Biology subjects

Didangelos, A.

Publications and source records attributed to Didangelos, A..

3 recordsLinked to original sources

bioRxiv2025

CTx001 for geographic atrophy: a gene therapy expressing soluble, truncated complement receptor 1 (mini-CR1)

Over-activation of the complement system is strongly associated with geographic atrophy (GA), a late-stage form of age-related macular degeneration (AMD) and major cause of blindness. Here we report the development of a candidate GA treatment that is a potent complement modifier (mini-CR1) that addresses consequences of complement over-activation including membrane attack complex (MAC) formation. Mini-CR1 acts a potent cofactor for factor I driven proteolysis of C3b leading to iC3b and then C3dg formation; iC3b itself remains a potent opsonin. As well as inhibiting the alternative complement pathway, mini-CR1 acts as a cofactor for C4b degradation thereby inhibiting the classical pathway. Mini-CR1 prevents MAC formation in activated human serum with an IC50 of 125 nM. Mini-CR1 was shown to cross human Bruchs membrane ex vivo, implying the ability to cross into the choroidal space. Transduction of RPE cell lines with rAAV2-mini-CR1 (CTx001) resulted in dose-dependent transcription, and both basolateral and apical secretion of mini-CR1 by monolayers of human iPSC derived RPE cells. Mini-CR1 transduction of ARPE19 cells resulted in increased consumption of C3b and iC3b1 in activated culture media and decreased MAC formation on the cell surfaces. Subretinal injection of CTx001 in rats resulted in dose-dependent mini-CR1 production as demonstrated by solid-phase immunoassay. MAC formation following laser induced CNV in a rat model was reduced by 75% in CTx001-treated animals relative to null vector (p<0.01). This first generation of CTx001 represents a potent single administration complement modifier capable of effectively addressing pathologic complement amplification in the retina/choroid.

biochemistry↗

bioRxiv2019

From expression footprints to causal pathways: contextualizing large signaling networks with CARNIVAL

While gene expression profiling is commonly used to gain an overview of cellular processes, the identification of upstream processes that drive expression changes remains a challenge. To address this issue, we introduce CARNIVAL, a causal network building tool which derives network architectures from gene expression footprints. CARNIVAL (CAusal Reasoning pipeline for Network identification using Integer VALue programming) integrates different sources of prior knowledge, including signed and directed protein-protein interactions, transcription factor targets, and pathway signatures. The use of prior knowledge in CARNIVAL allows the capture of a broad set of upstream cellular processes and regulators, which in turn delivered results with higher accuracy when benchmarked against related tools. Implementation as an integer linear programming (ILP) problem also guarantees efficient computation. As a case study, we applied CARNIVAL to contextualize signaling networks from gene expression data in IgA nephropathy, a chronic kidney disease. CARNIVAL identified specific signaling pathways and associated mediators with important bioactivity in IgAN including WNT and TGF-{beta}, that we subsequently validated experimentally. In summary, we demonstrated how CARNIVAL generates hypotheses on potential upstream alterations that propagate through signaling networks, providing valuable insights into disease processes. CARNIVAL, freely available as an R-package at https://saezlab.github.io/CARNIVAL, can be applied to any field of biomedical research to contextualize signaling networks and identify the causal relationships between downstream gene expression and upstream regulators.

systems biology↗

bioRxiv2017

Rats and axolotls share a common molecular signature after spinal cord injury enriched in collagen-1

Spinal cord injury (SCI) in mammals leads to irreversible tissue damage and loss of function. In contrast, axolotls are able to regenerate scar-free the injured spinal cord. To explore new pathological mechanisms, we compared rat versus axolotl transcriptomics and isolated genes shared between species post-SCI. Unexpectedly, multiple transcripts involved in extracellular matrix remodelling, in particular collagen-1, were upregulated in both species after SCI. Proteomics validated persistent expression of the collagen-enriched matrix signature at the protein level. Collagen-1 accumulated in early and advanced rat lesions. Importantly, collagen-1 was likely associated with pathological vascular remodelling rather than classic fibrosis and the transcription factor SP1 was predicted and validated to regulate, at least in part, the expression of collagen-1 in rat lesions.

pathology↗