image: Front row, left to right: Shir Quinn, Mor Yam, Danielle Galber Back row, left to right: Prof. Aviva Fattal-Valevski, Prof. Karen Avraham, Prof. Moran Rubinstein
Credit: Tel Aviv University
Researchers at the Gray Faculty of Medical and Health Sciences at Tel Aviv University have developed a model that accurately replicates an extremely rare and sometimes fatal genetic disorder caused by a mutation in the GRIN2D gene. This mouse model allows the research team to study the disease’s characteristics and test a variety of drugs and genetic therapies, offering hope to affected children and their families.
The study was led by Prof. Moran Rubinstein and Prof. Karen Avraham, Dean of the Faculty. Additional participants included students Mor Yam, Jolan Nassir, Danielle Galber, Shir Quinn, Roni Gal, Mor Ovadia, Mor Bordeynik-Cohen, and Eden Peled, from Tel Aviv University’s Gray Faculty of Medical and Health Sciences and the Sagol School of Neuroscience; Prof. Moran Hausman-Kedem and Prof. Aviva Fattal-Valevski from the Pediatric Neurology Institute at Dana-Dwek Children’s Hospital at the Tel Aviv Sourasky Medical Center; as well as Prof. Christopher Makinson and Prof. Wayne Frankel from Columbia University in the United States. The study was recently published in the journal Brain (Oxford University Press).
Prof. Avraham explains: “We were contacted by the parents of an Israeli child named Adam, now eight years old, who is one of only about 40 people worldwide diagnosed with this extremely rare genetic disease. 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, adds: “At Tel Aviv University, we met a wonderful, all-female team that took on the mission of finding a treatment for our son. I believe that their personal acquaintance with Adam and our family further strengthened their dedication and commitment. When Adam was two years old, we embarked on this long journey together, and today we are already seeing real light at the end of the tunnel.”
In the first stage, the researchers aimed to gain an in-depth understanding of the disease’s characteristics. To this end, they created a mouse model with a mutation similar to the one found in human patients—but the mice were so severely affected that they died within the first weeks of life, before any experiments could be conducted. This indicated that the mouse model accurately replicated aspects of the human disease, but also posed a major challenge: it was impossible to produce enough mice for research. To overcome this, the researchers used genetic engineering tools to create a strain of mice that carried the mutation without developing symptoms, allowing them to breed offspring in which half were healthy, and half were affected. The affected offspring displayed symptoms similar to those of human patients; most survived only a few weeks, with only a few living up to three months. The researchers examined their behavior and development at four stages: two weeks old (infancy), three weeks old (when mice transition to solid food, roughly equivalent to one-year-old children), four weeks old (roughly equivalent to six-year-old children), and five weeks old (early sexual maturity).
Prof. Rubinstein: “Because the disease is so rare, its progression over time is not well understood. The mouse model helped us characterize its symptoms at different ages, and the tests we performed revealed interesting findings: neurological symptoms such as epilepsy, hyperactivity, and severe motor impairments were evident in the mice from infancy. Cognitive impairment, by contrast, appeared later and gradually worsened. Additionally, the affected mice had a short lifespan—most did not survive to sexual maturity, dying from severe seizures.”
In another experiment, the researchers examined communication between neurons in the mice’s brains, particularly in the cerebellum, which controls motor function. The analysis showed that already at two weeks old, pathological changes were present, reflected in reduced neuronal activity. Later, as the mice matured, activity levels returned to normal, but defective communication between neurons developed. Finally, the researchers found structural changes in the neurons themselves. These findings help elucidate the disease’s underlying mechanisms.
Electroencephalography (EEG) tests conducted on the affected mice revealed a unique pattern that also characterizes the disease in humans. Prof. Rubinstein: “In most forms of epilepsy, seizures result from disrupted brain activity, but between seizures, brain activity is relatively normal. In this disease, however—both in children and in the mice—brain activity is continuously disrupted. Moreover, using specific metrics we developed, we identified the same abnormalities in both mice and humans—an especially strong indication of the model’s validity.”
After confirming that the model accurately replicates the human disease, the researchers began testing the effects of various drugs on symptom development. They found that ketamine, previously proposed as a treatment for this disease, actually worsened seizures. In contrast, memantine—another drug already in use for this disease—led to partial improvement in brain function, as did phenytoin, an anti-seizure medication that also improved certain brain activity markers.
Prof. Hausman-Kedem explains: “Modeling the disease with a mouse model is a crucial tool for guiding clinical decisions in treating patients with rare diseases. The model enables us to test the efficacy of existing drugs, as well as the safety and efficacy of new drugs before trying them on patients. For example, findings from the mouse model helped demonstrate that memantine may help prevent seizures. Using a mouse model provides critical information about new treatment approaches for rare diseases, where the number of patients is too small to allow broad statistical validation. In such cases, animal model experiments can offer breakthrough insights, advancing the ability to deliver personalized medicine.”
Prof. Rubinstein concludes: “In this study, we created a mouse model of a rare genetic disease caused by a mutation in the GRIN2D gene. Using this model, we gained a better understanding of disease progression and tested the efficacy of several existing drugs. Currently, in follow-up studies, we are testing additional treatments—both pharmacological and genetic—and have obtained promising results, such as improved cognition and motor function and extended lifespan in the affected mice. We very much hope that our work will bring hope and progress to families and children facing this severe and rare disorder, as well as to those affected by other brain diseases caused by similar mechanisms.”
Support for this research was provided by the US-Israel Binational Science Foundation, the GRIN2D Project Foundation, as well as CureGRIN, bringing together patients and their families with scientists and the medical community to benefit people with GRIN disorders.
Link to the article:
https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awaf149/8119851
Journal
Brain