Biology subjects

Landegger, L. D.

Publications and source records attributed to Landegger, L. D..

6 recordsLinked to original sources

bioRxiv2025

Distinct cerebrospinal fluid DNA methylation signatures linked to Alzheimer's disease

Alzheimers disease (AD) accounts for more than 60% of the dementia cases and currently there is no curative treatment for it. With the emergence of potentially disease modifying treatments, early diagnosis is key to identify patient groups that would benefit from such treatments, aiming to prevent severe cognitive decline. We previously identified a set of DNA methylation signatures that allow for accurate diagnosis of AD in cortical neurons and brain tissue, even before clinical manifestation of the disease [1]. Here we investigate 11 of these signature regions via targeted next-generation sequencing in cell-free DNA (cfDNA) isolated from cerebrospinal fluid (CSF) of AD patients homozygous for APOE4 (n=4) and sporadic AD (n=5) cases compared to age-matched control samples (n=5). Our analyses demonstrated that 6/11 of the tested DNA methylation signatures that had initially been identified in cortical neurons and brain tissue were also validated in cfDNA. The remainder of the tested regions either showed opposite trends (3/11) or did not result in any differences (2/11) between control and AD cases. Thus, this presents a direct approach allowing to test for these DNA methylation signatures in CSF-derived cfDNA, and bypasses the need to generate induced pluripotent stem cell-derived cortical neurons from patients.

neuroscience↗

bioRxiv2024

Direct and abscopal anti-tumor responses elicited by peripheral nerve schwannoma irradiation synergize with anti-PD1 treatment in vestibular schwannoma models

NF2-related schwannomatosis (NF2-SWN) is a progressive and disabling disease requiring effective treatments. The hallmark of NF2-SWN is bilateral vestibular schwannomas (VSs), which progressively enlarge, leading to permanent sensorineural hearing loss and severely impacting patients quality of life. Currently, there are no FDA-approved drugs for VS or the associated hearing loss. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, but have not yet been systematically investigated in non-malignant tumors such as VS. In our studies, we demonstrated that combining anti-PD1 (PD1) treatment with radiation therapy (RT) provides three significant therapeutic benefits: i) Enhanced PD1 efficacy and immune memory: RT induces immunogenic cell death and activates the STING pathway, enhancing PD1 efficacy and generating long-term immune memory, ii) Reduced RT dose and associated tissue injury: The combination strategy reduces the required RT dose necessary for effective tumor control, potentially minimizing RT injury to surrounding normal tissues, and iii) Elicited abscopal effects on cerebellopontine angle (CPA) schwannomas: RT to peripheral nerve tumor induces a systemic abscopal effect, which synergizes with PD-1 to effectively control intracranial schwannomas without direct irradiation, sparing the cochlea from radiation exposure and avoiding auditory radiation injury. Together, our findings provide a compelling rationale for deploying ICIs in combination with radiotherapy as a novel treatment approach for patients with VS and NF2-SWN.

cancer biology↗

bioRxiv2024

Enhanced Tumor Control and Hearing Loss Prevention Achieved with Combined Immune Checkpoint Inhibitor and Anti-VEGF Therapy in Vestibular Schwannoma Model

BackgroundNF2-related schwannomatosis (NF2-SWN) is a debilitating condition that calls for robust treatment options. The defining feature of NF2-SWN is the presence of bilateral vestibular schwannomas (VSs), which grow over time and can result in irreversible sensorineural hearing loss, significantly affecting the quality of life for those affected. At present, there are no FDA-approved medications specifically for treating VS or related hearing loss. VS management involves radiotherapy or surgical resection, while bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody (VEGF) may be used off-label in NF2-SWN to shrink the tumor. However, not all patients respond, and the effect is not always durable. There is a critical need for effective medications that can stop the growth of VS and prevent hearing loss associated with these tumors. While immune checkpoint inhibitors have transformed cancer therapy, their potential has not been thoroughly explored in non-malignant tumors such as VS. MethodsWe characterize the effects of anti-PD1 (PD1) treatment on tumor growth and hearing function in two syngeneic, immune-competent VS models. ResultsWe demonstrated that combining VEGF treatment with PD1 significantly enhances the efficacy of each monotherapy. Specifically, i) VEGF enhances PD1 efficacy by normalizing the tumor vasculature to improve drug delivery and immune cell infiltration, and by activating T cell and NK cell anti-tumor cytotoxicity via NKG2D upregulation; and ii) combining PD1 with VEGF treatment effectively controls tumors that progressed despite VEGF treatment. ConclusionThese findings provide a strong foundation for the development of PD1 with VEGF combination therapies for patients with NF2-SWN. Key pointsWe filled a critical gap in NF2 research: 1) we characterized the effects of immunotherapy on tumor growth and hearing function in non-malignant vestibular schwannomas 2) We showed combined anti-VEGF and anti-PD1 enhances the efficacy of each monotherapy Importance of the studyTreatment options for patients with NF2-SWN are limited or are associated with significant co-morbidities. There are no approved medical treatments for NF2-related tumors. While immune checkpoint inhibitors have transformed cancer therapy, their potential has not been thoroughly explored in non-malignant tumors such as VS. Our work filled this critical gap in NF2-SWN research. For the first time, we systemically evaluated ICI efficacy on tumor growth and hearing function in non-malignant schwannomas. Furthermore, we demonstrated that combining VEGF treatment with PD1 significantly enhances the efficacy of each monotherapy. Specifically: i) VEGF enhances PD1 efficacy by normalizing the tumor vasculature to improve drug delivery and immune cell infiltration, and by activating T cell and NK cell anti-tumor cytotoxicity via NKG2D upregulation; and ii) combining PD1 with VEGF treatment effectively controls tumors that progress despite VEGF treatment. Our findings provide a strong foundation for the development of PD1 with VEGF combination therapies for patients with NF2-SWN.

cancer biology↗

bioRxiv2024

A novel pyridoindole improves the recovery of residual hearing following cochlear implantation after a single preoperative application

Sensorineural hearing loss (SNHL) is the most common sensory deficit worldwide. Due to the heterogeneity of causes for SNHL, effective treatment options remain scarce, creating an unmet need for novel drugs in the field of otology. Cochlear implantation (CI) currently is the only established method to restore hearing function in profound SNHL and deaf patients. The cochlear implant bypasses the non-functioning sensory hair cells (HCs) and electrically stimulates the neurons of the cochlear nerve. CI also benefits patients with residual hearing by combined electrical and auditory stimulation. However, the insertion of an electrode array into the cochlea induces an inflammatory response, characterized by the expression of pro-inflammatory cytokines, upregulation of reactive oxygen species, and apoptosis and necrosis of HCs, putting residual hearing at risk. Here, we characterize the effects of the small molecule AC102, a pyridoindole, for its protective effects on residual hearing in CI. We show that AC102 significantly preserves hearing thresholds across the whole cochlea and confines the cochlear trauma to the directly mechanically injured area. In addition, AC102 significantly preserves auditory nerve fibers and inner HC synapses throughout the whole cochlea. AC102s effects are likely elicited during the inflammatory phase of electrode insertion trauma (EIT) and mediated by anti-apoptotic and anti-inflammatory properties, as uncovered by an in vitro assay of ethanol induced apoptosis and evaluation of mRNA expression of pro-inflammatory cytokines in an organotypic ex vivo model of EIT. The results in this study highlight AC102 as a promising compound for the attenuation of EIT during CI. Moreover, as the inflammatory response in cochlear implantation shares similarities to other etiologies of SNHL, a beneficial effect of AC102 can be inferred for other inner ear conditions as well.

neuroscience↗

bioRxiv2023

Large-scale annotated dataset for cochlear hair cell detection and classification

Our sense of hearing is mediated by cochlear hair cells, localized within the sensory epithelium called the organ of Corti. There are two types of hair cells in the cochlea, which are organized in one row of inner hair cells and three rows of outer hair cells. Each cochlea contains a few thousands of hair cells, and their survival is essential for our perception of sound because they are terminally differentiated and do not regenerate after insult. It is often desirable in hearing research to quantify the number of hair cells within cochlear samples, in both pathological conditions, and in response to treatment. However, the sheer number of cells along the cochlea makes manual quantification impractical. Machine learning can be used to overcome this challenge by automating the quantification process but requires a vast and diverse dataset for effective training. In this study, we present a large collection of annotated cochlear hair-cell datasets, labeled with commonly used hair-cell markers and imaged using various fluorescence microscopy techniques. The collection includes samples from mouse, human, pig and guinea pig cochlear tissue, from normal conditions and following in-vivo and in-vitro ototoxic drug application. The dataset includes over 90,000 hair cells, all of which have been manually identified and annotated as one of two cell types: inner hair cells and outer hair cells. This dataset is the result of a collaborative effort from multiple laboratories and has been carefully curated to represent a variety of imaging techniques. With suggested usage parameters and a well-described annotation procedure, this collection can facilitate the development of generalizable cochlear hair cell detection models or serve as a starting point for fine-tuning models for other analysis tasks. By providing this dataset, we aim to supply other groups within the hearing research community with the opportunity to develop their own tools with which to analyze cochlear imaging data more fully, accurately, and with greater ease.

neuroscience↗

bioRxiv2023

Identification of Immune-Related Candidate Biomarkers in Plasma of Patients with Sporadic Vestibular Schwannoma

Vestibular schwannoma (VS) is intracranial tumor arising from neoplastic Schwann cells, causing hearing loss in about 95% of patients. The traditional belief that hearing deficit is caused by physical expansion of the VS, compressing the auditory nerve, does not explain the common clinical finding that patients with small tumors can have profound hearing loss, suggesting that tumor-secreted factors could influence hearing ability in VS patients. Here, we conducted profiling of patients plasma for 67 immune-related factors on a large cohort of VS patients (N>120) and identified candidate biomarkers associated with tumor growth (IL-16 and S100B) and hearing (MDC). We identified the 7-biomarker panel composed of MCP-3, BLC, S100B, FGF-2, MMP-14, eotaxin, and TWEAK that showed outstanding discriminatory ability for VS. These findings revealed possible therapeutic targets for VS-induced hearing loss and provided a unique diagnostic tool that may predict hearing change and tumor growth in VS patients and may help inform the ideal timing of tumor resection to preserve hearing. TeaserProfiling of plasma in vestibular schwannoma patients revealed biomarkers that could predict hearing change and tumor growth.

neuroscience↗