Dr Bibek Gooptu, from the Institute for Structural and Molecular Biology (ISMB) at Birkbeck and UCL, has been awarded a grant by the Alpha-1 Foundation for research into new treatments for the condition Alpha-1 Antitrypsin Deficiency.
Alpha-1 Antitrypsin Deficiency
Alpha-1 Antitrypsin is a protein which is created in the liver and then carried in the blood to the lungs, where it protects lung tissue. In people with Alpha-1 Antitrypsin Deficiency, a mutant gene within the liver cells causes the Alpha-1 Antitrypsin protein to adopt a different structure, which causes individual protein molecules to link together in chains, known as polymers. The liver is not able to secrete these polymers and so they remain stuck inside liver cells, damaging them. It also means that not enough Alpha-1 Antitrypsin reaches the lungs from the blood stream. People with Alpha-1 Antitrypsin Deficiency are likely to suffer both from liver disease (e.g. cirrhosis or cancer of the liver) and, if they are smokers, they are likely to develop emphysema at a much younger age than someone without Alpha-1 Antitrypsin Deficiency – probably in their 30s or 40s.
One in 27 people in Northern Europe carry one copy of the mutant gene for Alpha-1 Antitrypsin Deficiency, but for the disease to manifest, two copies are required.
Understanding Alpha-1 Antitrypsin Deficiency
Dr Gooptu’s research aims to understand why the mutation in the gene causes the structure of Alpha-1 Antitrypsin to change from the healthy structure. The ultimate objective is to find a way of stopping the Alpha-1 Antitrypsin forming polymer chains, so that the liver can secrete it and it can carry out its correct function – protecting lung tissue.
Finding new treatments
Typically drug development is either done by blindly testing large numbers of existing compounds to see if any show promise (“high throughput screening”), or else by very carefully designing a molecule so it works very well in theory, and then testing them out (“rational drug design”). The approaches have opposite strengths and weaknesses but at the ISMB Dr Gooptu’s team will combine them to get the best of both worlds. In the first stage Dr Gooptu’s team will take around 750 promising compounds and direct them at Alpha-1 Antitrypsin. Using a method known as mass spectrometry, he and his colleagues will identify those compounds which successfully bind the protein.
In the second stage, those compounds which interact most successfully with Alpha-1 Antitrypsin will be tested within cells, to see whether they cause a decrease in the formation of polymer chains, cell damage and/or an increase in Alpha-1 Antitrypsin secretion.
In the third stage, using Nuclear Magnetic Resonance (NMR) techniques, the team will look closely at the structure of the protein and the compounds in solution, to try to understand which binding sites they are using and how the binding is taking place. This information will enable the team to go back to much larger libraries of compounds and test new ones which are related to those which were most successful in cells, but should work even better. The team will therefore tailor the compounds based not just on ‘trial and error’ but instead combining practical information with knowledge of how the binding process is taking place.
By combining high throughput screening with studies in cells and NMR techniques, Dr Gooptu and his team hope to develop new drug treatments for Alpha-1 Antitrypsin Deficiency.
This research is funded by the Alpha-1 Foundation. It will start in July 2012 and run for two years.
Dr Bibek Gooptu has been working on Alpha-1 Deficiency at Birkbeck since 2006. He is also a practising Registrar in Respiratory Medicine.
10 July 2012
An additonal message from Dr Gooptu:
Since this post went up a number of people have contacted us, both on- and off-thread, expressing interest in the work, including offers to assist as subjects in the research. In some cases people are getting in touch because of personal/family experience of this relatively under-reported condition. The feedback is very much appreciated. It is wonderful to have confirmation that our research is not an abstract intellectual bubble occurring inside ivory towers, but is of wider interest to the community as a whole. We hope to post updates, via this blog, every 6 months or so and we can email anyone who wishes to be notified as and when these go up.
It should be emphasised that the research underway at Birkbeck and UCL is not at a stage where trials in humans are planned within the next few years. On the other hand our group’s work sits within a strong network of researchers involved in a range of studies of alpha1-antitrypsin deficiency both within the ISMB; and elsewhere (in London, the wider UK and beyond). Sometimes samples (e.g. blood samples) from individuals can be very useful in such studies. Also, from time to time, ethically approved drug trials are conducted in alpha1-antitrypsin deficiency.
I can be contacted directly by email (mailto://email@example.com) about any of these issues, and will do my best to respond in a timely manner. For individuals who know they have alpha1-antitrypsin deficiency because they have 2 copies of the deficiency gene, and are interested in helping with ongoing research, an international registry has been set up based in Europe and the US. The situation with carriers (one normal + one deficiency gene) is more complex. Studies so far indicate the increased risk of disease in these individuals is very small indeed.
Useful resources that can be accessed online include*:
British Lung Foundation
American Thoracic Society/European Respiratory Society Guidelines on Diagnosis and Treatment of Alpha1-Antitrypsin Deficiency * http://www.thoracic.org/statements/resources/respiratory-disease-adults/alpha1.pdf
* Current treatment of alpha1-antitrypsin deficiency is slightly different in the UK to that practised in Europe and the US