Lorraine Owaid
Boehringer Ingelheim
AAV6.2-Based Preclinical Model to Investigate Skin Fibrosis Resolution and Therapeutic Interventions
Organ fibrosis poses a major challenge across various diseases, including fibrotic skin conditions like Systemic Sclerosis (SSc), that have limited therapeutic options. To expand our toolbox to understand fibrotic diseases of the skin, we developed an AAV-based preclinical model of skin fibrosis using intradermal delivery of AAV6.2 encoding a constitutively active form of TGFβ1. This skin model recapitulates hallmark features of SSc with increased dermal thickness, elevated collagen deposition, and dynamic transcriptional changes. Over a time course, we identified distinct temporal phases: an early inflammatory phase followed by a fibrotic phase, with fibrosis peaking and evidence of resolution. RNAseq analysis revealed overlap with SSc gene signatures, providing insights into molecular pathways driving fibrosis onset and progression. Treatment with the anti-fibrotic drug, nintedanib, successfully mitigated skin fibrosis demonstrating the model's utility for evaluating therapeutic interventions. To assess fibrosis resolution, we found that extending the model's duration revealed a secondary, more vigorous fibrotic phase with distinct gene expression signatures. The mechanisms driving this secondary phase are being investigated. Altogether, this AAV6.2-based model represents a robust platform for understanding fibrosis biology, including exploring mechanisms underlying both fibrosis progression and resolution, and provides a valuable tool for studying anti-fibrotic treatments.
Organ fibrosis poses a major challenge across various diseases, including fibrotic skin conditions like Systemic Sclerosis (SSc), that have limited therapeutic options. To expand our toolbox to understand fibrotic diseases of the skin, we developed an AAV-based preclinical model of skin fibrosis using intradermal delivery of AAV6.2 encoding a constitutively active form of TGFβ1. This skin model recapitulates hallmark features of SSc with increased dermal thickness, elevated collagen deposition, and dynamic transcriptional changes. Over a time course, we identified distinct temporal phases: an early inflammatory phase followed by a fibrotic phase, with fibrosis peaking and evidence of resolution. RNAseq analysis revealed overlap with SSc gene signatures, providing insights into molecular pathways driving fibrosis onset and progression. Treatment with the anti-fibrotic drug, nintedanib, successfully mitigated skin fibrosis demonstrating the model's utility for evaluating therapeutic interventions. To assess fibrosis resolution, we found that extending the model's duration revealed a secondary, more vigorous fibrotic phase with distinct gene expression signatures. The mechanisms driving this secondary phase are being investigated. Altogether, this AAV6.2-based model represents a robust platform for understanding fibrosis biology, including exploring mechanisms underlying both fibrosis progression and resolution, and provides a valuable tool for studying anti-fibrotic treatments.
