In a significant step toward treating an exceptionally rare and often fatal genetic disorder, researchers at Tel Aviv University have developed a mouse model that faithfully mimics the disease caused by mutations in the GRIN2D gene. The breakthrough offers a critical tool for studying the disease’s progression and testing both pharmacological and genetic therapies—potentially transforming care for affected children.
Led by Prof. Moran Rubinstein and Prof. Karen Avraham, Dean of the Gray Faculty of Medical and Health Sciences, the study was published in the journal Brain and included collaboration with scientists from Columbia University, the Dana-Dwek Children’s Hospital at Tel Aviv Sourasky Medical Center, and Tel Aviv University’s Sagol School of Neuroscience (A mouse model of GRIN2D developmental and epileptic encephalopathy recapitulates the human disease).
The research was initially inspired by Adam, an eight-year-old Israeli child who is one of just 40 known cases worldwide. “We were contacted by the parents of an Israeli child named Adam… diagnosed with this extremely rare genetic disease,” said Prof. Avraham. “It involves a mutation in a gene called GRIN2D, which causes developmental epilepsy, significant motor and cognitive delays, and in some cases, premature death.”
Adam’s mother, Eden Maimon Banet, reflected on the team’s personal investment in the case. “At Tel Aviv University, we met a wonderful, all-female team that took on the mission of finding a treatment for our son,” she said. “Today we are already seeing real light at the end of the tunnel.”
To study the disease, the researchers created a mouse model with a mutation replicating Adam’s. Initially, the mice died within weeks of birth, presenting a challenge to further research. The team overcame this by engineering a carrier strain that allowed for the breeding of both affected and unaffected offspring. The model revealed that symptoms such as epilepsy, hyperactivity, and motor deficits emerged early, while cognitive impairments appeared later and progressively worsened. Most affected mice lived only a few weeks, though a few survived up to three months.
“This mouse model helped us characterize symptoms at different developmental stages,” said Prof. Rubinstein. “Neurological symptoms appeared from infancy. Cognitive impairments emerged later. Most mice died before reaching sexual maturity due to severe seizures.”
Further studies on the mice’s brains revealed structural changes and disrupted neural communication, particularly in the cerebellum. EEG testing showed a continuous pattern of abnormal brain activity, consistent with observations in human patients. “We identified the same abnormalities in both mice and humans,” Rubinstein said. “That’s an especially strong indication of the model’s validity.”
The team also began testing existing drugs. Contrary to previous speculation, ketamine exacerbated seizures, while memantine—a treatment already in limited use for GRIN2D-related conditions—showed partial improvement. Phenytoin, a common anti-seizure medication, also helped improve neurological markers.
Prof. Moran Hausman-Kedem, a pediatric neurologist involved in the research, emphasized the clinical value of the model: “For rare diseases where patient populations are too small for large-scale trials, mouse models like this one offer a vital tool. They help guide treatment decisions by offering preclinical insight into safety and efficacy.”
The work continues. Follow-up studies are now underway to test additional drug and gene therapy approaches. Early results indicate improvements in both cognition and motor function and a modest extension in lifespan for the mice.
“In this study, we gained a better understanding of the disease and tested the efficacy of several existing drugs,” Rubinstein said. “Our current results are promising, and we hope our continued work will bring real hope to families affected by this devastating disorder—and to others facing similar neurological diseases.”
The research was supported by the US-Israel Binational Science Foundation, the GRIN2D Project Foundation, and CureGRIN, a collaborative initiative uniting scientists, clinicians, and families impacted by GRIN disorders.
