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

Wan C, Li F, Li H - Mol Med Rep (2015)

Bottom Line: 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.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.In addition, appropriately powered, focused ultrasound combined with microbubbles can induce a reversible disruption of the blood‑retinal barrier with no significant side effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Ultrasound, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China.

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.

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Related in: MedlinePlus

Micrographs of hematoxylin- and eosin-stained sections from each experimental group. Images on the right are high-magnification views of the boxed regions shown on the left. (A and B) Control eye without sonication; (C and D) 0.81 MPa; (E and F) 0.88 MPa; (G and H) 1.1 MPa. At 0.81 and 0.88 MPa, the retina in the sonicated region appeared to be generally unaffected except for a small number of small clusters of extravasated erythrocytes in the nuclear layers of the retina. More extensive damage was observed after sonication at 1.1 MPa. Scale bars, 100 mm. Image taken from Park et al (76).
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f7-mmr-12-04-4803: Micrographs of hematoxylin- and eosin-stained sections from each experimental group. Images on the right are high-magnification views of the boxed regions shown on the left. (A and B) Control eye without sonication; (C and D) 0.81 MPa; (E and F) 0.88 MPa; (G and H) 1.1 MPa. At 0.81 and 0.88 MPa, the retina in the sonicated region appeared to be generally unaffected except for a small number of small clusters of extravasated erythrocytes in the nuclear layers of the retina. More extensive damage was observed after sonication at 1.1 MPa. Scale bars, 100 mm. Image taken from Park et al (76).

Mentions: A non-invasive, reversible and targeted technique that combines low-energy ultrasound bursts with a microbubble ultrasound contrast agent to temporarily induce blood-brain barrier (BBB) disruption was identified (74). The barrier can be restored without significant side effects, and the method was shown to improve therapeutic outcomes in animal disease models (75). In principle, similar techniques may be used to deliver drugs or genes to the retina. Using a rat model, Park et al (76) demonstrated that burst ultrasound together with an intravenously (i.v.) administered microbubble agent was able to induce transient increases of retinal vascular permeability for ocular drug delivery. For BRB disruption, 10-msec bursts were applied at 1 Hz for 60 sec with different peak rarefactional pressure amplitudes (0.81, 0.88 and 1.1 MPa). To evaluate BRB disruption, a magnetic resonance imaging contrast agent gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA; Magnevist) was injected i.v. immediately after the last sonication, and serial T1-weighted magnetic resonance images were acquired at up to 30 min. No signal enhancement was observed, suggesting that no Gd-DTPA leakage into the retina or vitreous humor was present in the non-sonicated animals. All of the animals that received ultrasound and microbubbles showed detectable signal enhancement. Though the maximum signal enhancement was greatest after sonication at 1.1 MPa, the retinal damage was severe (Fig. 7). Increased petechaie and retinitis were observed after sonication at 1.1 MPa. No significant retinal damage was identified by histological analysis at the two lower acoustic pressure amplitudes tested, and the barrier was found to be restored 3 h after sonication. The study demonstrated that appropriately powered focused ultrasound combined with microbubble induced a temporary and reversible disruption of the BRB in rats without any significant side effects. The BRB appeared to be restored within a few hours, which provided a suitable time-window for ocular pharmaceutical agent delivery while avoiding undesired effects that may result from long-term BRB disruption (76).


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

Wan C, Li F, Li H - Mol Med Rep (2015)

Micrographs of hematoxylin- and eosin-stained sections from each experimental group. Images on the right are high-magnification views of the boxed regions shown on the left. (A and B) Control eye without sonication; (C and D) 0.81 MPa; (E and F) 0.88 MPa; (G and H) 1.1 MPa. At 0.81 and 0.88 MPa, the retina in the sonicated region appeared to be generally unaffected except for a small number of small clusters of extravasated erythrocytes in the nuclear layers of the retina. More extensive damage was observed after sonication at 1.1 MPa. Scale bars, 100 mm. Image taken from Park et al (76).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581786&req=5

f7-mmr-12-04-4803: Micrographs of hematoxylin- and eosin-stained sections from each experimental group. Images on the right are high-magnification views of the boxed regions shown on the left. (A and B) Control eye without sonication; (C and D) 0.81 MPa; (E and F) 0.88 MPa; (G and H) 1.1 MPa. At 0.81 and 0.88 MPa, the retina in the sonicated region appeared to be generally unaffected except for a small number of small clusters of extravasated erythrocytes in the nuclear layers of the retina. More extensive damage was observed after sonication at 1.1 MPa. Scale bars, 100 mm. Image taken from Park et al (76).
Mentions: A non-invasive, reversible and targeted technique that combines low-energy ultrasound bursts with a microbubble ultrasound contrast agent to temporarily induce blood-brain barrier (BBB) disruption was identified (74). The barrier can be restored without significant side effects, and the method was shown to improve therapeutic outcomes in animal disease models (75). In principle, similar techniques may be used to deliver drugs or genes to the retina. Using a rat model, Park et al (76) demonstrated that burst ultrasound together with an intravenously (i.v.) administered microbubble agent was able to induce transient increases of retinal vascular permeability for ocular drug delivery. For BRB disruption, 10-msec bursts were applied at 1 Hz for 60 sec with different peak rarefactional pressure amplitudes (0.81, 0.88 and 1.1 MPa). To evaluate BRB disruption, a magnetic resonance imaging contrast agent gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA; Magnevist) was injected i.v. immediately after the last sonication, and serial T1-weighted magnetic resonance images were acquired at up to 30 min. No signal enhancement was observed, suggesting that no Gd-DTPA leakage into the retina or vitreous humor was present in the non-sonicated animals. All of the animals that received ultrasound and microbubbles showed detectable signal enhancement. Though the maximum signal enhancement was greatest after sonication at 1.1 MPa, the retinal damage was severe (Fig. 7). Increased petechaie and retinitis were observed after sonication at 1.1 MPa. No significant retinal damage was identified by histological analysis at the two lower acoustic pressure amplitudes tested, and the barrier was found to be restored 3 h after sonication. The study demonstrated that appropriately powered focused ultrasound combined with microbubble induced a temporary and reversible disruption of the BRB in rats without any significant side effects. The BRB appeared to be restored within a few hours, which provided a suitable time-window for ocular pharmaceutical agent delivery while avoiding undesired effects that may result from long-term BRB disruption (76).

Bottom Line: 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.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.In addition, appropriately powered, focused ultrasound combined with microbubbles can induce a reversible disruption of the blood‑retinal barrier with no significant side effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Ultrasound, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China.

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.

Show MeSH
Related in: MedlinePlus