Microbubble-facilitated ultrasound pulsation promotes direct α-synuclein gene delivery

Lin, Chia Jung; Lin, Chung Yin; Lin, Ya Ping; Huang, Chiung Yin; Wei, Kuo-Chen; Chen, Jin-Chung; Lee-Chen, Guey Jen; Liu, Hao Li

doi:10.1016/j.bbrc.2019.07.017

Cited by 7 publications

(5 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These findings support the prospect that UTMD can fulfill any specific gene delivery to CNS targets. We have recently succeeded in directly transfecting WT αSNCA into target sites to induce aberrant αSNCA aggregation (resulting in both an approximately two-fold increase in in vitro cell lines and a 1.68-fold increase in in vivo as compared to controls) [26]. These preliminary results demonstrated that artificially created αSNCA aggregates significantly reduced mitochondrial function.…”

Section: Introductionmentioning

confidence: 92%

“…The GFP-tagged WT αSNCA (NM_000345) plasmid construct (pαSNCA) was obtained (a gift from Dr. Guey-Jen Lee-Chen, National Taiwan Normal University). The amplified αSNCA cDNA was applying 5 -CCATGGATGGATGTATTCATGAAAGGAC-3 forward and 5 -CCATGGCTTCAGGTTCGTAGTCTTG-3 reverse primers and ligated into NcoI site of pEGFP-N1 (Takara Bio., San Jose, CA, USA) to produce the pαSNCA [26]. The pαSNCA encapsulating liposomes to construct liposomal pαSNCA (LpαSNCA) was prepared as previously reported [23][24][25].…”

Section: Plasmid α-Synuclein (Pαsnca) and Liposomal Pαsnca (Lpαsnca) ...mentioning

confidence: 99%

See 1 more Smart Citation

Focused Ultrasound-Induced Blood–Brain Barrier Opening Enhanced α-Synuclein Expression in Mice for Modeling Parkinson’s Disease

et al. 2022

Self Cite

View full text Add to dashboard Cite

Parkinson’s disease (PD) is characterized by α-synuclein (αSNCA) aggregation in dopaminergic neurons. Gradual accumulation of αSNCA aggregates in substantia nigra (SN) diminishes the normal functioning of soluble αSNCA, leading to a loss of dopamine (DA) neurons. In this study, we developed focused ultrasound-targeted microbubble destruction (UTMD)-mediated PD model that could generate the disease phenotype via αSNCA CNS gene delivery. The formation of neuronal aggregates was analyzed with immunostaining. To evaluate the DA cell loss, we used tyrosine hydroxylase immunostaining and HPLC analysis on DA and its two metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). This loss of DA was associated with a dose-dependent impairment in motor function, as assessed by the rotarod motor assessment. We demonstrate that UTMD-induced SNCA expression initiates αSNCA aggregation and results in a 50% loss of DA in SN. UTMD-related dose-dependent neuronal loss was identified, and it correlates with the degree of impairment of motor function. In comparison to chemical neurotoxin 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated and conventional intracerebral (IC)-injected animal models of PD, the UTMD-mediated αSNCA-based mouse model offers the advantage of mimicking the rapid development of the PD phenotype. The PD models that we created using UTMD also prove valuable in assessing specific aspects of PD pathogenesis and can serve as a useful PD model for the development of new therapeutic strategies.

show abstract

Section: Introductionmentioning

confidence: 92%

Section: Plasmid α-Synuclein (Pαsnca) and Liposomal Pαsnca (Lpαsnca) ...mentioning

confidence: 99%

Focused Ultrasound-Induced Blood–Brain Barrier Opening Enhanced α-Synuclein Expression in Mice for Modeling Parkinson’s Disease

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…FUS-mediated BBBD is an attractive modality compared to surgery or global chemical BBBD methods, as it is non-invasive, targeted, and easily repeatable. This approach has enabled successful delivery of many therapeutics to the brain normally barred by the BBB, such as antibodies 5 - 7 , genes 8 - 10 , and neural stem cells 11 , 12 . Moreover, the safety of FUS-mediated BBBD has been asserted in several studies 3 , 13 , 14 and continues to be tested in multiple clinical trials (NCT02986932, NCT03739905, NCT03119961, NCT03671889, NCT04118764).…”

Section: Introductionmentioning

confidence: 99%

Multiple regression analysis of a comprehensive transcriptomic data assembly elucidates mechanically- and biochemically-driven responses to focused ultrasound blood-brain barrier disruption

2021

View full text Add to dashboard Cite

Background: Focused ultrasound (FUS) blood brain barrier disruption (BBBD) permits the noninvasive, targeted, and repeatable delivery of drugs to the brain. FUS BBBD also elicits secondary responses capable of augmenting immunotherapies, clearing amyloid-β and hyperphosphorylated tau, and driving neurogenesis. Leveraging these secondary effects will benefit from an understanding of how they correlate to the magnitude of FUS BBBD and are differentially affected by the mechanical and biochemical stimuli imparted during FUS BBBD. Methods: We aggregated 75 murine transcriptomes in a multiple regression framework to identify genes expressed in proportion to biochemical (i.e. contrast MR image enhancement (CE)) or mechanical (i.e. harmonic acoustic emissions from MB-activation (MBA)) stimuli associated with FUS BBBD. Models were constructed to control for potential confounders, such as sex, anesthesia, and sequencing batch. Results: MBA and CE differentially predicted expression of 1,124 genes 6 h or 24 h later. While there existed overlap in the transcripts correlated with MBA vs CE, MBA was principally predictive of expression of genes associated with endothelial reactivity while CE chiefly predicted sterile inflammation gene sets. Over-representation analysis identified transcripts not previously linked to BBBD, including actin filament organization, which is likely important for BBB recovery. Transcripts and pathways associated with neurogenesis, microglial activation, and amyloid-β clearance were significantly correlated to BBBD metrics. Conclusions: The secondary effects of BBBD may have the potential to be tuned by modulating FUS parameters during BBBD, and MBA and CE may serve as independent predictors of transcriptional reactions in the brain.

show abstract

“…FUS induced BBBD is an attractive alternative to surgical and chemical methods as it is targeted, noninvasive, and repeatable. Many therapies normally restricted by the BBB have been successfully delivered with FUS + MB, including antibodies, 5‐7 chemotherapeutics, 8‐10 neural stem cells, 11,12 and genes 13‐15 …”

Section: Introductionmentioning

confidence: 99%

Transcriptomic response of brain tissue to focused ultrasound‐mediated blood–brain barrier disruption depends strongly on anesthesia

Mathew

Gorick

Thim

et al. 2020

Bioengineering & Transla Med

View full text Add to dashboard Cite

Focused ultrasound (FUS) mediated blood–brain barrier disruption (BBBD) targets the delivery of systemically‐administered therapeutics to the central nervous system. Preclinical investigations of BBBD have been performed on different anesthetic backgrounds; however, the influence of the choice of anesthetic on the molecular response to BBBD is unknown, despite its potential to critically affect interpretation of experimental therapeutic outcomes. Here, using bulk RNA sequencing, we comprehensively examined the transcriptomic response of both normal brain tissue and brain tissue exposed to FUS‐induced BBBD in mice anesthetized with either isoflurane with medical air (Iso) or ketamine/dexmedetomidine (KD). In normal murine brain tissue, Iso alone elicited minimal differential gene expression (DGE) and repressed pathways associated with neuronal signaling. KD alone, however, led to massive DGE and enrichment of pathways associated with protein synthesis. In brain tissue exposed to BBBD (1 MHz, 0.5 Hz pulse repetition frequency, 0.4 MPa peak‐negative pressure), we systematically evaluated the relative effects of anesthesia, microbubbles, and FUS on the transcriptome. Of particular interest, we observed that gene sets associated with sterile inflammatory responses and cell–cell junctional activity were induced by BBBD, regardless of the choice of anesthesia. Meanwhile, gene sets associated with metabolism, platelet activity, tissue repair, and signaling pathways, were differentially affected by BBBD, with a strong dependence on the anesthetic. We conclude that the underlying transcriptomic response to FUS‐mediated BBBD may be powerfully influenced by anesthesia. These findings raise considerations for the translation of FUS‐BBBD delivery approaches that impact, in particular, metabolism, tissue repair, and intracellular signaling.

show abstract

Microbubble-facilitated ultrasound pulsation promotes direct α-synuclein gene delivery

Cited by 7 publications

References 25 publications

Focused Ultrasound-Induced Blood–Brain Barrier Opening Enhanced α-Synuclein Expression in Mice for Modeling Parkinson’s Disease

Focused Ultrasound-Induced Blood–Brain Barrier Opening Enhanced α-Synuclein Expression in Mice for Modeling Parkinson’s Disease

Multiple regression analysis of a comprehensive transcriptomic data assembly elucidates mechanically- and biochemically-driven responses to focused ultrasound blood-brain barrier disruption

Transcriptomic response of brain tissue to focused ultrasound‐mediated blood–brain barrier disruption depends strongly on anesthesia

Contact Info

Product

Resources

About