Dedos, S. G. | bioRxiv Science

bioRxiv2025

An aerosolised dual-action Autotaxin inhibitor- PPARγ agonist for the treatment of pulmonary fibrosis

Fibrosis is a significant mortality factor and health concern, promoting organ malfunction as well as immune and chemical resistance. Among the different fibroproliferative diseases, idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic interstitial lung disease (ILD) with limited therapeutic options. Autotaxin (ATX), an established therapeutic target in IPF, is a secreted lysophospholipase D that catalyses the extracellular production of lysophosphatidic acid (LPA), a growth factor-like signalling phospholipid. The many pathologic effects of LPA in the lung include the suppression of peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}), a therapeutic target in metabolic disorders, which are frequent comorbidities of IPF associated with unfavourable prognosis. In this report, we introduce EL244, the first-in-class dual ATX inhibitor and PPAR{gamma} agonist, which is endowed with drug-like properties. Developed through chemoinformatic repositioning, innovative rational design, targeted synthesis and pharmacological characterization, EL244 exhibited favourable ADMET and PK/PD profiles. Remarkably, EL244 inhalation, which alleviates systemic toxicity concerns, decreased pulmonary LPA levels and related effects in pulmonary cells, and attenuated bleomycin (BLM)-induced pulmonary fibrosis, restoring respiratory functions. Therefore, EL244 emerges as a promising candidate for the inhaled treatment of IPF and ILDs.

pathology↗

bioRxiv2024

A neural alternative splicing program controls cellular function and growth in Pancreatic Neuroendocrine tumours

Pancreatic neuroendocrine tumours (PanNETs) are a rare heterogeneous group of neoplasms that arise from pancreatic islet cells. The hormone secreting function of pancreatic neuroendocrine cells is altered in PanNETs, rendering these tumours functional or non-- functional (secreting excessive or lower levels of hormones, respectively). Genome wide approaches have revealed the genomic landscape of PanNETs but have not shed light on this problematic hormone secretion. In the present work, we show that alternative splicing (AS) deregulation is responsible for changes in the secretory ability of PanNET cells. We reveal a group of alternative microexons that are regulated by the RNA binding protein SRRM3 and are preferentially included in mRNAs in PanNET cells, where SRRM3 is also upregulated. These microexons are part of a larger neural program regulated by SRRM3. We show that their inclusion gives rise to protein isoforms that change stimulus-induced secretory vesicles and their trafficking in PanNET cells. Moreover, the increased inclusion of these microexons results in an enhanced neuronal component in PanNET tumours. Using knock-down and splicing switching oligonucleotides in cellular and animal PanNET models, we show that decrease of the SRRM3 levels or even of the inclusion levels of the three most deregulated microexons can significantly alter the PanNET cell characteristics. Collectively, our study links secretory impairment and nerve dependency to alternative splicing deregulation in PanNETs, providing promising therapeutic targets for PanNET treatment.

cancer biology↗