scholarly journals Ultrasound-Mediated Blood-Brain Barrier Opening Improves Whole Brain Gene Delivery in Mice

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1245
Author(s):  
Marie-Solenne Felix ◽  
Emilie Borloz ◽  
Khaled Metwally ◽  
Ambre Dauba ◽  
Benoit Larrat ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Gene Delivery ◽  
Blood Brain Barrier ◽  
Focused Ultrasound ◽  
Fold Increase ◽  
Brain Barrier ◽  
Whole Brain ◽  
External Threats ◽  
Blood Brain ◽  
The Brain

Gene therapy represents a powerful therapeutic tool to treat diseased tissues and provide a durable and effective correction. The central nervous system (CNS) is the target of many gene therapy protocols, but its high complexity makes it one of the most difficult organs to reach, in part due to the blood-brain barrier that protects it from external threats. Focused ultrasound (FUS) coupled with microbubbles appears as a technological breakthrough to deliver therapeutic agents into the CNS. While most studies focus on a specific targeted area of the brain, the present work proposes to permeabilize the entire brain for gene therapy in several pathologies. Our results show that, after i.v. administration and FUS sonication in a raster scan manner, a self-complementary AAV9-CMV-GFP vector strongly and safely infected the whole brain of mice. An increase in vector DNA (19.8 times), GFP mRNA (16.4 times), and GFP protein levels (17.4 times) was measured in whole brain extracts of FUS-treated GFP injected mice compared to non-FUS GFP injected mice. In addition to this increase in GFP levels, on average, a 7.3-fold increase of infected cells in the cortex, hippocampus, and striatum was observed. No side effects were detected in the brain of treated mice. The combining of FUS and AAV-based gene delivery represents a significant improvement in the treatment of neurological genetic diseases.

scholarly journals The Trojan Horse Liposome Technology for Nonviral Gene Transfer across the Blood-Brain Barrier

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Ruben J. Boado ◽  
William M. Pardridge
Keyword(s):  
Gene Therapy ◽  
Gene Delivery ◽  
Blood Brain Barrier ◽  
Trojan Horse ◽  
Brain Barrier ◽  
Viral Gene ◽  
Specific Gene ◽  
Gene Promoters ◽  
Blood Brain ◽  
The Brain

The application of blood-borne gene therapy protocols to the brain is limited by the presence of the blood-brain barrier (BBB). Viruses have been extensively used as gene delivery systems. However, their efficacy in brain is limited by the lack of transport across the BBB following intravenous (IV) administration. Recent progress in the “Trojan Horse Liposome” (THL) technology applied to transvascular non-viral gene therapy of the brain presents a promising solution to the trans-vascular brain gene delivery problem. THLs are comprised of immunoliposomes carrying nonviral gene expression plasmids. The tissue target specificity of the THL is provided by peptidomimetic monoclonal antibody (MAb) component of the THL, which binds to specific endogenous receptors located on both the BBB and on brain cellular membranes, for example, insulin receptor and transferrin receptor. These MAbs mediate (a) receptor-mediated transcytosis of the THL complex through the BBB, (b) endocytosis into brain cells and (c) transport to the brain cell nuclear compartment. The expression of the transgene in brain may be restricted using tissue/cell specific gene promoters. This manuscript presents an overview on the THL transport technology applied to brain disorders, including lysosomal storage disorders and Parkinson's disease.

scholarly journals Claudin-5 binder enhances focused ultrasound-mediated opening in an in vitro blood-brain barrier model

2021 ◽  
Author(s):  
Ratneswary Sutharsan ◽  
Liyu Chen ◽  
Jonathan LF Lee ◽  
Esteban Cruz ◽  
Tishila Palliyaguru ◽  
...  
Keyword(s):  
Cell Line ◽  
Blood Brain Barrier ◽  
Focused Ultrasound ◽  
Brain Barrier ◽  
Sodium Fluorescein ◽  
General Strategy ◽  
Blood Brain ◽  
Barrier Opening ◽  
The Brain ◽  
Bbb Opening

Rationale: The blood-brain barrier (BBB) while functioning as a gatekeeper of the brain, impedes cerebral drug delivery. An emerging technology to overcome this limitation is focused ultrasound (FUS). When FUS interacts with intravenously injected microbubbles (FUS+MB), the BBB opens, transiently allowing the access of therapeutic agents into the brain. However, the ultrasound parameters need to be tightly tuned: when the acoustic pressure is too low there is no opening, and when it is too high, bleeds can occur. We therefore asked whether BBB permeability can be increased by combining FUS+MB with a second modality such that in a clinical setting lower acoustic pressures could be potentially used. Methods: Given that FUS achieves BBB opening by the disruption of tight junction (TJ) proteins such as claudin-5 of brain endothelial cells, we generated a stable MDCK II cell line (eGFP-hCldn5-MDCK II) that expresses fluorescently tagged human claudin-5. Two claudin-5 binders, mC5C2 (a peptide) and cCPEm (a truncated form of an enterotoxin), that have been reported previously to weaken the barrier, were synthesized and assessed for their abilities to enhance the permeability of cellular monolayers. We then performed a comparative analysis of single and combination treatments. Results: We successfully generated a novel cell line that formed functional monolayers as validated by an increased transendothelial electrical resistance (TEER) reading and a low (< 0.2%) permeability to sodium fluorescein (376 Da). We found that the binders exerted a time- and concentration-dependent effect on BBB opening when incubated over an extended period, whereas FUS+MB caused a rapid barrier opening followed by recovery after 12 hours within the tested pressure range. Importantly, preincubation with cCPEm prior to FUS+MB treatment resulted in greater barrier opening compared to either FUS+MB or cCPEm alone as measured by reduced TEER values and an increased permeability to fluorescently labelled 40 kDa dextran (FD40). Conclusion: The data suggest that pre-incubation with clinically suitable binders to TJ proteins may be a general strategy to facilitate safer and more effective ultrasound-mediated BBB opening in cellular and animal systems and potentially also for the treatment of human diseases of the brain.

Enhanced therapeutic agent delivery through magnetic resonance imaging–monitored focused ultrasound blood-brain barrier disruption for brain tumor treatment: an overview of the current preclinical status

2012 ◽  
Vol 32 (1) ◽  
pp. E4 ◽  
Author(s):  
Hao-Li Liu ◽  
Hung-Wei Yang ◽  
Mu-Yi Hua ◽  
Kuo-Chen Wei
Keyword(s):  
Drug Delivery ◽  
Brain Tumor ◽  
Brain Tumors ◽  
Blood Brain Barrier ◽  
Focused Ultrasound ◽  
Therapeutic Agent ◽  
Brain Barrier ◽  
Term Survival ◽  
Blood Brain ◽  
The Brain

Malignant glioma is a severe primary CNS cancer with a high recurrence and mortality rate. The current strategy of surgical debulking combined with radiation therapy or chemotherapy does not provide good prognosis, tumor progression control, or improved patient survival. The blood-brain barrier (BBB) acts as a major obstacle to chemotherapeutic treatment of brain tumors by severely restricting drug delivery into the brain. Because of their high toxicity, chemotherapeutic drugs cannot be administered at sufficient concentrations by conventional delivery methods to significantly improve long-term survival of patients with brain tumors. Temporal disruption of the BBB by microbubble-enhanced focused ultrasound (FUS) exposure can increase CNS-blood permeability, providing a promising new direction to increase the concentration of therapeutic agents in the brain tumor and improve disease control. Under the guidance and monitoring of MR imaging, a brain drug-delivery platform can be developed to control and monitor therapeutic agent distribution and kinetics. The success of FUS BBB disruption in delivering a variety of therapeutic molecules into brain tumors has recently been demonstrated in an animal model. In this paper the authors review a number of critical studies that have demonstrated successful outcomes, including enhancement of the delivery of traditional clinically used chemotherapeutic agents or application of novel nanocarrier designs for actively transporting drugs or extending drug half-lives to significantly improve treatment efficacy in preclinical animal models.

Folate-conjugated gene-carrying microbubbles with focused ultrasound for concurrent blood-brain barrier opening and local gene delivery

Biomaterials ◽  
2016 ◽  
Vol 106 ◽  
pp. 46-57 ◽  
Author(s):  
Ching-Hsiang Fan ◽  
En-Ling Chang ◽  
Chien-Yu Ting ◽  
Yu-Chun Lin ◽  
En-Chi Liao ◽  
...  
Keyword(s):  
Gene Delivery ◽  
Blood Brain Barrier ◽  
Focused Ultrasound ◽  
Brain Barrier ◽  
Blood Brain ◽  
Barrier Opening ◽  
Blood Brain Barrier Opening
Sign in / Sign up

Export Citation Format

Share Document