Scripps Research Awarded $6 Million to Develop Potential Therapies to Fight Alcoholism and Autism-Linked Syndrome

By Eric Sauter

The Scripps Research Institute has been awarded a pair of grants totaling $6 million by the National Institutes of Health (NIH) to develop new therapeutic approaches to alcohol addiction and Fragile X syndrome, a form of inherited mental retardation that has often been linked to autism.

Claes Wahlestedt, a professor in the Departments of Neuroscience and Molecular Therapeutics at Scripps Florida, is the principal investigator for both projects.

"The majority of the work in our laboratory is about drug discovery," Wahlestedt said. "So even though we have targeted two completely different disorders, both grants focus on expanding our drug discovery platforms significantly. The NIH has become very attuned to the drug discovery potential of places like Scripps Research. Since the pharmaceutical industry has shown little interest in disorders like alcoholism, even Fragile X syndrome, if we want better drugs to treat these conditions, they will have to come from academic institutes like ours."

The four-year grant of approximately $3.6 million to study alcohol addiction was awarded by the NIH's National Institute on Alcohol Abuse and Alcoholism (NIAAA). The five-year grant of approximately $2.4 million to study Fragile X syndrome was awarded by the NIH's National Institute of Mental Health.

Tackling Alcohol Dependence

With the NIAAA grant, the team of researchers will take a classic drug-discovery approach.

In this work, the researchers will focus on identifying, designing, and then synthesizing a number of potent and selective neuropeptide antagonists (neuropeptides serve as signaling molecules in the brain) as potential therapeutic agents of a specific molecular target, a neuropeptide receptor that is closely associated with alcohol dependence.

"The alcoholism study really is a team effort that builds on our academic and industry expertise in drug discovery," Wahlestedt said. "It is also a perfect example of the collaboration and cooperation between the two campuses of Scripps Research. Professor Edward Roberts of Scripps California is a phenomenally skilled medicinal chemist who will be in charge of developing potential therapeutic molecules, while another highly qualified colleague, Dr. Michael Cameron of Scripps Florida, will determine their drug-like properties. Dr. Shaun Brothers, a staff scientist in my laboratory, has also been instrumental in the efforts to date. At the end of the four years we hope to have some vastly improved research tools as well as good drug candidates that we can move forward towards human trials."

In addition to the work done at Scripps Research, a number of in vivo assessments of compound activity on alcohol dependence in animal models will be performed by Markus Heilig, MD, Ph.D., chief of the clinical studies laboratory and director of the division's clinical and biological research at NIAAA.

Unlocking the Mysteries of Fragile X

While the alcoholism study is focused on potential therapeutic agents, the Fragile X study's primary target is uncovering the mechanisms underpinning the disease, which is caused by the silencing of a specific gene, known as FMR1.

Several years ago, Wahlestedt and his colleagues discovered a second, so-called antisense gene, FMR4, which is also silenced in Fragile X patients. What the scientists intend to do over the next four years is to explore the genetic locus – the neighborhood surrounding gene FMR1 and gene FMR4 – to identify and characterize currently unknown genetic mechanisms that might help in the development of novel strategies to restore the FMR1 gene's expression.

FMR4 is not a conventional gene—it's a non-coding RNA transcript, which produces functional RNA molecules rather than encoding proteins. These non-coding RNAs are active in a number of different processes, including RNA modification and cell survival. Wahlestedt pointed out that several studies suggest that some non-coding RNA genes can be involved in various human diseases, including fragile X, and FMR4 clearly falls into that category.

"Like the alcoholism study, we think we can accomplish something significant in terms of a potential therapy for Fragile X," Wahlestedt said. "The long-term objective is to uncover the reasons behind the silencing of FMR1 – opening a window on this disorder – which would be the first step to reactivating it. No one has had any success at doing that and if we could, it would be a highly significant achievement."

Understanding how the gene has been shut off holds significant future promise for other disorders where non-coding genes like FMR4 may play a role, Wahlestedt noted.

Send comments to: mikaono[at]scripps.edu

"Both grants focus on expanding our drug discovery platforms significantly," said Professor Claes Wahlestedt.