Imaging-guided gene delivery: seeing is delivering : Journal of Bio-X Research

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Letter to the Editor

Imaging-guided gene delivery: seeing is delivering

Qu, Shuai; Liu, Renfa; Dai, Zhifei*,

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Journal of Bio-XResearch 5(4):p 143-144, December 2022. | DOI: 10.1097/JBR.0000000000000133
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To the editor:Gene therapy is considered a promising treatment option for several diseases, including neuromuscular disease, cardiovascular diseases, immunodeficiencies, and cancer. However, the promise of gene therapy is largely compromised by a lack of suitable gene delivery systems.[1,2] Gene delivery approaches using common gene vectors including viral and nonviral vectors typically rely on specific targeting moieties or tissue tropism of the vectors. However, not all tissues possess unique receptors suitable for targeted gene delivery. This issue can be potentially solved by introducing external physical stimuli, such as ultrasound, magnetic force, heat, and light, which can guide the transgene expression independent of the intrinsic properties of the cells of interest.[3–5] In addition, such physical stimuli can be integrated with medical imaging, thus making imaging-guided gene delivery possible. In this scenario, physical stimuli are applied to the area of interest guided by medical imaging and can then trigger robust transgene expression in selected areas.

Recently, our team reported such a strategy that integrates ultrasound imaging, microbubbles (MBs), and adeno-associated virus (AAV) vectors for noninvasive spatial control of transgene expression in mouse artery.[6] In our study, a clinical diagnostic ultrasound imaging system, which is also used for clinical carotid ultrasound imaging, was used for simultaneously imaging and generating ultrasound stimuli. With color Doppler ultrasound imaging, the mouse’s carotid artery can be clearly visualized, and a region of interest can be randomly selected on the image, allowing the ultrasound to be focused on that region. Following the injection of MBs, the MBs can be selectively blasted in the region of interest by the ultrasound wave used for imaging, thereby increasing the permeability of the tissue in the selected region. The transient permeability changes can induce highly increased accumulation of AAVs and, thereby, robust transgene expression (Fig. 1). The transgene expression in arterial endothelial cells was increased by ~24-fold and persisted for >8 weeks. In addition, transgene expression in the vascular media and adventitia was also increased by approximately 86-fold. In theory, this ultrasound- and MB-guided AAV strategy can be used for gene delivery in all blood vessels that can be seen by ultrasound imaging. We have validated the feasibility of this strategy in the mouse carotid and femoral arteries and abdominal aorta. We also tested this strategy for gene therapy of atherosclerosis in a mouse model.[6]

The combination of ultrasound, MBs, and AAVs represents a unique strategy to achieve imaging-guided gene delivery. AAV gene vectors are the leading platform for gene delivery due to their capability to transduce a wide range of cell types in vivo. With the help of ultrasound and MBs, AAV gene vectors can induce potent transgene expression with spatial specificity in a noninvasive manner. In an earlier report by Szablowski et al,[7] a similar strategy was utilized to apply imaging-guided gene delivery to neurons for selective control over individual brain regions in a mouse model of memory formation. Focused ultrasound guided by magnetic resonance imaging was used to selectively open the blood–brain barrier in combination with MBs, which induced specific transgene expression by AAVs. In addition, cell-specific promoters were applied to confer the cell specificity of this strategy.[7]

Considering that ultrasound and MBs are widely used in clinical settings and AAVs have been verified in several clinical trials,[8] this strategy can be clinically translatable. However, further improvements are still needed. For example, instead of the one-dimensional array ultrasound probe used here, the use of two-dimensional probes could facilitate the scaling of the ultrasound- and MB-guided AAV strategy to larger animals. At the same time, three-dimensional real-time ultrasound imaging could make the ultrasound imaging and MB destruction more precise. Additional work is also warranted to make the AAV gene vectors more efficient in order to lower the required doses. The use of more robust cell-specific promoters could reduce nonspecific transgene expression in major organs. Considering the high price and potential safety issues of AAV gene vectors, developing nonviral alternatives, such as nucleic acid-loaded lipid or polymer nanoparticles, is needed.[2]

In summary, we believe combinatorial image-guided gene 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.

F1
Figure 1.:
UMGAAV paradigm. In the UMGAAV sequence, the mouse artery can be visualized by ultrasound imaging. After injecting microbubbles, microbubbles can be selectively destroyed with ultrasound wave generated by the imaging probe under color Doppler mode, increasing the permeability of artery endothelium. Then the injected adeno-associated virus (AAV) can specifically accumulate in the ultrasound-treated area, resulting in targeted transgene expression in mouse artery.

Acknowledgments

None.

Author contributions

SQ, RL, and ZD designed, wrote and edited the manuscript. All authors approved the final version of the manuscript.

Financial support

This work was financially supported by National Natural Science Foundation of China (No. 81930047, to ZD; No. 82102062 to RL) and China Postdoctoral Science Foundation (No. 2020TQ0008, to RL).

Conflicts of interest

The authors declare that they have no conflicts of interest.

Editor note: ZD is an Editorial Board member of Journal of Bio-X Research. He was blinded from reviewing or making decisions on the manuscript. The article was subject to the journal’s standard procedures, with peer review handled independently of this Editorial Board member and their research groups.

References

[1]. Dunbar CE, High KA, Joung JK, et al. Gene therapy comes of age. Science 2018;359:eaan4672.
[2]. Qu S, Liu RF, Zhang NS, et al. Non-viral nucleic acid therapeutics: Revolutionizing the landscape of atherosclerotic treatment. Nano Today 2022;45:101514.
[3]. 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.
[4]. Chertok B, Langer R, Anderson DG. Spatial control of gene expression by nanocarriers using heparin masking and ultrasound-targeted microbubble destruction. ACS Nano 2016;10:7267–7278.
[5]. Miller IC, Zamat A, Sun LK, et al. Enhanced intratumoural activity of CAR T cells engineered to produce immunomodulators under photothermal control. Nat Biomed Eng 2021;5:1348–1359.
[6]. Liu R, Qu S, Xu Y, et al. Spatial control of robust transgene expression in mouse artery endothelium under ultrasound guidance. Signal Transduct Target Ther 2022;7:225.
[7]. Szablowski JO, Lee-Gosselin A, Lue B, et al. Acoustically targeted chemogenetics for the non-invasive control of neural circuits. Nat Biomed Eng 2018;2:475–484.
[8]. Kuzmin DA, Shutova MV, Johnston NR, et al. The clinical landscape for AAV gene therapies. Nat Rev Drug Discov 2021;20:173–174.
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