Abstract

Basal stem cell-mediated regeneration of olfactory sensory neurons (OSNs) in the olfactory epithelium (OE) maintains the sense of smell. Acute inflammation destroys OSNs, causing hyposmia and anosmia. Manipulation of signal pathways to promote neuroregeneration would reveal novel therapeutic targets for smell deficits. We previously found that ciliary neurotrophic factor (CNTF) is highly expressed in quiescent stem cells, horizontal basal cells (HBCs), while the CNTF receptor is in globose basal cells (GBCs), the actively dividing cells that replace dying OSNs. Furthermore, the upregulation of CNTF by inhibiting focal adhesion kinase (FAK) promotes OE neuroregeneration in naïve mice. Here, we investigated the roles of CNTF and FAK in methimazole-induced acute inflammatory OE injury. Methimazole increased inflammatory markers, TNFα, IL-6, and CD45, and depleted OSNs in the OE at 3 and 5 days. Simultaneously, CNTF and the GBC marker Mash1 were upregulated, suggesting that HBCs produced more CNTF, as validated using primary HBC cultures, to promote GBC proliferation. Methimazole increased GBC proliferation, measured by BrdU incorporation, in CNTF+/+ but not CNTF-/- littermate mice. Also, CNTF+/+ mice had higher levels of neuroregeneration and better smell function than CNTF-/- littermates, suggesting that CNTF in HBCs promotes OSN regeneration and smell function recovery following methimazole. Incubation of primary HBC cultures with an FAK inhibitor or inducible and selective knockout of HBC FAK in mice enhanced methimazole-induced CNTF. Intranasal aspiration of a water-soluble FAK inhibitor, FAK14, dose-dependently increased CNTF and Mash1 and enhanced methimazole-induced GBC proliferation and neuroregeneration in C57BL/6 and CNTF+/+ but not CNTF-/- mice. Intranasal FAK14 treatment also accelerated the recovery of smell function. FAK14 did not alter TNFα and IL-1β, suggesting that its effect is not mediated through modifying methimazole-induced inflammation. This study highlights the therapeutic potential of targeting stem cell FAK-CNTF signaling to improve olfactory neuroregeneration and functional recovery following injury.

Abstract

Blue Cell Therapeutics is a biotechnology company developing long-lasting allogeneic “off-the-shelf” human mesenchymal stem cell (MSC) therapies for conditions in which angiogenesis and nerve regeneration may be beneficial, such as erectile dysfunction (ED).

Our method allows for the production of a standardized, pure, and potent allogeneic cell product. Due to high proliferation rates, it is possible to manufacture over 70,000 treatment doses from cells sourced from a single donor.

The initial focus is on addressing severe ED following radical prostatectomy by targeting the underlying issues of reduced blood flow and nerve injury. We have designed a scalable therapy intended to restore erectile function for extended periods.

An early proof-of-concept study using a single dose of autologous adipose MSCs reported that 8 out of 11 men (72%) who had undergone prostatectomy and were continent but had not achieved erectile function for over one year regained the ability to have erections and engage in sexual activity six months after treatment. Subsequently, Blue Cell adopted an allogeneic approach, with the aim of offering greater consistency, potency, manufacturability, and lower costs.

Preclinical in vitro and in vivo studies of BlueC-231 have shown angiogenesis, as well as endothelial and nerve cell regrowth, that surpassed results seen with autologous cells. To further investigate the mechanism of action in ED, including its molecular effects on vascular and neurogenic regenerative processes, the company has conducted scRNA sequencing and proteomics analyses, identifying several molecular effectors likely involved in angiogenesis and neurogenesis.

Approximately 490,000 men in Western countries undergo major prostate cancer surgery each year, with many experiencing persistent severe ED one year post-operatively. Overall, an estimated 85 million men are affected by ED globally, with about 30% not responding to pharmaceutical treatments.

Abstract

Organoids represent a transformative advance in biomedical research, offering three-dimensional (3D), physiologically relevant models that bridge the gap between traditional in vitro systems and in vivo conditions. In our work, we developed and implemented a high-throughput screening (HTS) platform using murine and ovine intestinal organoids to assess compound toxicity during early-stage drug discovery. The objective was to complement phenotypic screening for anthelmintic drugs by introducing a predictive, close-to-reality model to evaluate cytotoxic effects on intestinal tissues. Using intestinal organoids derived from mouse and sheep duodenum, we screened hits identified through nematode-based phenotypic assays, evaluating their safety profiles in both hepatic spheroids and enteroids. Notably, the platform revealed that certain promising anthelmintic hits exhibited favourable selective indices and minimal toxicity, underscoring the utility of organoids in refining lead compound selection.
Beyond veterinary and anthelmintic applications, this organoid-based HTS pipeline has wide translational potential. The method can be adapted to disease-specific enteroids or tumoroids, enabling precision toxicology and therapeutic efficacy screening in models that recapitulate patient-specific or pathology-driven responses. Future applications include testing for inflammatory bowel diseases, drug-induced intestinal injury, or tumour-specific responses to chemotherapeutics, potentially accelerating drug development pipelines while aligning with the 3Rs principles. Overall, organoids provide a versatile and ethically sustainable platform for drug screening, capable of improving predictive toxicology, reducing animal use, and facilitating the discovery of safer and more effective therapeutic candidates across human and veterinary medicine.

Financial disclosure: This presentation is part of the R&D project PID2020-119035RB-100, funded by MCINN/AEI/10.13039/501100011033 and “ESF Investing in your future”, including grant PRE2021-096909 funded by MCINN/AEI/10.13039/501100011033 and by “ESF Investing in your future”.

Abstract

Pancreatic cancer is a mortal malignancy, and recently, conventional chemotherapeutic agents, including gemcitabine, have limited efficacy due to hypovascularity, which leads to insufficient oxygen and nutrient supply in the tumor. To tolerate nutrient starvation, pancreatic cancer cells modify their energy metabolism, a phenomenon termed “austerity”. Therefore, an innovative approach for the new generation of anti-cancer drugs is the discovery of agents that preferentially kill these cells under nutrient starvation conditions. Over the past two decades, the screening utilizing the anti-austerity strategy has led to the discovery of several promising candidates. The anti-austerity activity is evaluated by their PC₅₀ values, which represent the concentration killing 50% of cells in a nutrient-deprived medium (NDM) without inducing toxicity in a nutrient-rich medium (e.g., DMEM). One of the outstanding candidates is arctigenin, an anti-cancer agent discovered through anti-austerity strategy showed potent anticancer activity against a number of human pancreatic xenograft tumor models. Most importantly, arctigenin had recently completed phase II human clinical trial against gemcitabine-refractory advanced pancreatic cancer patients. It showed a high safety profile and significant survival benefit among the pancreatic cancer patients. In the framework of the conference, I am very pleased to share my recent research with global audiences about calliviminone A (CVM-A) – a phloroglucinol–meroterpenoid isolated from Callistemon citrinus leaves, for its anti-austerity activity against PANC-1 human pancreatic cancer cells via inhibiting the PI3K/Akt/mTOR pathway. These findings highlight CVM-A as a promising lead compound for developing novel anticancer therapies that target the adaptive survival mechanisms and metastatic potential of pancreatic cancer in nutrient-deprived microenvironments.