Biology subjects

Raggioli, A.

Publications and source records attributed to Raggioli, A..

5 recordsLinked to original sources

bioRxiv2026

A novel Gorilla-derived oncolytic Adenovirus with natural selective replication in cancer cells

Oncolytic virotherapy exploits viruses to selectively infect and destroy cancer cells while sparing normal tissues and represents a promising strategy in oncology. Human adenovirus type 5 (HAd5), although widely used, shows limited clinical efficacy due to high levels of preexisting immunity and suboptimal tumor selectivity. In this study, we evaluated novel gorilla-derived adenoviruses (GRAd) as alternative oncolytic vectors. Two distinct GRAd groups, GRAdBs and GRAdCs, were characterized for replication and cytopathic activity. GRAd25 (GRAdB group) exhibited robust replication in both tumor and normal cells, whereas GRAd32 (GRAdC group) demonstrated selective replication in tumor cells. To broaden tumor tropism while preserving selectivity, we generated a chimeric GRAd32 vector, GRAd32Fk25, by replacing its native fiber knob with that of GRAd25, potentially shifting receptor usage from CAR to CD46, which is more abundantly expressed in tumor cells. The vector was further armed with a therapeutic antibody by inserting the coding sequence for the single-chain Fc form (scFv-Fc) of EV20, a humanized anti-HER3 antibody, under endogenous viral regulatory control. In vitro analyses showed that GRAd32Fk25 maintained tumor-restricted replication and produced functional EV20 capable of binding HER3 and inhibiting downstream PI3K/Akt signaling. These results indicate that engineered GRAd vectors, exemplified by GRAd32Fk25 armed with EV20, provide a selective and versatile platform for oncolytic virotherapy with potential advantages over HAd5-based approaches.

cancer biology↗

bioRxiv2025

Non-clinical safety of GRAd vector-based COVID-19 and HIV vaccines supports a platform regulatory approach

The rapid development of safe and efficacious vaccines is often hindered by extensive, mandated non-clinical safety evaluations in animals. Here we present the complete non-clinical studies for two investigational vaccines based on the GRAd platform, a gorilla-derived group C adenoviral vector. When administered intramuscularly, GRAd-COV2 and GRAdHIVNE1 were well tolerated. Studies in rats and rabbits showed localized distribution and transient, non-adverse inflammatory responses, while successfully inducing expected immune responses to their respective antigens. Notably, both vaccines demonstrated a consistent safety profile despite transgene and backbone differences, comparable to other replication-defective adenoviral vectors. The established non-clinical safety profile of the GRAd platform provides a robust foundation for a more efficient and streamlined regulatory pathway. By leveraging this prior knowledge, future GRAd-based vaccines can achieve accelerated clinical development while fully adhering to the ethical principles of replacement, reduction, and refinement of animal use in research.

pharmacology and toxicology↗

bioRxiv2020

Immunogenicity of a new gorilla adenovirus vaccine candidate for COVID-19

The COVID-19 pandemic caused by the emergent SARS-CoV-2 coronavirus threatens global public health and there is an urgent need to develop safe and effective vaccines. Here we report the generation and the preclinical evaluation of a novel replication-defective gorilla adenovirus-vectored vaccine encoding the pre-fusion stabilized Spike (S) protein of SARS-CoV2. We show that our vaccine candidate, GRAd- COV2, is highly immunogenic both in mice and macaques, eliciting both functional antibodies which neutralize SARS-CoV-2 infection and block Spike protein binding to the ACE2 receptor, and a robust, Th1- dominated cellular response in the periphery and in the lung. We show here that the pre-fusion stabilized Spike antigen is superior to the wild type in inducing ACE2-interfering, SARS-CoV2 neutralizing antibodies. To face the unprecedented need for vaccine manufacturing at massive scale, different GRAd genome deletions were compared to select the vector backbone showing the highest productivity in stirred tank bioreactors. This preliminary dataset identified GRAd-COV2 as a potential COVID-19 vaccine candidate, supporting the translation of GRAd-COV2 vaccine in a currently ongoing Phase I clinical trial (NCT04528641).

immunology↗

bioRxiv2019

Mouse model of the human serotonin transporter-linked polymorphic region

Genetic factors play a significant role in risk for mood and anxiety disorders. Polymorphisms in genes that regulate the brain monoamine systems, such as catabolic enzymes and transporters, are attractive candidates for being risk factors for emotional disorders given the weight of evidence implicating monoamines involvement in these conditions. Several common genetic variants have been identified in the human serotonin transporter (5-HTT) gene, including a repetitive sequence located in the promoter region of the locus called the serotonin transporter-linked polymorphic region (5-HTT-LPR). This polymorphism has been associated with a number of mental traits in both humans and primates, including depression, neuroticism, and harm avoidance. Some, but not all studies found a link between the polymorphism and 5-HTT levels, leaving open the question of whether the polymorphism affects risk for mental traits via changes in 5-HTT expression. To investigate the impact of the polymorphism on gene expression, serotonin homeostasis, and behavioural traits we set out to develop a mouse model of the human 5-HTT- LPR. Here we describe the creation and characterization of a set of mouse lines with single copy human transgenes carrying the short and long 5-HTT-LPR variants.

neuroscience↗

bioRxiv2017

Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction

Microglia are highly motile glial cells that are proposed to mediate synaptic pruning during neuronal circuit formation. Disruption of signaling between microglia and neurons leads to an excess of immature synaptic connections, thought to be the result of impaired phagocytosis of synapses by microglia. However, until now the direct phagocytosis of synapses by microglia has not been reported and fundamental questions remain about the precise synaptic structures and phagocytic mechanisms involved. Here we used light sheet fluorescence microscopy to follow microglia-synapse interactions in developing organotypic hippocampal cultures, complemented by three-dimensional ultrastructural characterization using correlative light and electron microscopy (CLEM). Our findings define a set of dynamic microglia-synapse interactions, including the selective partial phagocytosis, or trogocytosis (trogo-: nibble), of presynaptic structures and the induction of postsynaptic spine head filopodia by microglia. These findings allow us to propose a mechanism for the facilitatory role of microglia in synaptic circuits remodeling and maturation.

neuroscience↗