Gene Regulation, Stem Cells & Development

BSS, an extremely rare disorder, is distinguished by a diminished count of enlarged and functionally impaired platelets. Afflicted individuals endure uncontrolled bleeding, often escalating into life-threatening scenarios. In collaboration with Dr. Martin’s research group (GENyO), along with various national and international partners, we have successfully demonstrated the effectiveness of lentiviral vectors in genetically rescuing the GP9 gene within cellular models and primary cells derived from BSS Type C patients (Martinez-Navajas G et al. 2023).

Currently, we are analyzing the phenotype of an BSS Type C animal model (Gp9-KO) generated in our laboratory. Preliminary results suggest that Gp9-KO mice manifest similar symptoms to those observed in human patients, such as macrothrombocytopenia. Concurrently, we are performing ex vivo genetic rescue of hematopoietic stem cells extracted from these mice using the same lentiviral vectors that have been shown to be effective in vitro. These results are pivotal to complete the preclinical phase of our innovative treatment, allowing for a comprehensive assessment of both functionality and biosafety in this novel genecell therapy designed for BSS Type C patients.

To date, clinical interventions for BSS patients have primarily centered on providing temporary relief from symptoms, mitigating macrothrombocytopenia, and enhancing platelet clotting. Our proposal represents the first curative therapy described to treat BSS Type C patients. Our studies open the possibility of extending this kind of therapeutic approach not only to the other two BSS subtypes (Type A 86 STRATEGIC PLAN 2024-2027 and Type B), but also to a spectrum of platelet diseases of genetic origin, known as genetic thrombopathies.

The detection of early PDAC markers in plasma holds the potential to significantly enhance therapeutic interventions for patients in the early stages of the disease. Moreover, it opens avenues for the development of novel therapies designed to impede the communication pathways between platelets and pancreatic tumor cells. This communication plays a pivotal role in the initiation of metastasis, a process accountable for the majority of PDAC-related fatalities.

Pancreatic cancer (PDAC) is one of the most aggressive solid tumors, with a 5-year survival rate of less than 8%. This low life expectancy is associated to delayed diagnosis often with metastases in distant organs. Notably, PDAC is characterized by a strong association with a state of hypercoagulability, driven by an increase in the both number and activity of platelets; a phenomenon orchestrated through communication between tumor cells and platelets. In collaboration with clinical researchers from ibs-Granada, we proposed the use of platelets and the extracellular vesicles (EVs) generated by them as rich sources of information for PDAC.

Platelets have significant advantages compared to other blood components: they are abundant, have a reduced half-life and interact with tumor cells. This interaction involves the reciprocal exchange of EVs loaded with biomolecules (proteins and nucleic acids) that exert an impact on the cells that incorporate them.

Our aim is to identify distinctive platelet or EVs biomarkers exclusive to the early stages of PDAC for utilization in an early diagnostic kit. In pursuit of this objective, we employ in vitro cellular models that faithfully replicate the genetic progression of the disease, experimental animal models, and plasma samples from individuals diagnosed with PDAC.

We are mainly focusing in Pediatric Myeloid Leukemia, a rare a heterogeneous group of diseases. About 50% of patients experience a relapse, and the overall survival ranges between 20 to 70%, depending on the leukemia subtype. There is limited progress on targeted therapies, mainly due to its low frequency, the wide variety of genetic alterations associated to it and the scarce material available for studies. We are generating stem cells models for drug screening and understanding of fundamental pathogenic mechanisms.

Our ultimate goal is to gain knowledge on the cellular and molecular similarities and differences between a normal stem cell and its malignant counterpart, to understand, identify and attack cancer stem cells.