Gene therapy for ocular diseases meditated by ultrasound and microbubbles (Review)

Abstract

The eye is an ideal target organ for gene therapy as it is easily accessible and immune-privileged. With the increasing insight into the underlying molecular mechanisms of ocular diseases, gene therapy has been proposed as an effective approach. Successful gene therapy depends on efficient gene transfer to targeted cells to prove stable and prolonged gene expression with minimal toxicity. At present, the main hindrance regarding the clinical application of gene therapy is not the lack of an ideal gene, but rather the lack of a safe and efficient method to selectively deliver genes to target cells and tissues. Ultrasound-targeted microbubble destruction (UTMD), with the advantages of high safety, repetitive applicability and tissue targeting, has become a potential strategy for gene- and drug delivery. When gene-loaded microbubbles are injected, UTMD is able to enhance the transport of the gene to the targeted cells. High-amplitude oscillations of microbubbles act as cavitation nuclei which can effectively focus ultrasound energy, produce oscillations and disruptions that increase the permeability of the cell membrane and create transient pores in the cell membrane. Thereby, the efficiency of gene therapy can be significantly improved. The UTMD-mediated gene delivery system has been widely used in pre-clinical studies to enhance gene expression in a site-specific manner in a variety of organs. With reasonable application, the effects of sonoporation can be spatially and temporally controlled to improve localized tissue deposition of gene complexes for ocular gene therapy applications. In addition, appropriately powered, focused ultrasound combined with microbubbles can induce a reversible disruption of the blood-retinal barrier with no significant side effects. The present review discusses the current status of gene therapy of ocular diseases as well as studies on gene therapy of ocular diseases meditated by UTMD.

Ultrasound-targeted microbubbles combined with a peptide nucleic acid binding nuclear localization signal mediate transfection of exogenous genes by improving cytoplasmic and nuclear import

“…UTMD is considered to be an important method of gene delivery. Numerous studies have suggested that microbubbles, which serve as cavitation nuclei, facilitate cavitation during ultrasound exposure ( 5 , 18 , 19 ). To achieve good transfection efficiency, it is important for the pDNA to translocate from the cytoplasm to the nucleus.…”

Ultrasound-Responsive Materials for Drug/Gene Delivery

“…Ultrasound-responsive material-based drug/gene delivery has been explored widely in treating cancer (Khokhlova et al, 2015;Qin et al, 2016;Fan et al, 2017;Yue et al, 2018;Jing et al, 2019), cardiovascular diseases (Hua et al, 2014;Dixon et al, 2015;Castle and Feinstein, 2016), orthopedic diseases (Le et al, 2016;Pullan et al, 2017;Kuo et al, 2019), ocular diseases (Aptel and Lafon, 2012;Wan et al, 2015a;Wan et al, 2015b;Lafond et al, 2017) and brain diseases (Timbie et al, 2015;Song et al, 2018a), and also applied in vaccine immunization (Tachibana et al, 1997;Escoffre et al, 2016). However, application of ultrasound-responsive materials in drug/gene delivery faces certain challenges.…”

Current Approaches in Ocular Drug Delivery Systems

“…Çalışmalar sonucunda, viral sistemlerin hücrelere yüksek etkinlikte genetik materyal taşınmasını sağlayarak sürdürülebilir gen ekspresyonunu devam ettirdikleri görülmüştür. 44 Contreras-Ruiz ve ark., oküler yüzeye gen iletimi sağlamak için hiyalüronik asit ve kitozan gibi biyouyumlu ve biyoadeziv polisakkaritlerden oluşan nanopartiküller geliştirmişlerdir. 45 Kitosan nanopartikülleri uzun bir süre boyunca oküler mukozada kalır ve mukozayla etkileşir.…”