JUPITER, Fla.—A recent study from the Rumbaugh lab at Scripps Research challenges the presumption that people born with developmental brain disorders such as severe autism will benefit from medical interventions only if treated during a narrow window in infancy or early childhood. An article in the journal eLife, entitled “Re-expression of SynGAP Protein in Adulthood Improves Translatable Measures of Brain Function and Behavior,” reports improvement in measures of seizure and memory in adult mouse models of a genetic cause of autism, called SYNGAP1 disorder.
Children born with only one working copy of the SYNGAP1 gene don’t make enough of the critical SynGAP protein. Depending on the extent of their deficit, these children can develop a range of developmental challenges as they mature, such as intellectual disability, autism-like behaviors, disordered sensory processing and epileptic seizures.
The disorder likely affects one to four individuals per 10,000, according to Dr. Gavin Rumbaugh, an associate professor in the Department of Neuroscience at Scripps Research in Florida. But patients are only discovered through genetic tests and as a result, only a small fraction of patients with this disorder have been discovered.
According to a letter Rumbaugh wrote to the editor of eLife, “This study explores the duration and effectiveness of treatment windows for a genetically defined neurodevelopmental disorder (NDD) characterized by severe cognitive impairment, autistic features and medically refractory epilepsy. This study asks the question, ‘How can we improve relevant phenotypes, and do interventions started in adulthood alter disease course?’”
“In brief, we discovered that a gene restoration technique performed in adulthood improved memory and reversed seizure phenotypes in a mouse model for a severe genetically defined NDD. These findings are of high significance because many severe NDDs are characterized by cognitive impairments and medically-refractory seizures,” the letter continues. “In some cases, seizures, and underlying circuit-level excitatory imbalances that trigger these events, are thought to contribute to worsening of cognitive and behavioral phenotypes as patients get older.”
To study whether treatment of SYNGAP1 disorder in adulthood could be beneficial, Rumbaugh’s team genetically restored levels of the mice’s SynGAP protein to normal. The treated adult mice showed multiple improvements. This suggests that having one broken copy of the gene not only harms the brain as it develops, but also has effects in the adult brain. There may be reason to treat at any stage of life once options become available, Rumbaugh added. “Our findings in mice suggest that neurodevelopmental disorders’ disease course can be altered in adult patients,” he said. “We can correct brain dysfunction related to seizure as well as memory impairments after restoring SynGAP protein levels in the adult animals.”
“These findings are important because we improved phenotypes by restoring pathologically low levels of protein caused by genetic haploinsufficiency. In a haploinsufficiency disorder, the root cause of disease is reduced protein expression leading to cellular dysfunction. Thus, a protein replacement strategy targets the root cause,” Rumbaugh’s letter says. The paper offers a path to measure the effectiveness of potential medications or other therapies for neurodevelopmental disorders going forward. Electrographic spikes between seizures is an indicator of epilepsy. In the study, the researchers looked at human EEG data collected from a SYNGAP1 disorder patient registry and found that the appearance of these spikes were much more likely to occur during sleep.
Similar findings were observed from mouse models of SYNGAP1 disorder, offering a useful endpoint.
Rumbaugh noted that establishment of biomarkers which predict generalized improvements in brain function will be a critical step in advancing treatments for severe neurodevelopmental disorders.
“Our study is the first to demonstrate that protein replacement reversed both in vivo neurophysiological and behavioral phenotypes related to memory and seizure, two of the most clinically relevant phenotypes associated with NDDs,” the letter reads. “This prospective design, which followed individual mice over two months, allowed us to measure how hippocampal and cortical function changed in individual animals after whole-body protein restoration in adulthood. We observed an increase in hippocampal theta power (a biomarker for memory formation) and a reduction in generalized paroxysmal spiking across the forebrain (a biomarker for seizure susceptibility) in mutant mice that underwent gene restoration.
“These clear improvements in hippocampal and cortical function provide mechanistic insight into how behavioral measures of seizure and memory improved after protein re-expression in adult animals. The combined improvement in both in-vivo neurophysiology and behavior in response to adult gene repair provides very strong evidence that increasing the levels of pathologically low protein caused by severe genetic variants could be disease-altering in patients with pathogenic variants within a single gene.”
“We have confidence in the validity of these signals as a candidate biomarker because the signals worsened during sleep in both species,” Rumbaugh adds in his letter. “Sleep-driven worsening of pathological EEG signals is associated with declining cognitive function in NDD patients. Therefore, abolishment of these signals in mice, combined with improved behavioral measures of long-term memory, suggest that EEG signals can be a proxy measure for generalized improvements in cognitive function in single-gene causes of NDDs.”
The need for a treatment option is clear, continued Rumbaugh. Seizures typically become more frequent as children with SYNGAP1 disorders mature, and for many patients, those seizures do not respond to anti-epilepsy drugs.
“Getting to know families affected by this severe disorder has been invaluable, and drives us to develop treatments that will improve the lives of both children and adults,” Rumbaugh concluded. “It is encouraging that gene therapy techniques that increase pathologically low protein levels for other types of brain disorders are showing promise in the clinic now.”
