Drug Discovery & Pharmaceuticals
University College London Collaboration Aims to Treat Alpha-1-Antitrypsin Defi ciency (Case study)
Professor David Lomas, UCL (University College London)
Alpha-1-antitrypsin defi ciency is one of the most common inherited disorders in Caucasian populations. It is the only genetic factor that is widely accepted to predispose people to lung disease and can also cause a variety of liver disorders. In combination, these conditions have an estimated healthcare cost of nearly $50 billion a year in the US alone, and have a signifi cant impact on the lives of the patients and their families.
Understanding what drives the development of alpha-1-antitrypsin defi ciency has been a passion for Professor David Lomas, Dean of the Faculty of Medical Sciences at UCL (University College London), since he completed his medical degree and undertook a PhD working on the topic in the early 1980s. During these fi rst years, he showed that the disease is caused by unwanted polymerisation of alpha-1-antitrypsin in liver cells, where it is produced. This event is triggered by a mutation that is present in as many as 4% of the Caucasian population. The effect is that the protein cannot exit the liver and travel to the lungs to serve its protective function, leading to lung diseases such as chronic obstructive pulmonary disease (COPD).
A better appreciation of what causes alpha-1-antitrypsin polymerisation, and therefore accumulation, provided important insights into how the process might be blocked, providing an avenue for treatment. At the same time, the polymerisation of alpha-1-antitrypsin is used as a model for understanding a number of other diseases caused by members of the serine protease inhibitor (serpin) superfamily, the likes of which are associated with emphysema, thrombosis, angioedema, dementia and more.
Blocking Polymerisation
Over the course of a distinguished career, Professor Lomas has led academic research groups exploring the mechanism and importance of alpha-1-antitrypsin polymerisation using a wide range of research tools. These range from investigating the purifi ed protein with protein crystallography and biophysical methods through to in vitro studies using cell biology and in vivo experiments employing fruit fl y models.
Having identifi ed discrete areas of the alpha-1-antitrypsin protein involved in polymerisation, Professor Lomas and his team collaborated with the Scripps Research Institute to use in silico screening in the hope of discovering small molecule inhibitors that might bind to the protein and inhibit polymerisation. The initial compound was analysed in more detail by Lomas’ lab to see how it might perform in vitro and to optimise its properties to best inhibit alpha-1-antitrypsin polymerisation. This compound was not a viable starting point for generating a medicine and therefore new chemical series were needed.
Partnering to Develop a Treatment
for Alpha-1-Antitrypsin Defi ciency Having built a strong relationship with the GSK team over many years, starting in 1999 when he was co-lead Principal Investigator on the GSK International COPD Genetics Network and continuing through to his current position as chair of the GSK Respiratory Therapy Area Board, partnering with the company was a natural choice.
“It’s not easy to optimise small molecule candidates for use as treatment compounds,” said Lomas. “The best medicinal chemists tend to be in industry, and we felt that access to this knowledge was essential in our search for effective inhibitors of alpha-1- antitrypsin polymerisation and treatments for the associated liver and lung disease.”
He continued: “Realistically, although we have access to the right patients and samples as well as the disease area expertise to plan effective clinical trials, it is very challenging for academics to develop a drug all the way through from idea to marketed product on our own. Partnerships such as the one we have initiated with DPAc are perfect, as each partner brings something unique to the table, leveraging their unique skills for the good of the program. The aim of everyone involved is to fi nd a cure. If we succeed then everyone wins, most importantly of all the patients.”
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New Immunoassay Kits for use on High-Throughput Platform Launched
Merck Millipore, the Life Science division of Merck, has announced the release of five new immunoassay kits designed specifically for use on the Gyrolab™ workstation. The new, fully qualified GyroMark™ HT kits from Merck Millipore will enable clinical researchers and drug developers to generate valuable research data much faster than typical ELISA kits.
Traditional ELISAs can consume significant time, sample and reagents. With the fully automated, walk-away system from Gyros, approximately 500 samples can be analysed within four hours.
“Our collaboration with Gyros will fill a commercial need to provide immunoassay kits requiring only nanolitre sample volume on a truly high- throughput platform,” said Jehangir Mistry, PhD, General Manager, Multiplex & Immunoassays at Merck Millipore.
The initial launch includes five assays for important metabolic and toxicity biomarkers, such as GLP-1, Insulin, Clusterin and KIM-1. Merck Millipore plans to release additional kits this year, and is offering custom kits for companies with specific needs or unique or novel antibodies.
Because the Gyrolab™ platform employs microfluidic technology with parallel processing, it offers many advantages over traditional assays in addition to reagent and time savings. GyroMark™ HT assays provide accuracy over a four-log dynamic range (compared to two logs for ELISAs), elimination of cross-talk and plate position artifacts, and simplified sample prep (only 1:2 dilution necessary) with reduced matrix interference.
Gyros’ Global Marketing Director Maria Hjortsmark commented: “The Gyrolab™ platform revolutionises immunoassays, enabling scientists to analyse large numbers of samples in parallel, at nanolitre scale and using a fully automated system. We are delighted that Merck Millipore has chosen to work with us to develop off-the-shelf kits, to further reduce time to results that will free up analyst time, and offering an easier route to robust, reproducible data.”
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