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Lo DC, Hughes RE, editors. Neurobiology of Huntington's Disease: Applications to Drug Discovery. Boca Raton (FL): CRC Press/Taylor & Francis; 2011.

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Neurobiology of Huntington's Disease: Applications to Drug Discovery.

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At the time of this writing, 138 years have passed since the original published description of Huntington’s disease (HD). This remarkable account of HD, written by George Huntington in 1872, remains a fascinating and accurate read today. One hundred twenty-one years later, in 1993, a landmark article was published by the Huntington’s Disease Collaborative Research Group that reported the identification of the genetic mutation responsible for HD, a fundamental milestone in human genomics. The discovery of the primary cause of the disease, a CAG repeat expansion in a gene now known as HTT, catapulted the field of HD research into the modern era of genomics and, in so doing, created great expectations that the cutting-edge tools of molecular biology and chemistry would lead rapidly to the development of effective treatments for this devastating illness.

In the 16 years since the cloning of the gene, scientists in the HD field, as well as patients and their families, have witnessed an impressive expansion in our knowledge of the effects that this mutation in the HTT gene has on a wide range of neuronal functions and of its many deleterious effects outside of the nervous system. We have seen the field engage in extraordinary efforts to understand the nature of the HD mutation and how it can initiate and drive cellular dysfunction. From this work, the field has documented an unexpectedly large and diverse range of biochemical and genetic perturbations that seem to result directly from the expression of the mutant HTT gene. Indeed, at this point one is increasingly hard-pressed to name an aspect of cellular function that is not impacted by expression of mutant HTT.

Steady progress in elucidating the mechanistic consequences of the HTT mutation for cellular physiology has driven an explosive growth in translational research activities aimed at development of new drug therapies for HD. However, it is worth noting that effective treatments for HD remain elusive. The natural exuberance that followed the identification of the HD gene is now tempered by an appreciation of the complexities attending true understanding of HTT function and dysfunction. Distinguishing the biochemical perturbations merely associated with HD from those critical for disease progression is a major ongoing task.

Despite the challenges in developing drugs to treat HD, a strong basis for optimism stems from the monogenic nature of the disease. This aspect of HD offers significant advantages relative to other common neurodegenerative disorders, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). The sporadic and idiopathic natures of AD and PD make their underlying mechanisms fundamentally more uncertain. Despite all the complexities regarding the mechanistic consequences of mutant HTT expression, one thing is certain: HD is caused exclusively by a CAG expansion in the HTT gene. Furthermore, expression of the mutant HTT gene can consistently, indeed stereotypically, confer dysfunction and sickness when expressed in cultured cells, invertebrate animals, mice, and monkeys.

From the perspective of translational research, this confers enormous practical advantages in the face of the obstacles presented by HD. Ultimately, it has allowed the creation of robust experimental tools, models, and assays to facilitate discovery and validation of molecular targets and drug candidates for HD. Indeed, basic knowledge and assay development in the HD field have clearly matured to the point where we can begin to launch rational and effective drug discovery campaigns. This is, in part, evidenced by the proliferation of translational programs in HD, not just in academia but in biotechnology and pharmaceutical firms as well. The synergy of cell-based assays, mouse models, a highly organized consortium of clinical investigators, and increasing knowledge of the druggable target space around HD has brought us to the threshold of major breakthroughs in the quest for therapeutic agents.

As the editors of this volume, we have enlisted the help of key investigators in the field to give the reader an accurate and rigorous overview of an HD drug discovery pipeline that has been deliberately developed and coordinated in the century since George Huntington’s seminal report. We express our sincere gratitude to our dedicated colleagues for contributing these chapters. Finally, we acknowledge the many researchers, consortia, organizations—and the HD community—who have worked so hard to make this field into what it has become. In our experience, the HD research field is notable for its sense of common purpose, its spirit of cooperation and sharing, and its steadfast commitment to scientific rigor and excellence. In the end, these human qualities will prove to be as critical as the impressive array of drug discovery resources described here to delivering the effective drug therapies long-awaited by HD patients and their families.

Donald C. Lo

Durham, North Carolina

Robert E. Hughes

Novato, California

Copyright © 2011 by Taylor and Francis Group, LLC.
Bookshelf ID: NBK56002


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