Robert Bals, MD, PhD

Chaperone based therapy of alpha-1-antitrypsin-deficiency in a smoke-induced murine model of emphysema

AATD is caused by mutations of the AAT gene. The Z mutation accounts for most of the clinically relevant cases. PiZZ causes morbidity in two ways: 1) intracellular aggregates of AAT(Z) in hepatocytes induce liver damage, 2) decreased AAT levels in serum and lung interstitium results in increased susceptibility to COPD caused by cigarette smoke. The basic mechanism that underlies both pathogenic pathways is the accumulation of missfolded AAT in hepatocytes. AAT(Z) still retains 80 % of its activity to inhibit the neutrophil elastase. Therefore, a treatment that releases AAT(Z) from hepatocytes potentially addresses both pathogenic pathways.

Chaperones are a group of molecules that guide protein folding and reverse the missfolding and misslocalization of mutant proteins. In a recent study the group of Perlmutter showed that several chaperons facilitate the secretion of AAT(Z) in vitro and in a murine model. These results indicate that the application of chaperones is a novel therapeutic approach for the treatment of AAT-deficiency. Based on these results we will aim to apply these results to AAT-deficiency and to test whether AAT(Z) is capable to protect against smoke-induced emphysema in chaperone-based therapy.

It is the goal of the project to evaluate chaperone-based therapy of AAT-deficiency. The concept will be evaluated in vitro and translated into pre-clinical animal models. Several specific aims need to be answered before this type of therapy can be further advanced to the bedside:

  • Do different chaperones release AAT(Z) from cells? Novel chaperone classes are tested in vitro to evaluate their potential to rescue missfolded AAT.
  • Are serum levels reached in an animal model of chaperon-based treatment sufficient to protect from smoke induced lung damage?
  • Does long term application of chaperons protect from liver damage?

Future animal experiments will aim to answer the question whether chaperone-based rescue of AAT(Z) could protect from liver disease. An ultimate future step would be to initiate a Phase I trial to study toxicology and biochemical efficacy of chaperones in patients with AAT-deficiency. The results of the experiments reveal whether chaperon based treatment is a feasible approach to treat patients with this AAT deficiency.

Curriculum Vitae of Robert Bals: 

Birthdate August 2, 1968

1994 Medicine: MD, Ludwig-Maximilians University, Munich, Germany
1996 Biology: Dipl. Biol., Ludwig-Maximilians University, Munich, Germany
1996 - 1999 Gene therapy and innate immunity of cystic fibrosis: Postdoctoral training,
Institute for Human Gene Therapy, University of Pennsylvania,
Philadelphia, USA
1994 Medicine: MD, Ludwig-Maximilians University, Munich, Germany
Employment Experience

Nov 2001 - now Lecturer, Internal Medicine und Pulmonology, Hospital of the University of Marburg, Germany
Apr 1999 - Oct 2001 Resident and Research fellow, Medical Department I, Klinikum Grosshadern, University of Munich, Germany
Oct 1996 - Mar 1999 Post-Doctoral Research, Department of Molecular and Cellular Engineering, University of Pennsylvania, Philadelphia, PA
Jan 1996 - Oct 1996 Graduate Researcher, Institute of Anatomy, University of Munich, Munich, Germany
Jun 1994 - Dec 1995 Medical Intern, Institute of Anatomy, University of Munich, Munich, Germany
Jun 1994 - Dec 1995 Clinical Intern, Clinic for Internal Medicine, University of Munich, Munich, Germany
Selected Honors

Nov 2001 - now Paul-Martini-Preis 2000, Adolf-Windorfer-Preis of the Mukoviszidose e.V., Oct 1996 – Sept 1998 Fellowship, Deutsche Forschungsgemeinschaft, 1990 - 1994 Fellow of Medicine, Studienstiftung des deutschen Volkes

Dr. Robert Bals
Baldingerstr. 1
35043 Marburg
Telephone: 0049 6421 286 4994
Fax: 0049 6421 286 8987