Biology subjects

Ferro, F.

Publications and source records attributed to Ferro, F..

3 recordsLinked to original sources

bioRxiv2025

Anoctamin-2-specific T Cells Link Epstein-Barr Virus to Multiple Sclerosis

Multiple sclerosis (MS) occurs when the central nervous system (CNS) is damaged by misguided adaptive immune responses, likely caused by a combination of environmental factors in genetically susceptible individuals. A known prerequisite for disease is Epstein-Barr virus (EBV) infection, and previous studies have demonstrated elevated Epstein-Barr virus nuclear antigen 1 (EBNA1) antibodies which cross-react with the calcium-activated chloride channel anoctamin-2 (ANO2) in persons with MS (pwMS). ANO2-reactive antibodies have been associated with greater neuroaxonal damage in MS, although their exact effector function is still uncertain. Here, we demonstrate that ANO2 is also the target of IFN{gamma}-producing CD4+ T cells, which are more frequent in untreated and natalizumab-treated pwMS compared to control individuals. Immunisation of SJL/J mice with either ANO2 or EBNA1 elicited cross-reactive CD4+ T cell and antibody responses in vivo. Pre-immunisation of young mice with ANO2 worsened proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE), which in older mice included atypical clinical phenotype, immune infiltration into the brain and reduced survival. EAE exacerbation was recapitulated with the adoptive co-transfer of ANO2 and myelin antigen-specific CD4+ T cells, and ANO2-specific T cells alone could induce the cell death of ANO2-expressing glial cells in vitro. T cell clones with cross-reactivity to both EBNA1 and ANO2 antigens could be isolated from natalizumab-treated pwMS. Single cell sequencing of EBNA1 and ANO2-specific T cell receptors (TCR) from four pwMS revealed a significant overlap between their antigen-specific expanded TCR repertoires within donors and transcriptomic analysis showed cross-reactive T cells to have predominantly activated and cytotoxic phenotypes. In summary, we report the first mechanistic evidence that EBNA1 CD4+ T cells can target the MS-associated autoantigen ANO2, thereby establishing a link between EBV infection and development of autoimmune neuroinflammatory disease.

immunology↗

bioRxiv2025

Dyr726, a brain-penetrant inhibitor of PI3Kα, Type III receptor tyrosine kinases, and WNT signalling

The vast majority of clinical small molecule multi-kinase inhibitors (mKI) report abject failures in targeting cancers with high stem cell contents like high-grade glioma and colorectal cancers. The FDA-approved mKIs to date ablate receptor tyrosine kinase signaling but do not target the paradoxical WNT signaling which is a key survival driver for the self-renewing cancer stem cells. The WNT pathway enhances cancer plasticity and triggers relapse of highly heterogenous tumours. Using de novo synthesis and structure-activity-relationship (SAR) studies with blood-brain-barrier (BBB) penetrant mKI scaffolds, we designed a highly potent and selective small molecule inhibitor of PI3K, PDGFR/KIT, and the WNT pathway denoted Dyr726. Dyr726 is superior to clinical mKIs and inhibits PI3K-AKT-mTOR and WNT-pathway signaling at multiple nodes thereby impeding proliferation, invasion, and tumour growth. Phospho-proteomic, structural, and target engagement analyses, combined with in vitro, in vivo efficacy, and pharmacokinetic studies reveal that Dyr726 is a brain-penetrant small molecule which effectively reduces tumour volume and extends survival of murine orthotopic models. Our current work establishes a first-in-class brain penetrant small molecule mKI which simultaneously antagonize the PI3K-AKT-mTOR and WNT pathways in preclinical cancer stem cell cultures, adult and pediatric primary organoids, and orthotopic murine models with positive efficacy in combination with clinical standard of care.

cancer biology↗

bioRxiv2023

Novel in vivo TDP-43 stress reporter models to accelerate drug development in ALS.

The development of therapies to combat neurodegenerative diseases is widely recognised as a research priority, with conditions like Alzheimers, Amyotrophic lateral sclerosis (ALS) and Parkinsons set to place an ever-heavier burden on healthcare systems in the near future. Despite recent advances in understanding their molecular basis, there is a lack of suitable early biomarkers to test selected compounds and accelerate their translation to clinical trials. We have investigated the utility of in vivo reporters of cytoprotective pathways (e.g. NRF2, p53) as surrogate early biomarkers of the ALS degenerative disease progression. We hypothesized that cellular stress observed in a model of ALS may precede overt cellular damage and could activate our cytoprotective pathway reporters. To test this hypothesis, we generated novel ALS-reporter mice by crossing the hTDP-43tg model into our oxidative stress/inflammation (Hmox1; NRF2 pathway) and DNA damage (p21; p53 pathway) stress reporter models. Histological analysis of reporter expression in a homozygous hTDP-43tg background demonstrated a time-dependent and tissue-specific activation of the reporters in tissues directly associated with ALS. The activation occurs in Purkinje neurons and other parvalbumin-positive (PV+) cells within the cerebellum of mice, before moderate clinical signs are observed. In addition, reporter expression in hTDP-43tg hom peripheral tissues was not observed at the tested mouse ages (15 and 17 days postnatally). Further work is warranted to determine the specific mechanisms by which TDP-43 accumulation leads to reporter activation and whether therapeutic intervention modulates reporters expression. Our current studies suggest that these reporters may represent a powerful approach to accelerate preclinical studies targeting TDP-43 pathologies. We anticipate the reporter strategy could be of great value in developing treatments for a range of degenerative disorders.

neuroscience↗