Luis Galietta

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Principal Investigator
Head of Cell Culture and Cytogenetics Unit
Head of Electrophysiology Unit

Other positions:
Associate Professor of Medical Genetics, Department of Translational Medicine, University of Naples "Federico II", Italy

Luis Galietta completed his University studies in Biology in Naples, before moving to Genova in 1986 to work as a young investigator at the Gaslini Institute, one of the largest pediatric hospitals in Europe, and at the Institute of Biophysics of the CNR. In 1991, he obtained a permanent position at the Gaslini Institute researching the molecular and functional characterization of ion transport in epithelial cells, with a special focus on the elucidation of the pathogenic mechanisms underlying cystic fibrosis lung disease and the development of possible therapeutic strategies. From 2000 to 2003, he visited the laboratory of Prof. Alan S. Verkman at the University of California San Francisco, where he worked on the identification of pharmacological modulators of the mutant CFTR protein. In 2016, he moved to TIGEM to start a new laboratory and continue his research. His studies are supported by grants from Cystic Fibrosis Foundation (US), Vertex Innovation Award (VIA), Italian Cystic Fibrosis Foundation (FFC), Italian Ministry of Health, and the Million Dollar Bike Ride program.

Pharmacological modulation of ion transport to treat the basic defect in cystic fibrosis

Cystic fibrosis (CF), one of the most frequent genetic diseases, is caused by loss of function of CFTR, a membrane protein that mediates chloride and bicarbonate transport in different types of epithelial cells.  Loss of CFTR function affects multiple organs but the lung disease is the major cause of morbidity and mortality in CF.  The lack of CFTR impairs the innate natural defenses of the airways causing bacterial infection, mucus accumulation, and chronic inflammation. 

My research group has been particularly active in the search for effective correctors and potentiators to treat the basic defect in CF.  Such molecules correct the conformational defects of CFTR protein caused by mutations, thus resulting in improved CFTR trafficking (correctors) and channel gating (potentiators). In collaboration with Prof. Paola Barraja (University of Palermo), and with the support of the Italian Foundation for Cystic Fibrosis (FFC), we are working on the development of novel CFTR correctors (1). These compounds are first tested on a cell line expressing mutant CFTR and then evaluated on airway epithelia fully differentiated in vitro, derived from cells obtained from CF patients.

We are also interested in the modifications of the airway epithelium that are elicited by the inflammatory status. In particular, we found that interleukin-17A (IL-17A) induces a high-viscosity state of epithelial surface, probably due to hypersecretion of mucins (MUC5B) combined with electrolyte/fluid reabsorption (2). This high viscosity status is counteracted by CFTR activation. In CF epithelia, the lack of CFTR function traps the system in a vicious cycle of mucociliary clearance impairment, mucus accumulation, and further inflammation. Investigation of the underlying mechanisms induced by IL-17A can identify novel therapeutic targets. This is particularly important for CF patients who carry “undruggable” mutations, i.e. insensitive to potentiators and correctors.  In this respect, we are focusing on two proteins: TMEM16A, a second type of  chloride channel (3), and SLC26A4, an electroneutral anion exchanger (4). Pharmacological activation of TMEM16A could overcome defective anion secretion in CF (5). Inhibition of SLC26A4 could block airway surface dehydration (2).

Targeting nonsense mutations in CF is an unmet need since patients with such mutations are unresponsive to present therapies based on correctors and potentiators. Nonsense mutations, also known as premature termination codons (PTCs), besides leading to a truncated CFTR protein, also induce the nonsense-mediated RNA decay (NMD). Using a high-throughput assay, we recently screened a chemical library of more than 9,000 small molecules finding three compounds that act as NMD inhibitors. They are now being evaluated on epithelia from CF patients carrying PTCs in combination with other molecules acting as “readthrough agents”.

Luis Galietta is the head of two TIGEM Units:

Cell Culture and Cytogenetics, providing fully-equipped cell culture facilities and technical support for cellular and cytogenetic studies to TIGEM investigators

Electrophysiology measuring iron currents in cell cultures.