Non-Viral Nucleic Acid Delivery Strategies to the Central Nervous System

Tan, James-Kevin Y; Sellers, Drew L.; Pham, Binhan; Pun, Suzie H.; Horner, Philip J.

doi:10.3389/fnmol.2016.00108

Cited by 27 publications

(10 citation statements)

References 148 publications

(162 reference statements)

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“…Currently, the future of ZOLGENSMA use via intrathecal route remains unclear, but the available clinical safety information suggests using caution, when infusing ZOLGENSMA intravenously, and inclusion pre-treatment with corticosteroids, checking blood biochemistry and liver enzymes (https://www.zolgensma.com/how-zolgensma-works). Compared to non-viral vectors (e.g., polyplexes [144]), AAV vectors appear to be highly suitable for NDD gene therapy applications and, therefore, became highly popular for NDD gene therapy studies in the recent years. However, the problem with AAV crossing BBB along with the vector's immunogenicity [47] in human patients remains the main obstacle even for those vectors that are capable of effectively preventing NDD progression.…”

Section: Discussionmentioning

confidence: 99%

Battling Neurodegenerative Diseases with Adeno-Associated Virus-Based Approaches

Mijanović

Branković

Borovjagin

et al. 2020

Viruses

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Neurodegenerative diseases (NDDs) are most commonly found in adults and remain essentially incurable. Gene therapy using AAV vectors is a rapidly-growing field of experimental medicine that holds promise for the treatment of NDDs. To date, effective delivery of a therapeutic gene into target cells via AAV has been a major obstacle in the field. Ideally, transgenes should be delivered into the target cells specifically and efficiently, while promiscuous or off-target gene delivery should be minimized to avoid toxicity. In the pursuit of an ideal vehicle for NDD gene therapy, a broad variety of vector systems have been explored. Here we specifically outline the advantages of adeno-associated virus (AAV)-based vector systems for NDD therapy application. In contrast to many reviews on NDDs that can be found in the literature, this review is rather focused on AAV vector selection and their testing in experimental and preclinical NDD models. Preclinical and in vitro data reveal the strong potential of AAV for NDD-related diagnostics and therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Battling Neurodegenerative Diseases with Adeno-Associated Virus-Based Approaches

Mijanović

Branković

Borovjagin

et al. 2020

Viruses

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“…Targeting to tissues and organelles is generally dependent on peptides, antibodies and other proteins. Cargo release of the nucleic acid from the lipid or polymer carrier is dependent on disulfide linkages [30]. Table 1 provides a summary of some of the advances now found in the packaging and stability of nucleic acid delivery vehicles, and see Figure 2 below.…”

Section: Non-viral Instead Of Viral Gene Deliverymentioning

confidence: 99%

Non-Viral Delivery of RNA Gene Therapy to the Central Nervous System

Hauck

Hecker

2022

Pharmaceutics

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Appropriate gene delivery systems are essential for successful gene therapy in clinical medicine. Lipid-mediated nucleic acid delivery is an alternative to viral vector-mediated gene delivery and has the following advantages. Lipid-mediated delivery of DNA or mRNA is usually more rapid than viral-mediated delivery, offers a larger payload, and has a nearly zero risk of incorporation. Lipid-mediated delivery of DNA or RNA is therefore preferable to viral DNA delivery in those clinical applications that do not require long-term expression for chronic conditions. Delivery of RNA may be preferable to non-viral DNA delivery in some clinical applications, since transit across the nuclear membrane is not necessary, and onset of expression with RNA is therefore even faster than with DNA, although both are faster than most viral vectors. Delivery of RNA to target organ(s) has previously been challenging due to RNA’s rapid degradation in biological systems, but cationic lipids complexed with RNA, as well as lipid nanoparticles (LNPs), have allowed for delivery and expression of the complexed RNA both in vitro and in vivo. This review will focus on the non-viral lipid-mediated delivery of RNAs, including mRNA, siRNA, shRNA, and microRNA, to the central nervous system (CNS), an organ with at least two unique challenges. The CNS contains a large number of slowly dividing or non-dividing cell types and is protected by the blood brain barrier (BBB). In non-dividing cells, RNA-lipid complexes demonstrated increased transfection efficiency relative to DNA transfection. The efficiency, timing of the onset, and duration of expression after transfection may determine which nucleic acid is best for which proposed therapy. Expression can be seen as soon as 1 h after RNA delivery, but duration of expression has been limited to 5–7 h. In contrast, transfection with a DNA lipoplex demonstrates protein expression within 5 h and lasts as long as several weeks after transfection.

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“…Due to their enhanced membrane adhesive nature, particles carrying genes of interest enable enhanced transfection efficiency to recipient cells. Size and composition of CS nanoparticles are fundamental factors that determine targeting and biodistribution to tumors of various origins (55). Nanosized carriers are suitable for disease models that are hypervascularized, such as brain tumors, and would benefit from the enhanced permeability and retention effect permitting passive diffusion in the intratumoral space; this effect limits off-target toxicity (56).…”

Section: Chitosan-based Nanostructures For Brain Cancer Treatmentmentioning

confidence: 99%