Modeling lennox-gastaut syndrome for improved clinical and neurobehavioral outcomes - lennox-gastaut syndrome (LGS) is a developmental epileptic encephalopathy (seizures further contribute to…

New York Medical College received a $396,804 Project Grant award from the National Institute of Neurological Disorders and Stroke (NINDS) under the Extramural Research Programs in the Neurosciences and Neurological Disorders (CFDA 93.853) program, effective August 1, 2025 through July 31, 2026. The award supports research to develop and characterize a preclinical animal model of Lennox-Gastaut Syndrome (LGS), a severe developmental epileptic encephalopathy affecting 1-2 million people worldwide. During the R61 phase, the research team will develop and fully characterize spontaneous electroclinical signs of the LGS model in prepubertal rats using two complementary etiological approaches based on infantile epilepsy spasm syndrome, establishing a foundational platform for testing novel therapeutic interventions.

The deliverables under this award include comprehensive preclinical research infrastructure and scientific outputs necessary to advance treatment options for LGS, a condition that currently remains highly refractory to existing therapies and results in intellectual disability in over 90 percent of affected patients. By establishing a validated animal model with clearly defined seizure phenotypes and neurobehavioral characteristics, this research addresses a critical gap in LGS drug development and provides a vital tool for evaluating emerging therapeutic candidates beyond current standard medications.

Modeling lennox-gastaut syndrome for improved clinical and neurobehavioral outcomes - lennox-gastaut syndrome (LGS) is a developmental epileptic encephalopathy (seizures further contribute to cognitive deterioration). LGS is relatively frequent (1-2 million people worldwide), accounting for 1-2% of all patients with epilepsy, more in males. Though described in the sixties, international league against epilepsy (ilae) recently updated and focused LGS definition. LGS presents with: (1) variable seizure types starting before 18 years of age, however tonic seizures must be included plus one additional type. (2) cognitive and behavioral impairments (may not be present at seizure onset). (3) EEG must show diffuse slow spike-and-wave as well as generalized fast paroxysmal activity. LGS commonly develops from the severe infantile epilepsy, very often (in 20-30%) from infantile epilepsy spasm syndrome (iess). Conversely, 20-50% of infants with iess transition to LGS, especially those with structural- metabolic etiology of iess. Lamotrigine, felbamate and possibly topiramate may be helpful in treatment of drop attacks (atonic seizures) associated with LGS. Recently, fenfluramine appears to be promising in the reduction of drop attacks and tonic-clonic seizures in patients with LGS. LGS is otherwise very refractory, persists till adulthood, and remains resistant to therapy resulting in intellectual disability in more than 90% of patients. There is no animal model of LGS that would assist in testing new more effective treatments to improve dire neurobehavioral prognosis in most patients with LGS. The goal of this proposal is to develop model of LGS for testing novel treatments. In the R61 phase, the model will be developed and quantified. R61 specific aim is to fully characterize spontaneous electroclinical signs of the LGS model in large cohorts of prepubertal rats based on two complementary etiologies found in human condition (two different models of iess = two experimental arms). The milestone determining go/no go transition to the R33 phase is the 40% occurrence of electroclinical features of LGS (both EEG and behavioral signs in a single subject) in model animals. R61 specific aims are to provide external validation to the developed LGS model. If successful, the R33 phase will complete external validation in terms of face validity (adding behavioral testing on top of electroclinical features), comparing etiological efficacy for construct validity, and testing two different treatment paradigms used for LGS in humans as predictive validity. Methods use preparation of the iess models and controls, intracranial surgery, EEG electrode implantation, 24/7 video- EEG recordings and analysis, drug administration, as well as separate cohort behavioral testing for motor behaviors, anxiety, autistic traits and cognition. Purpose of the LGS model development is to provide a tool for testing new treatment approaches for this devastating developmental epileptic encephalopathy.