Biology subjects

Gravel, C.

Publications and source records attributed to Gravel, C..

3 recordsLinked to original sources

bioRxiv2025

Durability of DNA-LNP and mRNA-LNP Vaccine-Induced Immunity Against SARS-CoV-2 XBB.1.5

mRNA-lipid nanoparticle (LNP) vaccines induce robust adaptive immune responses and have proven highly effective against SARS-CoV-2. However, their long-term effectiveness is limited by waning humoral responses, which decline substantially within the first six months post-boost vaccination. DNA-LNPs are being investigated as an alternative vaccine platform, offering prolonged antigen expression and robust immunity. Here, we present the first comparison of SARS-CoV-2 DNA- and mRNA-LNP vaccines in a long-term in vivo challenge model. Both nucleic acid platforms induced strong neutralizing antibody responses and conferred equivalent protection in Syrian hamsters challenged three weeks post-boost. Notably, DNA-LNP vaccination maintained high binding and neutralizing antibody titers six months post-boost, whereas mRNA-LNPs exhibited a marked decline. Correspondingly, while DNA-LNPs completely protected from weight loss, viral replication, and lung pathology at this late timepoint, mRNA-LNP vaccination conferred minimal protection. These findings demonstrate that DNA-LNPs can sustain durable immunity, highlighting their potential as a next-generation vaccine platform that could reduce the need for frequent boosters.

immunology↗

bioRxiv2024

Virally encoded single-chain antibody fragments targeting alpha-synuclein protect against motor impairments and neuropathology in a mouse model of synucleinopathy

Parkinsons disease (PD) is a neurodegenerative disorder mainly characterized by the loss of dopaminergic neurons from the substantia nigra. Affected neurons exhibit intracellular aggregates primarily composed of misfolded and phosphorylated alpha-synuclein (aSyn). In pathological conditions, this presynaptic protein has been shown to be transmitted from cell to cell in a prion-like manner, which contributes to the progression of the disease. Single-chain variable fragments (scFvs) are small polypeptides derived from the binding domains of antibodies that are less immunogenic and have better tissue penetration compared to full antibodies. In this work, we aimed to demonstrate the potential of extracellular scFvs to slow down the propagation of pathological aSyn in an in vivo model of synucleinopathy. We generated scFvs that target aSyn, and tested two of them in a PD mouse model consisting of transgenic M83 mice injected with human aSyn pre-formed fibrils (PFFs). The sequence encoding each anti-aSyn scFv was cloned in a self-complementary AAV2 viral vector, and purified particles were administered intravenously. CNS expression of either scFv protected against the development of paralysis and limb weakness, in addition to significantly reducing pathologic aggregates of phosphorylated aSyn in the brain. Moreover, in vitro results in human iPSCs-derived dopaminergic neurons suggest that the scFvs can mitigate aSyn spreading by preventing its internalization. Overall, our findings demonstrate that single-chain antibody fragments exhibit strong therapeutic potential in a preclinical mouse model. Thus, our minimally invasive, gene-mediated immunotherapy approach has the potential to serve as an effective treatment for halting the progression of Lewy body diseases.

neuroscience↗

bioRxiv2020

Rit2 reduces LRRK2 kinase activity and protects against alpha-synuclein neuropathology

In Parkinsons disease (PD) misfolded alpha-synuclein (aSyn) accumulates in the substantia nigra, where dopaminergic neurons are progressively lost. The mechanisms underlying aSyn pathology are still unclear but hypothesized to involve the autophagy-lysosome pathway (ALP). LRRK2 mutations are a major cause of familial and sporadic PD, hyperactivate kinase activity and its pharmacological inhibition reduces pS129-aSyn inclusions. We observed selective downregulation of the novel PD risk factor RIT2 in G2019S-LRRK2 expressing cells. Here we studied whether RIT2 could modulate LRRK2 kinase activity. RIT2 overexpression in G2019S-LRRK2 cells rescued ALP abnormalities and diminished aSyn inclusions. In vivo, viral mediated overexpression of RIT2 conferred neuroprotection against AAV-A53T-aSyn. Furthermore, RIT2 overexpression prevented the A53T-aSyn-dependent increase of LRRK2 kinase activity in vivo. Our data indicate that RIT2 inhibits overactive LRRK2 to ameliorate ALP impairment and counteract aSyn aggregation and related deficits. Targeting RIT2 could represent a novel strategy to combat neuropathology in familial and idiopathic PD.

neuroscience↗