Biology subjects

Bourdon, A.

Publications and source records attributed to Bourdon, A..

3 recordsLinked to original sources

bioRxiv2024

Advancing Liver Gene Therapy: Enhanced Transduction with GalNAc-Bioconjugated rAAV Capsids

This study investigates novel approaches to improve targeted gene delivery to the liver, a crucial organ for metabolic processes that faces vulnerabilities from various pathologies. Adeno-associated virus (AAV)-based gene therapy has emerged as a promising approach for liver targeting, with numerous investigational avenues. However, administration of high doses of AAV vectors present safety concerns, often requiring the use of corticosteroids and immunosuppression to mitigate immune adverse events. To address this, substantial efforts are underway to engineer optimized capsids to enhance the efficiency and specificity of recombinant AAV (rAAV) targeting hepatocytes, aiming to reduce required dosages. In this study, we employed bioconjugation chemistry to target the Asialoglycoprotein receptor (ASGPR), a C-type lectin abundantly expressed at the surface of hepatocyte membranes. We demonstrated that covalently attaching carbohydrates derived from GalNAc (a known ASGPR ligand) to lysine amino-acids on the rAAV2 capsid significantly enhanced in vivo liver transduction efficiency in mice. These optimized vectors present a promising avenue for the treatment of a spectrum of liver diseases, providing an alternative solution within the framework of liver gene therapy.

bioengineering↗

bioRxiv2023

Dystrophin deficiency impairs cell junction formation during embryonic myogenesis

Mutations in the DMD gene lead to Duchenne muscular dystrophy, a severe X-linked neuromuscular disorder that manifests itself as young boys acquire motor functions. DMD is typically diagnosed at 2 to 4 years of age, but the absence of dystrophin negatively impacts muscle structure and function before overt symptoms appear in patients, which poses a serious challenge in the optimization of standards of care. In this report, we investigated the early consequences of dystrophin deficiency during skeletal muscle development. We used single-cell transcriptome profiling to characterize the myogenic trajectory of human pluripotent stem cells and showed that DMD cells bifurcate to an alternative branch when they reach the somite stage. Here, dystrophin deficiency was linked to marked dysregulations of cell junction protein families involved in the cell state transitions characteristic of embryonic somitogenesis. Altogether, this work demonstrates that in vitro, dystrophin deficiency has deleterious effects on cell-cell communication during myogenic development, which should be considered in future therapeutic strategies for DMD.

pathology↗

bioRxiv2022

AAV2/9-mediated gene transfer into murine lacrimal gland leads to a long-term targeted tear film modification

Corneal blindness is the fourth leading cause of blindness worldwide. Since the corneal epithelium is constantly renewed, non-integrative gene transfer cannot be used to treat corneal diseases. In numerous of these diseases, the tear film has been reported to be defective. Tears are a complex biological fluid secreted by the lacrimal apparatus. Their composition is modulated according to the context. For instance, after a corneal wound, the lacrimal gland secretes reflex tears, which contain specific growth factors supporting the wound healing process. In specific pathological contexts, such as dry eye diseases, the tear composition can support neither corneal homeostasis, nor wound healing. Here, we propose to use the lacrimal gland as bioreactor to produce and secrete specific factors to support corneal physiology. In this study, we used an AAV2/9-mediated gene transfer to supplement the tear film. First, we demonstrate that a single injection of AAV2/9 is sufficient to transduce all epithelial cell types of the lacrimal gland efficiently and widely. Then, we show that lacrimal gland physiology and corneal integrity are maintained after the injection of an AAV2/9-mediated nerve growth factor expression in the lacrimal gland. Remarkably, this injection induces an important and long-lasting secretion of this growth factor in the tear film. Altogether, our findings provide a new clinically applicable approach to tackle corneal blindness.

physiology↗