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

Meet One of the Recipients of the Abramson Fellowship at Harvard University

Christopher Devine

The Samuel H. Abramson Memorial Research Fellowship (Abramson Fellowship) at Harvard University was established in 1983 by Edward and Harriet Abramson in honor of Edward’s father to support students conducting research on issues related to Israel and Jewish studies.  However, when Edward passed away in 2001 after a courageous battle with ALS, the focus of the fellowship shifted to support students conducting stem cell research particularly in the areas of ALS and neurodegenerative disease.  

The Abramson Fellowship is open to Harvard University students in their sophomore, junior, or senior years. The Abramson Fellowship has been awarded to more than 250 of Harvard’s best and brightest students.

Thank you to Prize4Life supporter and ALS advocate Harriet Abramson, as well as Dr. Jeffrey Macklis, Professor of Stem Cell and Regenerative Biology at Harvard University and mentor to many of the students that receive the Abramson Fellowship, for the opportunity to get to know some of the most recent recipients of the Abramson Fellowship.

Christopher Devine, Class of 2013

Harvard University senior and Abramson Fellowship awardee Christopher Devine grew up just outside of New York City in Ramsey, New Jersey.  Before beginning his studies at Harvard in the fall of 2009, Christopher attended high school at Bergen County Academies (BCA) where he chose to specifically focus on medical science technology.  While at BCA, Christopher honed his leadership and communication skills.  These skills have matured and continue to serve him well with his studies and scientific research efforts at Harvard.

We recently asked Christopher to share his thoughts about being awarded an Abramson Fellowship in the summer of 2012 and how his research at Harvard may impact the understanding of neurodegenerative diseases such as ALS.

Q: How did you become involved in the Abramson Fellowship program?

A: Since arriving at Harvard, I have been actively involved with a number of activities including peer advising and tutoring, and have held leadership roles in Student Government and on the Student Life Committee. However, my most personally and professionally defining experience at Harvard has been being a member of Dr. Jeffrey Macklis’ laboratory in the Harvard Department of Stem Cell and Regenerative Biology.  I joined the lab in the spring of my freshman year as an undergraduate concentrating in Neurobiology.  Two years later, in the summer of 2012, I had the honor of receiving the Abramson Fellowship to support my research efforts. The research I conducted with the support of the Abramson Fellowship culminated in my senior thesis, “Investigating the Fidelity of Axolotl Forebrain Regeneration.”

Q: What type of research are you currently conducting?

A: Research in the Macklis lab is at the forefront of developmental and regenerative biology. I am currently working with postdoctoral fellow Dr. Hari Padmanabhan to better understand neuronal development and regeneration. More specifically, I work with a unique species of salamander that can naturally regenerate its body parts, including the spinal cord and brain. If we are able to better understand the mechanisms involved with brain regeneration and repair, it will bring us one step closer to understanding the complexity of neurodegenerative diseases like ALS.

Q: Why did you choose to focus your research on understanding neuronal regeneration and neurodegenerative diseases?

A: Of all known medical conditions, neurodegenerative diseases are by far the least understood.  The fact that so little is known about neurodegenerative diseases, and in particular ALS, has served as a powerful motivator for me to engage in basic scientific research focused on the development and regeneration of the central nervous system. It is important for me know that my research, no matter how small the contribution is, may in fact contribute to the fight against ALS and possibly provide hope to those who are currently battling the disease or will be diagnosed in the future.

Q: How has being awarded an Abramson Fellowship motivated you to continue with your research?

A: Being awarded an Abramson Fellowship has empowered me to become involved with understanding how to translate basic research findings into discoveries that can one day help treat patients with neurodegenerative diseases. I have shadowed neurologists and have seen how debilitating neurodegenerative diseases such as ALS and Parkinson’s disease can be to patients and their loved-ones. These diseases can strike anyone regardless of who you are, where you come from, or what you have done with your life.  Not only is the research I am conducting intellectually stimulating, it reminds me that I am making a difference for ALS patients.  I am truly lucky to be participating in cutting edge research that will contribute to a better understanding of the cellular mechanisms that drive neuron development and repair.

Q: What are your plans for the future?

A: My long term goal is to help those who suffer from neurodegenerative diseases as a physician-scientist. This will allow me to engage in both medical practice and in translational research. I am confident that the foundation I have built at Harvard will help me to achieve this goal.  Following graduation this May, I will be attending the University of Cambridge in the United Kingdom to pursue my MPhil in Translational Medicine and Therapeutics as well as continue to develop my skills in translational research. After that, I plan to return to Harvard Medical School and then eventually practice medicine with the hope of using translational research to take potential therapies from the bench to the bedside.

Q: What is your message to ALS community?

A: Conducting innovative research and working together is what I believe will lead to effective treatments and a cure for ALS and other neurodegenerative diseases.  And it is not just the work I am conducting in the Macklis lab as an Abramson Fellowship awardee; it is the work of other Abramson Fellowship awardees, undergrads, graduate students, post docs, and researchers around the world as well who are studying basic biology and making new scientific discoveries to advance our understanding of neurodegeneration. I would like to express my appreciation to the ALS community for being so supportive and passionate.  This is incredibly meaningful to students like myself and keeps us motivated to continue pursuing scientific research that contributes to the fight against ALS.  I want to say to the ALS community and the supporters of the Abramson Fellowship, thank you for allowing young researchers like me to be involved in such an important mission.