One of Drug Discovery 2015’s Plenary keynote speakers is Dr. David Y. Thomas, CEO of Traffick Therapeutiques/Therapeutiques, Inc., of Montreal, Canada, a company specializing in the development of therapies for protein trafficking diseases such as cystic fibrosis.
The company collaborates with pharmaceutical and medicinal chemistry companies and has project-specific investments. Dr Thomas obtained his Ph.D., at University College London and has made original contributions in several areas of genetics and biochemistry. Through discovery of the components of the ‘Calnexin cycle’ he established the mechanism of folding and quality control of secreted proteins.
In an exclusive interview with ELRIG’s Liz Quinn, Dr. Thomas shares his opinion on the future strategies for protein trafficking diseases and challenges to realizing the full potential of new therapeutic development for Cystic Fibrosis (CF).
LQ: You have been an academic all your career focused on understanding fundamental cell biology. Yet you have also had many collaborations with industry over the years. What have been the benefits of working with industry partners? What are the challenges?
DT: I was trained as a geneticist and have worked on a variety of topics, including mitochondrial genetics, and the MAP kinase cascade. Also we discovered a protein that we called Calnexin that links protein folding and the N-glycosylation of proteins in the Endoplasmic Reticulum. Together with the enzymes involved in N-glycan processing, this forms the Calnexin Cycle that constitutes the protein quality control system.
I had served on various advisory boards of biopharmaceutical companies and collaborations with industry. When I was recruited 14 years ago to the Faculty of Medicine at McGill University, I was interested in studying protein trafficking diseases. I was surprised to learn that Cystic Fibrosis (CF), for which the CFTR gene that is responsible for the disease had been identified by my Toronto colleagues and their US collaborators in 1989, still had no therapy that addressed the basic trafficking defect of the most common mutation, F508del-CFTR.
I recall that at the time of the CFTR discovery, we were all optimistic that this would be first of many triumphs for a cure by gene therapy and maybe with the results of the Multidose Gene Therapy (Wave 1) Trial from the Gene Therapy Consortium (GTC) this will finally be realized. But in the meantime, there are many efforts to identify small molecules that correct the basic trafficking defect of F508del-CFTR and place the mutant, but otherwise functional, protein at its correct location on the cell surface.
There is a very nice complementation of between industry and academic cultures. I can look back on a series of excellent and productive projects that have been very enjoyable. The many benefits of working with industry include their impressive expertise in medicinal chemistry, their extensive resources and their project management expertise and focus on deliverables. Challenges remain in that industry scientists have obligations to other projects and there are often changes in company structure and ownership that inhibit progress. As we know, mergers and acquisitions can result in rapid changes and priorities.
LQ: You have recently been working on drug discovery for CF. As an academic, how have you been able to access chemistry and screening? What do you think are the challenges facing academic drug discovery?
DT: I set up a consortium with colleagues at the Universities in Montreal, Toronto, Vancouver and Hamilton called the Canadian Chemical Biology Network. This consortium is funded by the Canadian Institutes for Health Research and provides high quality chemical libraries to academic investigators. Thanks also to the Canada Foundation for Innovation we have been able to set up screening centres at these universities. Each centre has evolved its own specialties and there have been a series of exciting molecules found for a wide variety of diseases through these efforts.
The challenge for academic centres is to obtain expert medicinal chemistry and convert hits into quality lead molecules. Paradoxically (and unfortunately), this has become easier lately as many pharmaceutical companies have centralized their operations. In Montreal, where many pharmaceutical companies have closed their research operations, we have some excellent medicinal chemistry companies that have been founded by some expert medicinal chemists and we have really benefitted from this expertise. Another challenge is the availability of venture capital for early stage projects, but this is fortunately changing and improving.
LQ: At the Drug Discovery 2015 conference in Telford, UK in September, you will be delivering a talk on the development of new therapeutics for CF. Can you give us a preview of your findings and how your work is being applied for new drug development?
DT: I will discuss the development of correctors of protein trafficking of F508del-CFTR and our own programme at Traffick Therapeutics /thérapeutiques Inc. with our partners. My talk will describe the success of the CF programme of Vertex Pharmaceuticals together with the Cystic Fibrosis Foundation Therapeutics, Inc., which is now the benchmark for F508del-CFTR therapy. I will discuss their development of an effective potentiator drug (Kalydeco) for the G551D CFTR mutation, where the CFTR protein trafficks to the plasma membrane, but is not functionally active. Their recent report of the clinical trial using a combination of corrector and potentiator drugs sets the bar for the development of new therapies. I will also discuss our programme at Traffick Therapeutics /thérapeutiques Inc.
LQ: What do you think the prospects are for CF therapy? What are some of the hurdles or challenges that the drug discovery industry needs to overcome in order to realize the full potential of these strategies?
DT: The initial focus after the discovery of the CFTR gene was on gene therapy. At that time, there was extensive funding for this strategy at many academic centres. It seemed to many of us in the field that CF was an ideal candidate disease for gene therapy. However, these pioneering efforts did not yield a successful therapy and so the results from the UK Multidose Gene Therapy (Wave 1) Trial are eagerly awaited.
The present state of CF research and therapeutic development is very exciting. There are some sound proof-of-principle compounds and there are now CF programmes at several drug companies. There are also indications that CFTR may be involved in other respiratory diseases such as “acquired CF” and the possibility that correctors may be useful in other protein trafficking diseases. CF drug development has a unique challenge in that it requires us to be able to increase the levels of correction of F508del-CFTR.
This may have to be achieved with combinations of correctors which adds a level of complexity to drug development. And as therapies change and improve, other problems may arise if/when CF changes into a chronic disease and requires long term applications of drugs. From the effects of modifier genes on the severity of CF, we might anticipate that individual responses to corrector therapies will vary and effective ways of measuring short and long term correction in patients will be needed.