Alan Wooler, David Lomas & Emma Wooler
On Monday 3rd February 2020, Alan and Emma Wooler of Alpha-1 Awareness went to UCL (University College London) to see Professor David Lomas, and presented him with a cheque for £10,000 to go towards his research of a cure for Alpha-1.
“A great deal of our time is spent supporting those who are newly diagnosed and sending out our leaflets and booklets around the UK to help educate people and bring awareness of Alpha-1. There are a lot of organisations around the world who are looking for better treatment which would be accessible to all, and we must do what we can to help the advancement. We are very pleased that over the last 3 years we have been able to donate £45,000 to Professor Lomas and his team at UCL who have made some great advancements.” 5.2.2020 Alan Wooler
“The work of our research group has, over 30 years, described the mechanism underlying the accumulation of mutants of a1-antitrypsin within liver cells. We showed that the mutant protein forms long chains of ordered polymers that accumulate as the inclusions that are the hallmark of the a1-antitrypsin deficiency and which underlie the development of liver cirrhosis. The polymers that form in the liver can also be found in the lining fluid of the lung. We believe that this causes inflammation which, in addition to the lack of an important antiprotease, leads to the development of lung disease.
The instability of recombinant (artificially produced) forms of a1-antitrypsin has hindered efforts to characterise the abnormal protein conformations, particularly formed by the severe Z variant (Glu342Lys). We have recently developed NMR spectroscopy of human a1-antitrypsin to investigate the structural and dynamical consequences of disease-causing variants. This technique has allowed us to identify the protein intermediate that precedes polymer formation, accessed on a sub-millisecond timescale. It proves new information on the changes in the protein that underlie the formation of polymers.
It has always been my long term goal to find a cure for a1-antitrypsin deficiency. I have taken several approaches to blocking the abnormal protein-protein interaction that underlies the formation of polymers. The most recent is work with GSK to use a DNA-encoded chemical library to identify small molecules that preferentially bind to, and stabilise Z a1-antitrypsin. The lead compound binds to a cryptic pocket to negate the local effects of the Z mutation. It blocks polymer formation in vitro and in cell models of disease and increases the secretion of Z a1-antitrypsin into the plasma of transgenic mice by 7 fold. This study provides proof-of-principle that ‘mutation ameliorating’ small molecules represent a viable approach to treat a1-antitrypsin deficiency. We have recently licenced them to a US biotechnology company to progress into man https://www.uclb.com/2019/10/08/uclb-reaches-an-exclusive-license-agreement-for-the-treatment-of-alpha-1-antitrypsin-deficiency
Our future work will use biophysical and structural techniques to define the structure of the pathological polymer that underlies a1-antitrypsin deficiency. This will allow us to better design strategies that will block the protein-protein interaction and so treat the associated disease. We are also using screens of worm (C. elegans) models of a1-antitrypsin deficiency in the hope of identifying pathways that underlie cell death. If successful this may open new approaches to prevent the cell damage caused by the accumulation of toxic a1-antitrypsin polymers within cells.” 21.1.20 David Lomas