Ultrasound-mediated blood–spinal cord barrier opening prolongs survival in an ALS mouse model
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PROVIDER: PRJNA1124127 | ENA |
REPOSITORIES: ENA
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Project description:Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons. The limited efficacy of recent therapies in clinical development may be linked to lack of drug penetration to the affected motor neurons due to the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB). Methods: In this work, the safety and efficacy of repeated short transient opening of the BSCB by low intensity pulsed ultrasound (US, sonication) was studied in females of an ALS mouse model (B6.Cg-Tg(SOD1*G93A)1Gur/J). The BSCB was disrupted using a 1 MHz ultrasound transducer coupled to the spinal cord, with and without injection of insulin-like growth factor 1 (IGF1), a neurotrophic factor that has previously shown efficacy in ALS models. Findings: Results in healthy mouse models demonstrated that the BSCB can be safely disrupted and IGF1 concentrations significantly enhanced after a single session of transient BSCB disruption (176 ±32 µg/g vs. 0.16 ±0.008 µg/g, p<0.0001). Five repeated weekly US performed in female ALS mice demonstrated a survival advantage in mice treated with IGF1 and ultrasound (US+IGF1) compared to treatment with IGF1 alone (176 vs. 166 days, p=0.0038). Surprisingly, this survival advantage was also present in mice treated with ultrasound (US) alone vs untreated mice (178.5 vs. 166.5 days, p=0.0061). Analysis of glial cell immunoreactivity and microglial transcriptome showing reduced cell proliferation pathways, in addition to lymphocyte infiltration, suggested that the beneficial effect of US or US+IGF1 could act through immune cell modulation. Interpretation: These results show the first step towards a possible beneficial impact of transient BSCB opening for ALS therapy and suggest implication of immune cells.
2024-07-15 | GSE269925 | GEO
Project description:Therapeutic antibodies targeting immune checkpoints have shown limited efficacy in clinical trials in glioblastoma (GBM) patients. Ultrasound-mediated blood-brain barrier opening (UMBO) using low-intensity pulsed ultrasound improved drug delivery to the brain. We explored the safety and the efficacy of UMBO plus immune checkpoint inhibitors in preclinical models of GBM. A Blood-brain barrier (BBB) opening was performed using a 1 MHz preclinical ultrasound system in combination with 10µl/g microbubbles. Brain penetration of immune checkpoint inhibitors was determined, and immune cell populations were evaluated using flow cytometry.The impact of repeated treatments on survival was determined. In syngeneic GL261-bearing immunocompetent mice, we showed that UMBO safely and repeatedly open the BBB. BBB opening was confirmed visually and microscopically using Evans’s blue dye and magnetic resonance imaging. UMBO plus anti-PDL-1 was associated with a significant improvement of the overall survival compared to anti-PD-L1 alone. Using mass spectroscopy, we showed that the penetration of therapeutic antibodies can be increased when delivered intravenously compared to non-sonicated brains. Furthermore, we observed an enhancement of activated microglia percentage when combined with anti-PD-L1. Here, we report that the combination of UMBO and anti-PD-L1 dramatically increases GL261-bearing mice's survival compared to their counterparts treated with anti-PD-L1 alone. Our study highlights the BBB as a limitation to overcome to increase the efficacy of anti-PD-L1 in GBM and supports clinical trials combining UMBO and in GBM patients.
2023-02-28 | GSE220909 | GEO
Project description:Activating microbubbles (MBs) with focused ultrasound (FUS) for blood-brain (BBB) and blood-tumor barrier (BTB) opening permits targeted therapeutic delivery. While the effects of FUS-mediated BBB opening have been investigated for normal brain tissue, no such studies exist for intracranial tumors. As this technology advances into clinical immunotherapy trials, it will be crucial to understand how FUS modulates the tumor immune microenvironment. Here, bulk RNA sequencing revealed that FUS BTB/BBB opening (1 MHz, 0.5 MPa peak-negative pressure) of intracranial B16F1cOVA tumors increases the expression of genes related to proinflammatory cytokine and chemokine signaling, pattern recognition receptor signaling, and antigen processing and presentation. Flow cytometry revealed increased maturation (i.e. CD86) of dendritic cells (DCs) in the meninges and altered antigen loading of DCs in both the tumor and meninges. For DCs in tumor draining lymph nodes, FUS had no effect on maturation and elicited only a trend towards increased presentation of tumor-derived peptide by MHC. Neither tumor endothelial cell adhesion molecule expression nor homing of activated T cells was affected by FUS. In conclusion, FUS-mediated BTB/BBB opening elicits signatures of inflammation; however, the response is mild, transient, and unlikely to elicit a systemic response independent of administration of immune adjuvants.
2020-06-10 | GSE152138 | GEO
Project description:Single-cell sequencing of brain macrophages after focused-ultrasound blood-brain barrier opening
| PRJNA816515 | ENA
Project description:Focused Ultrasound (FUS) combined with microbubbles (FUS+MB) to transiently open the blood brain barrier (BBB) has shown promise as an immunotherapeutic in models of neurodegenerative disorders - resulting in significantly reduced pathological load and improved cognition. Preliminary histology and bulk tissue analysis of FUS+MB have indicated brain macrophage changes as a potential mechanism of the immunotherapy. However, prior to this study the temporal effect of FUS+MB on the two dominant brain macrophage populations - microglia and central nervous system associated macrophages (CAM) has not been reported. In this study, we establish that FUS+MB triggers a biphasic process involving both microglia and CAM. In the Phase I, 24h after treatment, microglia and resident CAM exhibit an early response signature, characterized by the upregulation of recruitment-associated chemokine and cytokines. In Phase II, 72h after treatment, CAM population size increases dramatically and both cell types exhibit a late response signature, characterized by upregulation of interferon genes indicative of cellular activation and immune response. Next, cell cycle analysis and immunohistochemistry indicate that microglia exhibit increased proliferation across both phases but CAM do not. Finally, the brain macrophage population size is correlated with the ultrasound-induced cavitation dose, indicating a dose-dependent response to treatment. The findings presented herein not only provide insight into the mechanism of the FUS+MB immunomodulatory effects but also into a mechanism of brain macrophage response that is capable of ameliorating neurological disease.
2023-06-17 | GSE198707 | GEO
Project description:Immunomodulation of Intracranial Melanoma in Response to Blood-Tumor Barrier Opening with Focused Ultrasound - Bulk RNA seq
| PRJNA638393 | ENA
Project description:Insults to the cerebral cortex, such as trauma, ischemia or infections, may result in the development of epilepsy, one of the most common neurological disorders. Previous studies have suggested that perturbations in neurovascular integrity and breakdown of the blood-brain barrier (BBB) lead to neuronal hypersynchronization and epileptiform activity, but the underlying mechanisms are unknown. As with BBB opening, treatment with albumin or with TGF-?1 results in the development of hypersynchronized epileptiform activity. Given the latent period before the appearance of epileptiform activity, we hypothesized the underlying mechanism is a transcriptional response which would be similar for BBB breakdown and exposure to albumin or TGF-?1. In search of a common pathway and transcriptional activation pattern we performed a genome wide analysis. Genomic expression analyses demonstrated similar expression patterns for BBB opening, albumin and TGF-?1 exposure. Most importantly, TGF-? pathway blockers suppressed most albumin-induced transcriptional changes. RNA was extracted from cortical regions of rats treated with sodium deoxycholate (DOC, to induce BBB opening), albumin or TGF-?1 for various durations (7/8, 24, 48hr). Control RNA was extracted from a sham-operated animal and one array was run for each treatment and time point A second set of animals (labeled as Set 2) was treated with either albumin (n=3) or albumin in the presence of TGF-? receptor blockers (n=4; TGF-?R1 kinase activity inhibitor SB431542 and TGF-?R2 antibody) and sacrificed 24 hr following treatment. Sham-operated animals served as controls (n=2).
2009-07-15 | E-GEOD-12304 | biostudies-arrayexpress
Project description:A prevalent view in treating age-dependent disorders including Alzheimer’s disease (AD) is that the underlying amyloid plaque pathology must be targeted for cognitive improvements. In contrast, we report here that repeated scanning ultrasound (SUS) treatment at 1 MHz frequency can ameliorate memory deficits in the APP23 mouse model of AD without reducing amyloid-β (Aβ) burden. Different from previous studies that had shown Aβ clearance as a consequence of blood-brain barrier (BBB) opening, here, the BBB was not opened as no microbubbles were used. Quantitative proteomics and functional magnetic resonance imaging revealed that ultrasound induced long-lasting functional changes that correlate with the improvement in memory. Intriguingly, the treatment was more effective at a higher frequency (1MHz) than at a frequency within the range currently explored in clinical trials in AD patients (286 kHz). Together, our data suggest frequency-dependent bio-effects of ultrasound and a dissociation of cognitive improvement and Aβ clearance, with important implications for the design of trials for AD therapies.
2024-03-19 | PXD050248 | Pride
Project description:Low-intensity pulsed ultrasound-mediated blood-brain barrier opening increases anti programmed death-ligand 1 delivery and efficacy in Gl261 mouse model
| PRJNA911839 | ENA
Project description:Identification of amyotrophic lateral sclerosis (ALS) associated genes. Post mortem spinal cord grey matter from sporadic and familial ALS patients compared with controls.
2007-09-26 | E-GEOD-833 | biostudies-arrayexpress