Test-driving a potential autism drug

Research shows drug candidate NitroSynapsin helps correct signaling imbalances in animal models

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LA JOLLA, Calif.—A multi-institution collaboration on autism has demonstrated the utility of a candidate drug in animal models, which could bode well for humans as the compound approaches clinical trials. The collaborators included scientists from the Scintillon Institute, Sanford Burnham Prebys Medical Discovery Institute, the University of California, San Diego School of Medicine and other institutions. The study, “NitroSynapsin therapy for a mouse MEF2C haploinsufficiency model of human autism,” was published in Nature Communications.
This recent work built off of a study conducted in 1993 by Dr. Stuart Lipton, professor and Hannah and Eugene Step Chair at The Scripps Research Institute (TSRI), and his laboratory at Harvard Medical School. At that time, the team identified a gene known as MEF2C as possibly playing a significant role in brain development.
The researchers further investigated MEF2C in animal models in 2008, discovering that disrupting MEF2C in the brains of mice early in fetal development caused mice to be born with severe, autism-like abnormalities. The gene encodes a protein that serves as a transcription factor. Since then, other teams have shared cases of children with a similar disorder resulting from a mutation to one copy of MEF2C, a condition now known as MEF2C haploinsufficiency syndrome (MHS). While MHS only accounts for a fraction of autism spectrum disorder (ASD) cases, large-scale genomic studies have demonstrated that mutations associated with various autism disorders frequently involves genes that are activated by MEF2C.
“Because MEF2C is important in driving so many autism-linked genes, we’re hopeful that a treatment that works for this MEF2C-haploinsufficiency syndrome will also be effective against other forms of autism, and in fact, we already have preliminary evidence for this,” Lipton said in a news release. He served as senior investigator for the recent Nature Communications study.
He adds that “The transcription factor MEF2C is important in neuronal development and also in the immune and cardiac systems. There are other isoforms of MEF2 that may compensate for some of these functions, but the nervous system is particularly vulnerable to MEF2C haploinsufficiency (when one allele of the gene is mutated to affect it abrogate it function).”
In this most recent work, Lipton and colleagues developed a laboratory model of MHS by engineering mice with only one functioning copy of the mouse version of MEF2C. These mice presented with abnormal anxiety, abnormal repetitive movements and impairments in spatial memory, as well as other signs that match human MHS. Brain analyses of the mice revealed issues such as excessive excitatory signaling over inhibitory signaling in key brain regions. A similar imbalance of excitatory/inhibitory (E/I) signaling is seen in the majority of forms of ASD.
After developing their animal model, the team treated the mice with NitroSynapsin for three months. The drug candidate is an aminoadamantane nitrate compound related to memantine, an Alzheimer’s disease drug that was previously developed by Lipton’s group and has been approved by the FDA, and is known to reduce excess excitatory signaling in the brain. NitroSynapsin did prove capable of reducing the E/I imbalance and abnormal behaviors in the mice, and improved their performance on cognitive/behavioral tests, with some improving to near-normal levels.
“The dual-functional drug acts both as an NMDAR open-channel blocker and redox modulator; in fact, the aminoadamantane moiety targets the nitro payload to the second site of action, the redox modulatory sites of the NMDAR, composed of critical regulatory cysteine residues. Recent publications have discussed the excellent CNS permeation of the drug and its very good pharmacokinetic and phamacodynamic parameters,” the authors noted in the paper.
They add that one explanation for NitroSynapsin’s effects is that “NitroSynapsin treatment, by protecting synapses, may indirectly increase excitatory input onto compromised inhibitory neurons in Mef2c-hets, thus enhancing their activity in order to compensate for the E/I imbalance.”
As for where the research will go from here, Lipton tells DDNews that “We have shown E/I imbalance and neurobehavioral abnormalities in other forms of ASD are also benefitted by NitroSynapsin. We are currently trying to raise funds to finish preclinical studies for the FDA in order to perform a clinical trial.”
In the meantime, the team is applying stem cell technology to generate cell-based models of MHS using skin cells from children with MHS. Thus far, NitroSynapsin seems to work in these human models.

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