Fast-fail for success

LOS ANGELES—Can autism actually be cured? James McCracken, aprofessor of psychiatry at the University of California, Los Angeles (UCLA),thinks so. Apparently, so does the National Institute of Mental Health (NIMH),which in April awarded a $9-million contract to UCLA for an ambitious plan tofast-track a study of promising new drugs that may help restore normaldevelopment and brain function in children with autism spectrum disorders(ASD).

Led by McCracken, the project's principal investigator anddirector of the division of child and adolescent psychiatry at the SemelInstitute for Neuroscience and Human Behavior at UCLA, the effort will createand lead a network of U.S. academic centers to carry out earlyhigh-risk/high-reward studies of experimental medications over a three-yearperiod. The goal of the project, titled New Experimental Medicine Studies:Fast–Fail Trials in Autism Spectrum Disorders, is to determine withinweeks—rather than years—if a particular pharmacological compound is working ornot.

The NIMH initiative, launched in February, attempts toredefine clinical trials for autism by funding short, biomarker-based studiesto allow investigators to quickly rule out ineffective compounds. To do this,researchers will focus on analyzing how novel molecular and clinical targetsfor ASD are affected by both new and repurposed compounds. The outcome isexpected to lead to an enhanced understanding of the mechanisms that underlayASD and the development of innovative pharmacological treatment approaches forthe disorder.

At UCLA, testing will involve scientists and clinicians fromthe fields of psychiatry, radiology and biostatistics, while the UCLA Clinicaland Translational Science Institute will use sophisticated measures of brainand behavioral responses to identify signs of successful drug action in keybrain regions. Positive findings could then be followed up by other large-scalenational and international studies.

There is an urgency to this experiment, as the Centers forDisease Control and Prevention estimates that one in 88 children in the UnitedStates has been identified with an ASD. Despite the difficulties in treatingthe pervasive development disorder, which is characterized by delays in basiccommunication, socialization and daily life skills that impact every aspect ofa child's life and into adulthood, McCracken declares, "This is definitely themost exciting time yet to be involved in treatment research for ASD."

"Our basic science colleagues are generating enormousinformation on the likely underlying causes of this common and often disablingcondition," he says. "We are well positioned to apply the basic science andfind drugs that make a difference."

Although behavioral and developmental interventions,including programs developed at UCLA in the 1980s, offer hope of improvementfor many, and behavioral and medical interventions can address behaviorproblems, at present, there are no established medical treatments for the coresocial deficits of ASD, despite its acknowledged genetic and biological basis.

Ironically, the explosion of basic-science knowledge aboutASD and possible drug treatments is emerging at a time when majorpharmaceutical companies are canceling drug-development programs for ASD andother mental disorders, citing costs, difficulties and the recent failures ofwhat were deemed good prospects, according to the NIMH. Many U.S. NationalInstitutes of Health officials, research scientists and affected familiesare fearful that progress in medication development will slow in the face ofthe industry's retreat from neuroscience drug development.

"It's a challenge," McCracken concedes. "There are now somany possible experimental medicines and approaches from basic science for ASDthat we find ourselves way behind. We need a new paradigm to test the manypossible compounds, and we need to quickly and accurately identify which onesare really ready for 'prime time.'"

Large-scale studies of possible medications take years andcan cost upwards of $500 million dollars before yielding an approved, marketeddrug, McCracken points out.

Recent progress in identifying the genes and biologicalcomponents involved in autism spectrum disorders (ASD) holds great promise forthe identification of life-changing treatments for individuals of all ages,McCracken says.

"Current medical treatments are commonly prescribed byphysicians for ASD, but only to manage difficult behaviors like aggressiveness,hyperactivity and self-injury," he says. "Such treatments can be important andhelpful, but they do not impact the core problems of the disorders."