Rare diseases
Group leaders
Strategic Lines
Main activities and calendar of the Translational Research Program
Description of the research lines, specific scientific and training tasks, and specific actions to promote the visibility of the Program.
Research lines
The Translational Research Program on Rare Diseases will be articulated around research lines addressing shared molecular and cellular mechanisms underlying different rare disorders. These lines will be complementary and open, allowing the incorporation of additional groups and topics as the Program evolves.
They exemplify the rare disorder catalog, as we include genetic and non-genetic pediatric and adult diseases, often multisystemic or, if confined to a single organ, involving complex communication among multiple cell types.
Proposed research lines include:
Research Line 1. Mitochondrial dysfunction and oxidative stress in Friedreich Ataxia
This line will address Friedreich Ataxia (FA) as a rare cardio-neurodegenerative disease caused by frataxin deficiency.
The focus will be on understanding how altered iron metabolism, redox imbalance, and defects in the mitochondrial electron transport chain contribute to neuronal and cardiac dysfunction.
Studies will integrate neuronal and cardiomyocyte models, patient-derived cell cultures and mouse models to dissect tissue-specific vulnerabilities and identify molecular pathways that could be targeted to restore mitochondrial function and cellular homeostasis.
Research Line 2. Neuronal vulnerability and degeneration in rare neuromuscular diseases
This line addresses the molecular mechanisms underlying selective neuronal vulnerability in rare neuromuscular disorders, with a particular focus on Spinal Muscular Atrophy (SMA).
Research activities will explore how alterations in SMN-dependent pathways impact motor neuron survival, intracellular homeostasis and stress responses, and how these mechanisms may contribute to disease progression and variable responses to current SMN-targeted therapies.
Research Line 3. Disrupting the pro-tumoral environment of rare brain cancers
Neuronal activity and glial cells in the tumor microenvironment fuel tumor growth.
This research line aims to investigate pharmacological and genetic strategies to disrupt the glioblastoma-supportive microenvironment by modulating multiple ion channels expressed both in glioblastoma cells, glial cells (astrocytes and microglia) and neurons.
Each strategy will be evaluated in controlled monoculture systems and in organotypic or defined co-culture models to capture cell-type-specific and interactive effects.
Approaches demonstrating robust efficacy in vitro will be advanced to preclinical validation using murine models of glioblastoma.
Research Line 4. Shared molecular mechanisms of genome instability in rare genetic disorders
This research line focuses on rare inherited syndromes with closely related molecular etiologies, including Fanconi anemia, Bloom syndrome and Atelis syndrome, which are characterized by defects in DNA replication, DNA repair and the maintenance of genome stability.
These disorders will be used as complementary models to dissect fundamental mechanisms of replication stress, chromosomal instability and cellular responses to DNA damage, with the aim of identifying shared vulnerabilities and conserved molecular pathways.
Research Line 5: Mechanistic and translational research in amyotrophic lateral sclerosis
This research line integrates mechanistic studies and clinical translation in amyotrophic lateral sclerosis (ALS) by combining in vitro and preclinical models to dissect molecular and cellular pathways driving motor neuron degeneration and disease progression.
These insights support the development of tailored RNA-based therapies, including antisense oligonucleotides (ASOs), and guide the identification and validation of novel and established biomarkers, such as neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), to improve patient stratification, treatment monitoring, and clinical management.
Research Line 6. Mitochondrial dysfunction in rare forms of diabetes
This research line will focus on rare forms of diabetes of mitochondrial origin, using them as model systems to investigate how mitochondrial dysfunction contributes to metabolic dysregulation and tissue-specific vulnerability.
The line will address defects in mitochondrial bioenergetics, redox balance, calcium homeostasis and stress signaling pathways that impair insulin secretion and glucose homeostasis.
By integrating cellular models, patient-derived samples and functional assays, this research line aims to identify molecular mechanisms linking mitochondrial impairment to endocrine dysfunction, and to explore shared pathways with other mitochondrial and neurodegenerative rare diseases included in the Program.
