UCSD. US: Autism spectrum disorders (ASD) affect 1 to 2 percent of children in
the United States. Hundreds of genetic and environmental factors have
been shown to increase the risk of ASD. Researchers at UC San Diego
School of Medicine previously reported that a drug used for almost a
century to treat trypanosomiasis, or sleeping sickness, reversed
environmental autism-like symptoms in mice.
Now, a new study published in this week’s online issue of Molecular Autism,
suggests that a genetic form of autism-like symptoms in mice are also
corrected with the drug, even when treatment was started in young adult
mice.
The underlying mechanism, according to Robert K. Naviaux, MD, PhD,
the new study’s principal investigator and professor of medicine at UC
San Diego, is a phenomenon he calls the cellular danger response (CDR).
When cells are exposed to danger in the form of a virus, infection,
toxin, or even certain genetic mutations, they react defensively,
shutting down ordinary activities and erecting barriers against the
perceived threat. One consequence is that communication between cells is
reduced, which the scientists say may interfere with brain development
and function, leading to ASD.
Researchers treated a Fragile X genetic mouse model, one of the most
commonly studied mouse models of ASD, with suramin, a drug long used for
sleeping sickness. The approach, called antipurinergic therapy or APT,
blocked the CDR signal, allowing cells to restore normal communication
and reversing ASD symptoms.
“Our data show that the efficacy of APT cuts across disease models in
ASD. Both the environmental and genetic mouse models responded with a
complete, or near complete, reversal of ASD symptoms,” Naviaux said.
“APT seems to be a common denominator in improving social behavior and
brain synaptic abnormalities in these ASD models.”
Weekly treatment with suramin in the Fragile X genetic mouse model
was started at nine weeks of age, roughly equivalent to 18 years in
humans. Metabolite analysis identified 20 biochemical pathways
associated with symptom improvements, 17 of which have been reported in
human ASD. The findings of the six-month study also support the
hypothesis that disturbances in purinergic signaling – a regulator of
cellular functions, and mitochondria (prime regulators of the CDR) –
play a significant role in ASD.
Naviaux noted that suramin is not a drug that can be used for more
than a few months without a risk of toxicity in humans. However, he said
it is the first of its kind in a new class of drugs that may not need
to be given chronically to produce beneficial effects. New
antipurinergic medicines, he said, might be given once or intermittently
to unblock metabolism, restore more normal neural network function,
improve resilience and permit improved development in response to
conventional, interdisciplinary therapies and natural play.
“Correcting abnormalities in a mouse is a long way from a cure in
humans,” cautioned Naviaux, who is also co-director of the Mitochondrial
and Metabolic Disease Center at UC San Diego, “but our study adds
momentum to discoveries at the crossroads of genetics, metabolism,
innate immunity, and the environment for several childhood chronic
disorders. These crossroads represent new leads in our efforts to
understand the origins of autism and to develop treatments for children
and adults with ASD.”
Co-authors include Jane C. Naviaux, Lin Wang, Kefeng Li, A. Taylor
Bright, William A. Alaynick, Kenneth R. Williams and Susan B. Powell,
all at UC San Diego.
This study was supported, in part, by the Jane Botsford Johnson
Foundation, the UC San Diego Christini Foundation, the UC San Diego
Mitochondrial Research Fund, and the Wright Family Foundation.