Potential new autism drug shows promise in mice

November 14, 2017, The Scripps Research Institute

Scientists have performed 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.

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," said senior investigator Stuart Lipton, M.D., Ph.D., Professor and Hannah and Eugene Step Chair at The Scripps Research Institute (TSRI), who is also a clinical neurologist caring for patients.

The research, published on today in the journal Nature Communications, was a collaboration involving scientists at the Scintillon Institute; the University of California, San Diego School of Medicine; Sanford Burnham Prebys Medical Discovery Institute and other institutions. Lipton's fellow senior investigators on the project were Drs. Nobuki Nakanishi and Shichun Tu of the Scintillon Institute in San Diego.

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 percent of boys and 0.5 percent of girls.

Genetic Analysis Leads to Potential Treatment

The new study stemmed from a 1993 study in which Lipton and his laboratory, then at Harvard Medical School, identified a gene called MEF2C as a potentially important factor in brain development.

This breakthrough led Lipton and 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 (human DNA normally contains two copies of every gene, one copy inherited from the father and one from the mother). 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," Lipton said.

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.

"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," Lipton said, "and in fact we already have preliminary evidence for this."

For the 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 (which causes neurons to fire) over inhibitory signaling (which suppresses neuronal activity).

In short, 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 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.

Lipton and colleagues are currently testing the drug in mouse models of other autism disorders, and they hope to move NitroSynapsin into clinical trials with a biotechnology partner.

The work also has support from parents of children with MHS. "We are all hanging on to the hope that one day our children will be able to speak, to understand and to live more independent lives," said Michelle Dunlavy, who has a son with MHS.

In fact, Lipton's group is 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. Dunlavy and other parents of children with MHS recently organized an international, Facebook-based support group, which is coordinating to assist in Lipton's research going forward.

In an amazing twist, the scientific team also found in Alzheimer's disease models that the new NitroSynapsin compound improves synapse function, the specialized areas for communication between nerve cells. Thus, the ability of the drug to improve 'network' communication in the brain may eventually lead to its use in several neurological diseases.

Explore further: Breakthrough research suggests potential treatment for autism, intellectual disability

More information: Shichun Tu et al, NitroSynapsin therapy for a mouse MEF2C haploinsufficiency model of human autism, Nature Communications (2017). DOI: 10.1038/s41467-017-01563-8

Related Stories

Breakthrough research suggests potential treatment for autism, intellectual disability

November 13, 2017
A breakthrough in finding the mechanism and a possible therapeutic fix for autism and intellectual disability has been made by a University of Nebraska Medical Center researcher and his team at the Munroe-Meyer Institute ...

Signaling pathway may be key to why autism is more common in boys

October 17, 2017
Researchers aiming to understand why autism spectrum disorders (ASD) are more common in boys have discovered differences in a brain signaling pathway involved in reward learning and motivation that make male mice more vulnerable ...

Finding the clues for better autism treatments

October 26, 2016
As a researcher at Harvard Medical School, Christopher W. Cowan, Ph.D., used to watch autistic kids come onto campus to attend a special school.

Scientists provide insight into genetic basis of neuropsychiatric disorders

July 21, 2017
A study by scientists at the Children's Medical Center Research Institute at UT Southwestern (CRI) is providing insight into the genetic basis of neuropsychiatric disorders. In this research, the first mouse model of a mutation ...

Recommended for you

Autism might be better detected using new two-minute questionnaire

February 5, 2018
Researchers at Rutgers New Jersey Medical School have developed a two-minute questionnaire for parents that could help pediatricians and other primary care providers detect autism in toddlers, at a time when intervention ...

Research compares neural activity in children with and without autism spectrum disorder

January 29, 2018
Pick a hand, any hand. That familiar refrain, repeated in schoolyards the world over, is the basis of a simple guessing game that was recently adapted to study how and why kids with autism spectrum disorder (ASD) interact ...

Zebrafish study provides new insights into autism spectrum disorder research

January 24, 2018
Exposure to a compound used to treat migraines and seizures causes characteristics associated with autism, groundbreaking research with zebrafish has demonstrated.

Genes contribute to biological motion perception and its covariation with autistic traits

January 22, 2018
Humans can readily perceive and recognize the movements of a living creature, based solely on a few point-lights tracking the motion of the major joints. Such exquisite sensitivity to biological motion (BM) signals is essential ...

Nearly imperceptible fluctuations in movement correspond to autism diagnoses

January 17, 2018
A new study led by researchers at Indiana University and Rutgers University provides the strongest evidence yet that nearly imperceptible changes in how people move can be used to diagnose neurodevelopmental disorders, including ...

Epigenetics study helps focus search for autism risk factors

January 16, 2018
Scientists have long tried to pin down the causes of autism spectrum disorder. Recent studies have expanded the search for genetic links from identifying genes toward epigenetics, the study of factors that control gene expression ...

3 comments

Adjust slider to filter visible comments by rank

Display comments: newest first

TheGhostofOtto1923
not rated yet Nov 14, 2017
"Thus, the ability of the drug to improve 'network' communication in the brain may eventually lead to its use in several neurological diseases."

-I wonder if this offers hope of reconnecting those portions of the brain responsible for empathy and emotion in PSYCHOPATHS?

Assuming of course that those portions are still there, and that psychopaths weren't simply born without them.

Seriously, this could potentially be a monumental change in the restoration of trust in society. Crime would plummet. News stories about abuse in the workplace would disappear.

It could even mitigate things like market crashes and inflation.
TheGhostofOtto1923
not rated yet Nov 14, 2017
"The high incidence of [psychopathy] in human society has a profound effect on the rest of us who must live on this planet, too, even those of us who have not been clinically traumatized. The individuals who constitute this 4 percent drain our relationships, our bank accounts, our accomplishments, our self-esteem, our very peace on earth."

-Hopefully psychopaths involved in the whole clinical trial and regulating process wont feel threatened and somehow quash the approval by manipulating data or otherwise influencing the outcome.
TheGhostofOtto1923
not rated yet Nov 14, 2017
Funny, this reminds me of a recent storyline in the tv series 'Agents of Shield'... The character Agent Leopold Fitz was trapped in an alternate timeline where, as a psychopath, he did a lot of nasty things.

His fellow agents rescued him and brought him back to this timeline where his empathy was restored, and he struggled with the guilt of all that he had done.

Given the prospect that this drug could successfully treat psychopaths, might we then have to treat them for things like PTSD and depression?

Story on the news this morning;

"What music do psychopaths like? More Bieber, less Bach... Justin Bieber's "What Do You Mean" was popular with those students who scored high on the psychopathy scale."
https://www.washi...df8b4cd1

What a strange malformity.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.