By Geri Dawson, Chief Science Officer, Autism Speaks
When I am giving talks to families about the research Autism Speaks funds, I am sometimes asked why we are funding a particular study when that study appears to have very little to do with the majority of people who actually are living and struggling with autism. This especially comes up when I am talking about studies involving animal models, brain tissue, and rare genetic conditions. Parents often express their frustration that scientists have not yet developed medications that can improve the quality of life for people with autism, medications that can help a child or adult with autism spectrum disorders (ASD) communicate better or be more comfortable around other people. I realize then that the connection between many of the studies we fund and our goal of developing medications that can help people with autism may not be clear. In this article, I hope to illustrate how many of the individual studies that we fund – which in isolation may not seem relevant – are part of a discovery and development process ultimately aimed at providing medications that can improve the life of individuals with ASD.
I will begin with some background on the process of moving from basic laboratory studies to delivery of a useful medication to the community, a process often referred to as “translational research.” The process of drug discovery begins with identification of a “drug target.” A drug target is a component of a biochemical pathway, sometimes referred to as a “signaling” or “metabolic” pathway. How do we figure out what signaling or metabolic pathways are affected in ASD? One way is to closely examine the actual brain cells of persons with autism, which is only possible with post-mortem brain tissue donated by families (view a recently funded study using post-mortem brain tissue).
Another way is to use animal models (see a perspective on mouse models from Craig Powell) to study the effects of a genetic mutation that is known to result in ASD or ASD symptoms. It has also been useful to start by studying conditions such as Rett syndrome and Fragile X syndrome because the genetics of these conditions are well understood. In addition, we know that these conditions are often associated with autism (e.g., about 30 percent of individuals with Fragile X also have autism). Animal models of these syndromes are becoming well developed, allowing scientists to study how the genetic mutation influences the biochemistry and brain functioning (view a recently funded study of synaptic alterations in the amygdala). These types of studies pointed scientists to specific signaling pathways; for example, a pathway involving two neurotransmitters: GABA and glutamate. These chemicals are crucial for neurons (brain cells) to establish a communication network through the formation of synapses (connections between neurons). Specifically, the genetic mutation alters the amount of these chemicals released in the brain (i.e., too much glutamate), resulting in over-excitation of the neural circuits. This disrupts learning.
Interestingly, at the same time these discoveries were being made, other scientists discovered that many of the genetic mutations that result in autism also disrupt the functioning of the synapse (view a recently funded study of synapse function). The strategy here is to look for common signaling pathways that are disrupted by different risk genes. These pathways offer the best hope for developing a medication that can be helpful not just with one genetic subtype of ASD, but more generally for many individuals who have ASD (even those where an environmental trigger might have been involved).
The process of drug target identification
Once a disrupted pathway or pathways contributing to a condition is discovered, scientists can start testing (“validating”) whether certain medications can restore the functioning of that pathway and improve behavioral functioning in animal models and humans. Another strategy for testing different medications is to examine the effects of the medication on cells (neurons) derived from freshly isolated post-mortem brain tissue that was donated by individuals with autism through Autism Speaks’ Autism Tissue Program.
Currently, several medications that are designed to improve behavioral functioning in autism are being tested in persons with associated genetic disorders such as Rett syndrome, Tuberous Sclerosis, and Fragile X syndrome (view two recently funded human clinical trials of medications for Rett syndrome and Tuberous Sclerosis ). If these medications are found to improve behavioral functioning in individuals with these conditions, plans to study some of these medications with people with ASD will follow. The hope is that because these conditions share some biological and behavioral similarities, these same medications will be more widely effective. At the same time, drawing from what we have learned about the role of glutamate from studies of Fragile X syndrome, Autism Speaks is currently funding a “phase one” or “proof of concept” clinical trial of memantine, a medication that reduces the availability of glutamate, for persons with ASD. As we understand more about the underlying biology of ASD using the strategies described above, there will be more promising leads for new medications that can improve the lives of persons with ASD.
The process from target identification to FDA approval of a new medication is arduous. Animal and human studies are needed to examine safety, side effects, optimal dosing, and other factors (these are referred to as Phase I, II, and III clinical trials). This “drug development pipeline” involves the collaboration among agencies such as the NIH and Autism Speaks that provide research funding; academic scientists who often conduct the high risk research that leads to target identification and validation; pharmaceutical companies who, once a target is validated, have the capability and resources of conducting the larger Phase II and III trials; and the FDA who is responsible for approving the medication for wide usage. This collaboration is essential for drug discovery and development.
Translational research moves findings from the lab to the families. It is one of many diverse areas of research emphasis at Autism Speaks. This type of research provides hope for the future. But, at the same time, we are funding studies that have more immediate impact on people lives. These include studies of novel behavioral and other types of interventions that can be quickly implemented by parents, therapists, and teachers, as well as many others (see examples of recently funded studies on Pivotal Response Training and Cognitive Enhancement Therapy that can have immediate impact. This balance between short- and long-term research is a key part of Autism Speaks’ overall funding strategy.
In honor of the anniversary of Autism Speaks’ founding on Feb 25, for the next 25 days we will be sharing stories about the many significant scientific advances that have occurred during our first five years together. Our 11th item, Translational Research Takes Hold , is from Autism Speaks’ Top 10 Autism Research Events of 2008.
In honor of the anniversary of Autism Speaks’ founding on Feb 25, for the next 25 days we will be sharing stories about the many significant scientific advances that have occurred during our first five years together. Our eighth item, Creation of Neuroligin-3 Mutant Mouse, is from Autism Speaks’ Top 10 Autism Research Events of 2007.
Animal models have long been employed to replicate some of the behavioral and biochemical characteristics of autism. The models are chosen for study either because they have behaviors reminiscent of autism, or because they have received genetic or environmental manipulations believed to be linked, directly or indirectly, to autism.
Yet, only with the recent progress of detailed genetic studies in developmental disorders have these models been based on the actual genetic differences found in humans with autism. Some of these newer models for autism include mouse models of medical genetic syndromes that show overlap with autism, e.g., Fragile X syndrome, Rett syndrome and Tuberous Sclerosis. However, no model existed that contained the precise genetic defect found in anyone whose autism is not caused by one of these other genetic syndromes. This changed in October 2007, when researchers in Texas reported they had succeeded in replacing the mouse neuroligin-3 gene with a human version containing the exact mutation discovered in 2004 to be the cause of autism in a Swedish family with two affected brothers. Excitingly, the initial exploratory studies have found the “humanized neuroligin-3″ mouse has several unusual behaviors, including deficits in some social behaviors and an increased ability for spatial learning in a swimming test.
This mouse provided the research community with a strong new tool to directly assess the neurobiology, behavioral deficits and, conceivably soon enough, treatment approaches for autism. Such models are a vital part of the drug discovery process because measurement of changes in their behaviors can be used as surrogate markers for preclinical evaluation of new therapeutics.
Since this story was first run: Genetic studies continue to provide new opportunities for the generation of animal models of autism, including many related to the function of the neuroligins. In 2009 the same group of researchers carried out a behavioral characterization of mice lacking the neurexin-1alpha gene, which creates proteins that serve as binding partners for the neuroligins. Published in the Proceedings of the National Academies of Science, the scientists have now discovered that the neurexin-1alpha mice have abnormal brain physiology and increased repetitive behaviors.