This post is by Leanne Chukoskie, Ph.D. Dr. Chukoskie is the Asst. Director Science Communication and Special Projects at Autism Speaks and Asst. Project Scientist, Institute for Neural Computation, UCSD.
On Friday, the New York Times published a story about a small clinical trial for a drug that ameliorated some of the symptoms of Fragile X Syndrome in some of the participants in the trial. Single-gene disorders, such as Fragile X Syndrome have been instructive in helping us understand the biology of the broader autism spectrum disorders (30% of people with Fragile X have an ASD). The effort described in the New York Times is not singular, but instead an area of active pursuit by many. Here is some history behind the Fragile X drug story and a summary of clinical trials for single-gene causes of ASD.
As noted in the article, the excitement began in 1991 when Steve Warren, Ph.D. (Professor at Emory University and member of Autism Speaks’ Scientific Advisory Committee) and his colleagues identified the gene, FMR1 (fragile X mental retardation 1), that causes Fragile X syndrome. At that point, Warren and others began probing the FMR1 gene pathway to learn its properties and seek a way of correcting the genetic error. The promise of basic research findings was coming to light in Fragile X as early as 2005, with a small workshop organized by Autism Speaks’ staff titled “Promising new leads for autism research: a potential cure for Fragile X” at the International Meeting for Autism Research (IMFAR). At this meeting, Mark Bear, Ph.D. (MIT), Tom Jongens, Ph.D (UPenn) and Bob Wong Ph.D. (SUNY Downstate) presented preliminary findings related to a theory that Fragile X may be caused by over-excitation of synapse (the connections between nerve cells). Proper functioning of the connections between nerve cells requires a balance between excitatory and inhibitory neurotransmitters. It appears that the FMR1 gene was causing this balance to be disrupted so that there was an abundance of the excitatory influences. These researchers found that by damping the activity of a common excitatory neurotransmitter (glutamate) in the brain, many of the symptoms that characterized the animal models of Fragile X disorder disappeared. This theory was referred to as the mGluR theory (for metabatropic Glutamate Receptor) of Fragile X. The drugs that produced improvements in animal models are called mGluR antagonists, because they act by blocking the actions of this glutamate receptor.
Previously, it was believed that one must act early in neurodevelopment to see any improvement in the symptoms of ASD. This basic research was incredibly exciting because several labs were learning that behaviors related to ASD could be ameliorated with drugs in adult animals.
That was several years ago and one might wonder what is taking so long to see useful medicines for these disorders. The process of approving drugs in any field is long and arduous (see blog on translational research and what Autism Speaks has funded). The translation of basic research into viable drugs in clinical trial is often referred to as crossing the “Valley of Death” as so few molecules tested in basic research make it through the process to become useful medicines. That said, several efforts have been made to create drugs for single-gene disorders related to ASD (see 2008 Top 10 story).
In 2008 researchers from the MIND Institute and Rush University reported results from the first trial of mGluR5 antagonists. Results from the small trial indicate that six out of the twelve adults with Fragile X showed improvements in cognitive deficits. This was the first promising news that mGluR drugs were safe and effective in humans and are related to those reported in the New York Times’ article from the Novartis study, which began around the same time.
Seaside Therapeutics is a small biotechnology company founded by Dr. Bear to see if the promising results observed in animals could be offered to families. In 2008, Seaside began enrollment for a clinical trial using a drug that would also dampen glutamate activity but through a different pathway for treating Fragile X. This drug enhanced the activity of a class of receptors that typically suppress glutamate activity. Seaside Therapeutics has expanded this trial to include patients with autism, and has also launched a clinical trial of its own formulation of a specific mGluR5 antagonist for Fragile X. If positive results are found, the next step will be to test these medications on individuals with ASD who do not have Fragile X syndrome.
We’ve been talking a lot about Fragile X, but there is another disorder, called Tuberous Sclerosis Complex (TSC), which offers another path to understanding ASD (approximately 25-50 percent of people with TSC also have an ASD). In 2008, UK researchers conducting a clinical trial with individuals with TSC reported positive outcomes on short-term memory tests of those receiving treatment. Rapamycin, the drug used in this trial and already FDA-approved for cancer, targets the brain signaling pathway that has been found to be disrupted in TSC and that has recently been implicated in autism as well (see 2007 Top 10 story related to TSC and 2008 Top 10 story about translational research).
Basic research in the biological pathways highlighted by genetic studies of Fragile X and TSC was the starting point for these exciting clinical trials. Autism Speaks continues to identify basic research opportunities that may lead to successful treatments as well as support the translation of research on molecules that have shown promise in the lab to medications that help families.
