New Autism Drug Shows Promise in Preclinical Study

There is currently no single drug treatment for autism. Many doctors treat autistic patients with a variety of psychotropic drugs geared at managing their perceived antisocial symptoms, but this is reasonably controversial, especially in children.

Research concerning autism spectrum disorder (ASD) has seen its fair share of controversy over the years, but as researchers relentlessly pursue the underlying causes of this developmental disorder, scientific consensus and public awareness grow.

Adding to the exponential growth of data for ASD, a group of investigators led by researchers at Sanford Burnham Prebys Medical Discovery Institute has just released findings from a successful test of a possible new drug in a mouse model of an autism disorder. The candidate drug, called NitroSynapsin, largely corrected electrical, behavioral and brain abnormalities in the mice.

Findings from the new study were published today in Nature Communications in an article entitled “NitroSynapsin Therapy for a Mouse MEF2C Haploinsufficiency Model of Human Autism.” NitroSynapsin is intended to restore an electrical signaling imbalance in the brain found in virtually all forms of ASD.

“This drug candidate is poised to go into clinical trials, and we think it might be effective against multiple forms of autism,” noted senior study investigator Stuart Lipton, M.D., Ph.D., a professor at The Scripps Research Institute (TSRI), who is also a clinical neurologist caring for patients.

ASD is brain development disorder that affects 1 in 68 children in the United States alone. Because ASD has been diagnosed more often in recent years, most Americans now living with autism diagnoses are children—roughly 2.4% of boys and 0.5% of girls.

The data from this new analysis stemmed from a 1993 study in which Dr. Lipton’s laboratory, then at Harvard Medical School, identified a gene called MEF2C as a potentially critical factor in brain development. This breakthrough led Dr. Lipton and his colleagues to the discovery that disrupting the mouse version of MEF2C in the brain, early in fetal development, causes mice to be born with severe, autism-like abnormalities. Since that discovery in mice in 2008, other researchers have reported many cases of children who have a very similar disorder, resulting from a mutation to one copy of MEF2C. The condition is now called MEF2C haploinsufficiency syndrome (MHS).

“This syndrome was discovered in people only because it was first discovered in mice – it’s a good example of why basic science is so important,” Dr. Lipton remarked. “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.”

MEF2C encodes a protein that works as a transcription factor, like a switch that turns on the expression of many genes. Although MHS accounts for only a small proportion of autism disorder cases, large-scale genomic studies in recent years have found that mutations underlying various autism disorders frequently involve genes whose activity is switched on by MEF2C.

In the current study, the researchers created a laboratory model of MHS by engineering mice to have—like human children with MHS—just one functioning copy of the mouse version of MEF2C, rather than the usual two copies. The mice showed impairments in spatial memory, abnormal anxiety, and abnormal repetitive movements, plus other signs consistent with human MHS. Analyses of mouse brains revealed a host of problems, including an excess in key brain regions of excitatory signaling over inhibitory signaling.

Thus, these two important kinds of brain signals were out of balance. A similar excitatory/inhibitory (E/I) imbalance is seen in most forms of ASD and is thought to explain many of the core features of these disorders, including cognitive and behavioral problems and an increased chance of epileptic seizures.

The researchers treated the MHS-mice for three months with NitroSynapsin, an aminoadamantane nitrate compound related to the Alzheimer’s FDA-approved drug memantine, which was previously developed by Dr. Lipton’s group. NitroSynapsin is known to help reduce excess excitatory signaling in the brain, and the team found that the compound did reduce the E/I imbalance and also reduced abnormal behaviors in the mice and boosted their performance on cognitive/behavioral tests—in some cases restoring performance essentially to normal.

The research team is currently testing the drug in mouse models of other autism disorders, and they hope to move NitroSynapsin into clinical trials with a biotechnology partner. Moreover, the investigators also now using stem cell technology to create cell-based models of MHS with skin cells from children who have the syndrome—and NitroSynapsin appears to work in this “human context” as well.