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JOURNAL OF LETTER TO THE EDITOR http://dx.doi.org/10.1097/JBR.0000000000000133 Shuai Qu, Renfa Liu, Zhifei Dai* To the editor: strategy can be used for gene delivery in all blood vessels that Gene therapy is considered a promising treatment option for sev- can be seen by ultrasound imaging. We have validated the feasi- eral diseases, including neuromuscular disease, cardiovascular bility of this strategy in the mouse carotid and femoral arteries diseases, immunodeficiencies, and cancer. However, the promise and abdominal aorta. We also tested this strategy for gene ther-  of gene therapy is largely compromised by a lack of suitable apy of atherosclerosis in a mouse model. [1,2] gene delivery systems. Gene delivery approaches using com- The combination of ultrasound, MBs, and AAVs represents mon gene vectors including viral and nonviral vectors typically a unique strategy to achieve imaging-guided gene delivery. AAV rely on specific targeting moieties or tissue tropism of the vec- gene vectors are the leading platform for gene delivery due to tors. However, not all tissues possess unique receptors suitable their capability to transduce a wide range of cell types in vivo. for targeted gene delivery. This issue can be potentially solved With the help of ultrasound and MBs, AAV gene vectors can by introducing external physical stimuli, such as ultrasound, induce potent transgene expression with spatial specificity in a  magnetic force, heat, and light, which can guide the transgene noninvasive manner. In an earlier report by Szablowski et al, a expression independent of the intrinsic properties of the cells of similar strategy was utilized to apply imaging-guided gene deliv- [3–5] interest. In addition, such physical stimuli can be integrated ery to neurons for selective control over individual brain regions with medical imaging, thus making imaging-guided gene deliv- in a mouse model of memory formation. Focused ultrasound ery possible. In this scenario, physical stimuli are applied to the guided by magnetic resonance imaging was used to selectively area of interest guided by medical imaging and can then trigger open the blood–brain barrier in combination with MBs, which robust transgene expression in selected areas. induced specific transgene expression by AAVs. In addition, Recently, our team reported such a strategy that integrates cell-specific promoters were applied to confer the cell specificity  ultrasound imaging, microbubbles (MBs), and adeno-associated of this strategy. virus (AAV) vectors for noninvasive spatial control of transgene Considering that ultrasound and MBs are widely used in  expression in mouse artery. In our study, a clinical diagnos- clinical settings and AAVs have been verified in several clini-  tic ultrasound imaging system, which is also used for clinical cal trials, this strategy can be clinically translatable. However, carotid ultrasound imaging, was used for simultaneously imag- further improvements are still needed. For example, instead of ing and generating ultrasound stimuli. With color Doppler the one-dimensional array ultrasound probe used here, the use ultrasound imaging, the mouse’s carotid artery can be clearly of two-dimensional probes could facilitate the scaling of the visualized, and a region of interest can be randomly selected ultrasound- and MB-guided AAV strategy to larger animals. At on the image, allowing the ultrasound to be focused on that the same time, three-dimensional real-time ultrasound imaging region. Following the injection of MBs, the MBs can be selec- could make the ultrasound imaging and MB destruction more tively blasted in the region of interest by the ultrasound wave precise. Additional work is also warranted to make the AAV used for imaging, thereby increasing the permeability of the tis- gene vectors more efficient in order to lower the required doses. sue in the selected region. The transient permeability changes The use of more robust cell-specific promoters could reduce can induce highly increased accumulation of AAVs and, thereby, nonspecific transgene expression in major organs. Considering robust transgene expression (Fig. 1). The transgene expression the high price and potential safety issues of AAV gene vectors, in arterial endothelial cells was increased by ~24-fold and per- developing nonviral alternatives, such as nucleic acid-loaded  sisted for >8 weeks. In addition, transgene expression in the lipid or polymer nanoparticles, is needed. vascular media and adventitia was also increased by approxi- In summary, we believe combinatorial image-guided gene mately 86-fold. In theory, this ultrasound- and MB-guided AAV delivery holds tremendous potential, with many aspects still unexplored, to overcome several critical challenges faced by gene therapy today and significantly expand its clinical utility . SQ and RL contributed equally to the writing of the article. Department of Biomedical Engineering, College of Future Technology, National Biomedical Imaging Center, Peking University, Beijing, China Acknowledgments *Corresponding author: Zhifei Dai, Department of Biomedical Engineering, College None. of Future Technology, National Biomedical Imaging Center, Peking University, Beijing 100871, China. E-mail: email@example.com Copyright © 2022 The Chinese Medical Association, Published by Wolters Author contributions Kluwer Health, Inc. This is an open-access article distributed under the terms of SQ, RL, and ZD designed, wrote and edited the manuscript. All the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 authors approved the final version of the manuscript. (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Financial support Journal of Bio-X Research (2022) 5:143–144 Received: 08 August 2022; Accepted: 24 August 2022 This work was financially supported by National Natural Science Foundation of China (No. 81930047, to ZD; No. http://dx.doi.org/10.1097/JBR.0000000000000133 143 LETTER TO THE EDITOR Journal of Bio-X Research Figure 1. UMGAAV paradigm. In the UMGAAV sequence, the mouse artery can be visualized by ultrasound imaging. After injecting microbubbles, microbub- bles can be selectively destroyed with ultrasound wave generated by the imaging probe under color Doppler mode, increasing the permeability of artery endo- thelium. Then the injected adeno-associated virus (AAV) can specifically accumulate in the ultrasound-treated area, resulting in targeted transgene expression in mouse artery.  Qu S, Liu RF, Zhang NS, et al. Non-viral nucleic acid therapeutics: 82102062 to RL) and China Postdoctoral Science Foundation Revolutionizing the landscape of atherosclerotic treatment. Nano (No. 2020TQ0008, to RL). Today 2022;45:101514.  Zhu H, Zhang L, Tong S, et al. Spatial control of in vivo CRISPR-Cas9 genome editing via nanomagnets. Nat Biomed Eng 2019;3:126–136. Conflicts of interest  Chertok B, Langer R, Anderson DG. Spatial control of gene expression by nanocarriers using heparin masking and ultrasound-targeted micro- The authors declare that they have no conflicts of interest. bubble destruction. ACS Nano 2016;10:7267–7278. Editor note: ZD is an Editorial Board member of Journal of  Miller IC, Zamat A, Sun LK, et al. Enhanced intratumoural activity of Bio-X Research. He was blinded from reviewing or making deci- CAR T cells engineered to produce immunomodulators under photo- sions on the manuscript. The article was subject to the journal’s thermal control. Nat Biomed Eng 2021;5:1348–1359. standard procedures, with peer review handled independently of  Liu R, Qu S, Xu Y, et al. Spatial control of robust transgene expres- sion in mouse artery endothelium under ultrasound guidance. Signal this Editorial Board member and their research groups. Transduct Target Ther 2022;7:225.  Szablowski JO, Lee-Gosselin A, Lue B, et al. Acoustically targeted che- mogenetics for the non-invasive control of neural circuits. Nat Biomed References Eng 2018;2:475–484.  Dunbar CE, High KA, Joung JK, et al. Gene therapy comes of age.  Kuzmin DA, Shutova MV, Johnston NR, et al. The clinical landscape Science 2018;359:eaan4672. for AAV gene therapies. Nat Rev Drug Discov 2021;20:173–174.
Journal of Bio-X Research – Wolters Kluwer Health
Published: Dec 31, 2022
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