Mall Lab - Pediatric Pulmonology and Immunology
The research focus of the Mall lab is on the pathogenesis of and novel therapeutic strategies for cystic fibrosis (CF) lung disease. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and remains the most common fatal genetic disease in Caucasian populations. In healthy airways, CFTR encodes a cAMP-regulated anion channel that plays a key role in epithelial anion (Cl- and HCO3-) and fluid secretion. In the CF lung, CFTR dysfunction causes dehydration and acidification of airway surfaces, which leads to abnormal viscoelastic properties of the mucus and impairs important airway defence functions such as mucociliary clearance (MCC) and bacterial killing. These defects trigger a pathogenetic cascade of mucus plugging, chronic neutrophilic inflammation, infection and progressive structural lung damage that that remains the main cause of death in patients with CF.
Over the past 20 years, the Mall lab has made several contributions to our current understanding of the pathogenesis of CF lung disease and the development of therapeutic strategies. These include studies on the role of the epithelial Na+ channel ENaC, the development of the ENaC-overexpressing mouse as the first animal model with CF-like lung disease, and studies of functional consequences and pharmacological modulation of a large spectrum of CFTR mutations in model systems and patients with CF. The results of these studies contributed to the development of mucolytic and anti-inflammatory strategies, as well as emerging CFTR modulator therapies for CF. More recently, the Mall lab has focussed on the alternative epithelial Cl- conductance SLC26A9 as disease modifier and potential mutation-agnostic therapeutic target, the role of membrane-bound protease activity on airway neutrophils in structural lung damage, and the role of altered microbiota in CF airway inflammation.
Findings and novel therapeutic targets identified in experimental model systems are tested in observational studies and investigator-initiated clinical trials to accelerate the development of more effective therapies for patients with CF. In addition, the Mall lab has started to explore how results obtained from CF may be leveraged to improve our understanding of other severe progressive lung diseases such as primary ciliary dyskinesia (PCD) and interstitial lung diseases in children (chILD).
- Regulation and pharmacological modulation of epithelial ion transport, airway surface liquid and mucociliary clearance in health and cystic fibrosis lung disease
- Role of the Cl- transporter SLC26A9 as therapeutic target in cystic fibrosis
- Role of surface-bound protease activity in cystic fibrosis airway inflammation and lung damage
- Therapeutic targeting of altered airway microbiota to prevent airway inflammation and lung
Simon Gräber, MD, Clinician Scientist
Annalisa Addante, PhD, Postdoc
Anita Balázs, MD, Postdoc
Constanze Vitzthum, PhD, Postdoc
Markus Bardua, PhD, Postdoc
Marika Drescher, M.Sc. Technical Assistant
Maria Daniltchenko, MD, Technical Assistant
Alexander Rohrbach, M.Sc. Technical Assistant
Middleton PG*, Mall MA*, Dřevínek P, Lands LC, McKone EF, Polineni D, Ramsey BW, Taylor-Cousar JL, Tullis E, Vermeulen F, Marigowda G, McKee CM, Moskowitz SM, Nair N, Savage J, Simard C, Tian S, Waltz D, Xuan F, Rowe SM, Jain R. Elexacaftor-Tezacaftor-Ivacaftor for cystic fibrosis with a single Phe508del allele. New England Journal of Medicine 2019;381:1809–1819. (*equal contribution)
Stahl M, Wielputz MO, Ricklefs I, Dopfer C, Barth S, Schlegtendal A, Graeber SY, Sommerburg O, Diekmann G, Husing J, Koerner-Rettberg C, Nahrlich L, Dittrich AM, Kopp MV, Mall MA. Preventive inhalation of hypertonic saline in infants with cystic fibrosis (PRESIS). A randomized, double-blind, controlled study. Am J Respir Crit Care Med 2019;199:1238-1248.
Guerra M, Frey D, Hagner M, Dittrich S, Paulsen M, Mall MA*, Schultz C*. Cathepsin G activity as a new marker for detecting airway inflammation by microscopy and flow cytometry. ACS Cent Sci 2019;5:539-548. (*equal contribution)
Margaroli C, Garratt LW, Horati H, Dittrich AS, Rosenow T, Montgomery ST, Frey DL, Brown MR, Schultz C, Guglani L, Kicic A, Peng L, Scholte BJ, Mall MA*, Janssens HM*, Stick SM*, Tirouvanziam R*. Elastase exocytosis by airway neutrophils is associated with early lung damage in children with cystic fibrosis. Am J Respir Crit Care Med 2019;199:873-881. (*equal contribution)
Stahl M, Joachim C, Wielputz MO, Mall MA. Comparison of lung clearance index determined by washout of N2 and SF6 in infants and preschool children with cystic fibrosis. J Cyst Fibros 2019;18:399-406.
Graeber SY, Dopfer C, Naehrlich L, Gyulumyan L, Scheuermann H, Hirtz S, Wege S, Mairbaurl H, Dorda M, Hyde R, Bagheri-Hanson A, Rueckes-Nilges C, Fischer S, Mall MA*, Tummler B*. Effects of lumacaftor-ivacaftor therapy on cystic fibrosis transmembrane conductance regulator function in Phe508del homozygous patients with cystic fibrosis. Am J Respir Crit Care Med 2018;197:1433-1442. (*equal contribution)