A new collaboration based at the University of Cambridge will aim to discover and develop new medicines to treat liver disease

The partnership, between the University of Cambridge and global pharmaceutical company GlaxoSmithKline (GSK), will build upon the work of researchers who have identified a molecular mechanism that plays a major role in the life-threatening liver disease that develops in a population of patients with a particular mutant gene.

Alpha-1 antitrypsin (A1AT) deficiency is one of the most common genetic disorders in the UK, affecting approximately one in 2,000 people. The A1AT protein is produced mainly in the liver and circulates to the lungs, where it serves a protective function against enzymes which can break down lung tissue.

In patients with A1AT deficiency, the protein cannot circulate freely and accumulates in the liver, leading to potentially life-threatening liver conditions including neonatal hepatitis, cirrhosis and hepatocellular carcinoma. Additionally, without A1AT circulating to the lungs, lung tissue can break down, predisposing patients to early onset emphysema. Currently, the only available treatments are liver transplantation for cirrhosis and protein replacement therapy for emphysema.

The mechanism that underlies protein accumulation in the livers of individuals with A1AT deficiency has been defined by the team led by Professor David Lomas in the University's Cambridge Institute for Medical Research (CIMR). The collaboration with GSK will combine Professor Lomas' long-term research with GSK's expertise in drug discovery and development in order to develop new therapeutics. Work on the project will be carried out both at GSK and at the CIMR.

Lung density associates with survival in alpha 1 antitrypsin deficient patients.

Abstract

INTRODUCTION:

CT density correlates with quality of life (QOL) scores and impaired upper zone lung density associates with higher mortality in alpha one antitrypsin deficiency (A1ATD). We hypothesised that decline in CT densitometry would relate to survival or deterioration in QOL in A1ATD.

METHODS:

All augmentation naïve PiZZ patients in the UK A1ATD registry with ≥ two successive quantitative CT scans were selected. Patients were divided into groups based on CT density decline and the relationship to survival and change in QOL compared by univariate analyses and multivariate Cox regression. Analyses were performed for whole lung, upper zone and lower zone density separately. Exploratory analyses of FEV1 subgroups were conducted.

RESULTS:

110 patients were identified; 77 had whole lung and lung zone density recorded on two CT scans, 33 patients had upper zone data only on four scans. Decline in lower zone density associated with survival, even after adjustment for baseline lung density (p = 0.048), however upper zone density and whole lung density decline did not. This difference appeared to be driven by those with FEV1 >30% predicted.

CONCLUSION:

Rate of change in lung densitometry could predict survival in A1ATD.

 

KEYWORDS:

 

PMID:

26874894

DOI:

10.1016/j.rmed.2016.01.007