Turning Basic Research Discoveries into Drugable Targets and Treatments for Alcoholism

Alcoholism is a chronic, progressive, and sometimes fatal disease. After prolonged exposure to alcohol, the brain adapts to the changes alcohol makes and becomes dependent on it. In the United States, relapse rates for addictive diseases range from 50 to 90 percent (National Institute for Alcohol Abuse and Alcoholism 2005). It is known that stressful events may lead to a variety of health and psychiatric illnesses ranging from depression to drug abuse (Herman and Cullinan 1997; Sarnyai et al. 2001; Reul and Holsboer 2002). Despite its devastating impact on society, there are still few effective medications currently available for the treatment of alcoholism. There have been two medications approved by the U.S. Food and Drug Administration since 1995 for alcoholism: naltrexone (ReViaTM) and acamprosate (CampralTM). In addition, one other medication is in the process of being approved: naltrexone depot (VivitrolTM). Naltrexone is only minimally effective if taken on a regular basis and has significant side effects. Acamprosate showed promise in treating alcoholism, however it requires three times daily dosing, and patient compliance is an issue. There is a great need for the development of more effective medications for the treatment of alcoholism. The Gallo Center’s strategy is thus to accelerate the rational development of new therapeutic approaches by uncovering the basic molecular and neurophysiological mechanisms that underlie alcohol and substance abuse. In order to fulfill its translational mission, the Gallo Center has created new structures within its organization to accelerate the transfer of scientific discoveries from the laboratory into clinical application. These new structures include the Preclinical Development Group.

Preclinical Development Group

Selena Bartlett, Director of Preclinical Development, selenab@gallo.ucsf.edu
Jade Bito-Onon, Staff Research Associate, jbitoonon@gallo.ucsf.edu
Susmita Chatterjee, PhD, Postdoctoral Fellow, schatterjee@gallo.ucsf.edu
Allison Feduccia, PhD, Postdoctoral Research Fellow, afeduccia@gallo.ucsf.edu
Carolina Haass-Koffler, Postdoctoral Fellow, chaasskoffler@gallo.ucsf.edu
Andrea Henry, Staff Research Associate, ahenry@gallo.ucsf.edu
Joan Holgate, Specialist, jholgate@gallo.ucsf.edu
Rui Li, Research Student, rli@gallo.ucsf.edu
Douglas Mill, Research Student, dmill@gallo.ucsf.edu
Mohammed Naeemuddin, Senior Staff Research Associate, mnaeemuddin@gallo.ucsf.edu
Carsten Nielsen, PhD, Associate Research Scientist, cnielsen@gallo.ucsf.edu
Nathan Santos, Laboratory Assistant, nsantos@gallo.ucsf.edu
Jeffrey Simms, Manager of Preclinical Development, jsimms@gallo.ucsf.edu
Subhashini Srinivasan, Postdoctoral Research Fellow, ssrinivasan@gallo.ucsf.edu

General Approach

Our unique, interactive, multidisciplinary environment combines human genetic research with state-of-the-art molecular and cell biology, electrophysiology, and animal genetics and behavior to provide exceptional experimental flexibility and power for the analysis of addictive disorders. Because alcohol-related behaviors in animals may also reflect their responses in other important areas, such as anxiety and pain, this research may also yield new therapeutics for other central nervous system-based conditions. The Gallo Center does not currently have the resources to support a comprehensive therapeutic development program, which requires medicinal chemistry and other downstream components for creating an effective, FDA-approved medication. Therefore, at some point in the development process, it is essential to hand the program off to a pharmaceutical or biotech company that does have downstream development capability. Because of the plethora of possible targets available to pharma, from genomic approaches to molecular pathophysiology, it is now difficult to attract pharma interest in licensing additional new targets for compound development. A basic mechanism-based hypothesis is not sufficiently persuasive to cause a pharmaceutical company to give up its other promising targets to make room for the new one. Lead compounds and substantial preclinical characterization are thus increasingly required before a discussion can even be initiated. Such development is not often conducted by a basic science laboratory. Indeed, the intellectual and organizational aspects of development are quite different from that of discovery.

Once a promising new component of the alcohol response is discovered in a Gallo Center lab, it is important to extend and validate the discovery to create a persuasive case that therapeutics targeting the newly discovered proteins are likely to be clinically efficacious. This development process differs significantly in its approach from that of the academic lab, and favors a more linear, project management style. To facilitate this development process, we have created a new unit within our Translational Research Program: the Preclinical Development Group (PDG). The Preclinical Development Group represents a new and compelling model for translating discoveries along the path of drug development. The PDG has already been successful in developing a number of agents, either developed by in-house screening of compound libraries, or by collaborating with biotech groups. These agents are undergoing preclinical validation in our cell culture and animal model systems, in anticipation of their licensing to pharmaceutical companies for further clinical development.

Currently we are specifically testing a number of different targets which have been identified from Gallo Center laboratories as being involved in the addiction response: some of which are related to opioid receptors, NK1 receptors, and orexin receptors.