stability, and easy production. The three main components of niosome formulations include a cationic lipid that is responsible for the electrostatic interactions with the negatively charged genetic material, a non-ionic surfactant that enhances the long-term stability of the niosome, and a helper component that can be added to improve its physicochemical properties and biological performance. This review is aimed at providing recent information about niosome-based non-viral vectors for gene delivery purposes. Specially, we will discuss the composition, preparation methods, physicochemical properties, and biological evaluation of niosomes and corresponding nioplexes that result from the addition of the genetic material onto their cationic surface. Next, we will focus on the in situ application of such niosomes to deliver the genetic material into immune-privileged tissues such as the brain cortex and the retina. Finally, as future perspectives, non-invasive administration routes and different targeting strategies will be discussed.

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Section: General Conceptsmentioning

confidence: 99%

Section: General Conceptsmentioning

confidence: 99%

Niosome-Based Approach for In Situ Gene Delivery to Retina and Brain Cortex as Immune-Privileged Tissues

et al. 2020

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“… 3 , 4 , 5 , 6 , 7 Today, viral gene therapy with a variety of viruses is used in oncology, vaccination, and many other disciplines in clinical science. 8 , 9 , 10 , 11 Gene therapy vectors have been used preclinically for host genome editing and clinically for the expression of intracellular proteins, surface receptor presentation, and/or the secretion of therapeutics. 12 , 13 , 14 , 15 Recently, multiple gene delivery vectors have been developed in the expanding field of cancer immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

iMATCH: an integrated modular assembly system for therapeutic combination high-capacity adenovirus gene therapy

Brücher

Kirchhammer

Smith

et al. 2021

Molecular Therapy - Methods & Clinical Development

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Adenovirus-mediated combination gene therapies have shown promising results in vaccination or treating malignant and genetic diseases. Nevertheless, an efficient system for the rapid assembly and incorporation of therapeutic genes into high-capacity adenoviral vectors (HCAdVs) is still missing. In this study, we developed the iMATCH (integrated modular assembly for therapeutic combination HCAdVs) platform, which enables the generation and production of HCAdVs encoding therapeutic combinations in high quantity and purity within 3 weeks. Our modular cloning system facilitates the efficient combination of up to four expression cassettes and the rapid integration into HCAdV genomes with defined sizes. Helper viruses (HVs) and purification protocols were optimized to produce HCAdVs with distinct capsid modifications and unprecedented purity (0.1 ppm HVs). The constitution of HCAdVs, with adapters for targeting and a shield of trimerized single-chain variable fragment (scFv) for reduced liver clearance, mediated cell- and organ-specific targeting of HCAdVs. As proof of concept, we show that a single HCAdV encoding an anti PD-1 antibody, interleukin (IL)-12, and IL-2 produced all proteins, and it led to tumor regression and prolonged survival in tumor models, comparable to a mixture of single payload HCAdVs in vitro and in vivo . Therefore, the iMATCH system provides a versatile platform for the generation of high-capacity gene therapy vectors with a high potential for clinical development.

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“…Gene therapy is a fast-growing field of biomedical research, recently exceeding more than 4000 ongoing or completed clinical trials . This rapid progress became possible due to successes in numerous DNA delivery methods, including physical gene transfer, synthetic nanoparticles, and viral or cellular vectors. , Especially for in vivo applications, viral vectors have been shown to achieve high transduction rates and sustained expression. − Adenoviral vectors (AdVs) in particular are among the most frequently applied gene vectors, and they are currently being investigated for multiple clinical applications, including but not limited to the fields of vaccines, oncology, or rare diseases. ,− Among the more than 100 human adenovirus serotypes, the most prominent and best studied AdV serotype is the human adenovirus serotype C5 (HAdV-C5). , …”

mentioning

confidence: 99%

Modular Adapters Utilizing Binders of Different Molecular Types Expand Cell-Targeting Options for Adenovirus Gene Delivery

et al. 2022

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Efficient and cell-specific delivery of DNA is essential for the effective and safe use of gene delivery technologies. Consequently, a large variety of technologies have been developed and applied in a wide range of ex vivo and in vivo applications, including multiple approaches based on viral vectors. However, widespread success of a technology is largely determined by the versatility of the method and the ease of use. The rationally designed adapter technology previously developed redirects widely used human adenovirus serotype 5 (HAdV-C5) to a defined cell population, by binding and blocking the adenoviral knob tropism while simultaneously allowing fusions of an N-terminal retargeting module. Here we expand modularity, and thus applicability of this adapter technology, by extending the nature of the cell-binding portion. We report successful receptor-specific transduction mediated by a retargeting module consisting of either a DARPin, a single-chain variable fragment (scFv) of an antibody, a peptide, or a small molecule ligand. Furthermore, we show that an adapter can be engineered to carry more than one specificity, allowing dual targeting. Specific HAdV-C5 retargeting was thus demonstrated to human epidermal growth factor receptor 2 (HER2), human folate receptor α, and neurotensin receptor 1, effective at vector concentrations as low as a multiplicity of infection of 2.5. Therefore, we report a modular design which allows plug-and-play combinations of different binding modules, leading to efficient and specific mono-or dual-targeting while circumventing tedious optimization procedures. This extends the technology to combinational applications of cell-specific binding, supporting research in gene therapy, synthetic biology, and biotechnology.G ene therapy is a fast-growing field of biomedical research, recently exceeding more than 4000 ongoing or completed clinical trials. 1 This rapid progress became possible due to successes in numerous DNA delivery methods, including physical gene transfer, synthetic nanoparticles, and viral or cellular vectors. 2,3 Especially for in vivo applications, viral vectors have been shown to achieve high transduction rates and sustained expression. 4−6 Adenoviral vectors (AdVs) in particular are among the most frequently applied gene vectors, and they are currently being investigated for multiple clinical applications, including but not limited to the fields of vaccines, oncology, or rare diseases. 1,7−13 Among the more than 100 human adenovirus serotypes, the most prominent and best studied AdV serotype is the human adenovirus serotype C5 (HAdV-C5). 14,15

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Repairing the Brain: Gene Therapy

Cited by 4 publications

References 70 publications

Niosome-Based Approach for In Situ Gene Delivery to Retina and Brain Cortex as Immune-Privileged Tissues

Niosome-Based Approach for In Situ Gene Delivery to Retina and Brain Cortex as Immune-Privileged Tissues

iMATCH: an integrated modular assembly system for therapeutic combination high-capacity adenovirus gene therapy

Modular Adapters Utilizing Binders of Different Molecular Types Expand Cell-Targeting Options for Adenovirus Gene Delivery

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