Friday, March 29, 2013

Prize4Life's Coverage of the 7th Annual Drug Discovery for Neurodegeneration Conference

Prize4Life is pleased to bring you coverage of the 7th Annual Drug Discovery for Neurodegeneration Conference, a conference presented by the Alzheimer’s Drug Discovery Foundation (ADDF). The conference, held February 10-12, 2013 in sunny San Francisco, California, brought together attendees from a variety of different sectors including academia, industry, biotech, government, and non-profit organizations. The goal of the meeting was to delve into the details of the drug discovery process -- covering topics from high throughput screening, to identifying and optimizing a lead compound, to preclinical studies – all in the context of the important considerations that need to be addressed when developing drugs for neurodegenerative diseases such as Alzheimer’s disease and ALS.

Dr. Howard Fillit, ADDF Executive Director and Chief Science Officer, opened the conference with a broad overview of the current state of the field. In his talk, Fillit suggested that the drug development landscape is changing. There is much more collaboration between industry and academia then even five years ago, and such collaboration is necessary for successful drug development. Yet, although we are making progress and these collaborations are helping advance discoveries, scientists in the business of developing drugs for neurodegenerative diseases still face tremendous challenges. Three of these challenges will be covered in today’s post: 1. the changing and evolving use of animal disease models in translational research, 2. the rising importance of biomarkers, and 3. the
inherent difficulties in targeting protein-protein interactions (particularly in the brain).

The first plenary speaker Dr. Piet van der Graaf, Senior Director of Clinical Pharmacology/Pharmacometrics at Pfizer, didn’t shy away from one of the most controversial topics discussed at the meeting -- the reliability of using animal models of disease for preclinical testing. In his presentation “Transforming Drug Discovery for Complex Diseases: A Systems Biology Approach” van der Graaf suggested that all too often animal disease models have little predictive value. His comments echoed the recent findings published in Proceedings of the National Academy of Sciences that showed some mouse models of disease may not recapitulate the immune response observed in human disease. The discussions at the conference emphasized the growing concern in the drug development community of whether mice are an appropriate model for human disease, or if we need to find new disease models. Computational and iPS cell derived models are two alternatives that were discussed in detail at the conference.

But should we really leave our mice behind? Dr. Katya Tsaioun of Pharma Launcher challenged van der Graaf’s thinking about animal models. She argued that we need to closely examine the black/white thinking that animal models “don’t predict” -- perhaps we just need to be more aware of the limitations of our animal models. Both Tsaioun, during her talk “Absorption, Distribution, Metabolism, Excretion and Toxicology (ADME-Tox) in Compound Refinement”, and Fillit in his opening remarks, suggested that animal models are highly useful for collecting multiple supporting pieces of data critical for successful drug development. Effective and well-understood animal models of disease allow us to look at disease mechanisms and investigate what is going on at the molecular level. Using animal models to collect these types of data might be the best way to harness these models in a productive way. Although the jury is still out on the utility of animal models of neurodegeneration -- this is clearly a perennially hot topic that was in hot debate at the conference!

The importance of identifying and developing biomarkers, was another underlying theme highlighted by several speakers at the conference. Dr. Kalpana M. Merchant, Chief Scientific Officer for Translational Science at Eli Lilly and Company, in her talk “Improving Clinical Success through Optimal Target Validation” emphasized that biomarkers are essential for monitoring whether therapies have engaged their target. How do you successfully choose the right biomarker? Make sure that you know your therapy’s target and then make sure you have a disease-associated biomarker that you can use to monitor target engagement. Tsaioun also pointed out that once you have a druggable target, biomarkers can help with correlating your in vitro results with your in vivo results. Further to her point about changing the way we use our animal models, Tsaioun suggested that animal-based disease models can be useful for collecting biomarker data.

One of the biggest questions on everyone’s mind throughout the conference was: why don’t we have more drugs for neurodegenerative diseases? One obvious answer is that it is hard to get drugs across the blood-brain barrier. Dr. Bruce Morimoto of Allon Therapeutics Inc. in his talk “Peptide Therapeutics and Mechanisms for Intranasal Delivery” suggested that one solution to this problem is to use intranasal delivery, which allows drugs to bypass the blood-brain barrier entirely. Another answer for why there are so few drugs for CNS diseases is that many neurodegenerative diseases are protein-aggregation diseases, and protein-protein interactions are notoriously difficult to target. Dr. Jim Wells, Professor in the Department of Pharmaceutical Chemistry at the University of California, San Francisco, discussed two key limitations to targeting protein-protein interactions in his talk entitled “Challenges of Protein-Protein/Protein-Peptide Targets.” First, proteins often associate with one another using large interfaces that make preventing these interactions difficult. Second, proteins often form tight complexes with one another that need to be dissociated in order to restore function and/or remove dysfunctional proteins from the cell. Wells mentioned that one way to target unwanted protein-protein interactions is to use alanine-scanning mutagenesis to identify hot spots of binding and then you could potentially find ways to target these hot spots with drugs. Dr. Ryan Watts, Associate Director and Head of Neurodegeneration Labs in the Department of Neuroscience at Genentech, Inc., suggested in his talk “Developing Therapeutic Antibodies for Neurodegenerative Disease” that antibodies are the best way to target protein-protein interactions. However, despite the promise antibodies hold for targeting and disrupting protein-protein interactions, they do have some limitations including the challenge of getting the antibodies across the blood-brain barrier (bringing things full circle!).

This summary is only a small taste of the numerous useful topics discussed at ADDF’s 7th Annual Drug Discovery for Neurodegeneration Conference. The conference was a great success -- the attendees received some hearty "food for thought" about our current system of drug development, especially in the complex and challenging neurodegenerative disease space. For those of you who weren’t able to make it to California for the conference (maybe you happened to be snowed in by a blizzard) but want to learn more, the entire 2013 Drug Discovery Conference webcast is now available. Click here to watch it for free. - Jessica Goodman

1 comment:

  1. Hi i read this article this is very nice and helpful article for everyone and specially for old men and women you done this is very smartly and take good point to explain people that,s why i really like this.

    And i really like you 4th paragraph and thanks for sharing such a nice type of info.