Tuberous sclerosis complex (TSC) is a multisystem genetic disorder caused by mutation in one of two genes, TSC1 or TSC2. The central nervous system (CNS or brain) is severely affected in TSC. Over 80% of TSC individuals show CNS symptoms, including epilepsy, cognitive impairment, and behavioral abnormalities such as autism. However, no treatment has been found completely effective for the neurological manifestations of TSC.

Our group developed, characterized, and patented the drug Memantine, which was subsequently approved by the US Food and Drug Administration (FDA), European Union, and Japanese regulatory authorities for treatment of moderate-to-severe Alzheimer's disease. Our group discovered that Memantine blocks excessive electrical activity in the brain engendered by stimulation of a particular protein that binds glutamate, known as the N-methyl-D-aspartate-type glutamate receptor. Importantly, hyperactivity of these glutamate receptors is thought to occur in TSC and has been shown to be associated with epilepsy, cognitive impairment, and autism. Indeed, Memantine is in clinical trials for children with epilepsy, cognitive impairment, and autism. However, the drug has not been formally tested in humans with TSC or in animal models of the disease.

Recently, we developed a new, improved series of Memantine derivatives, termed NitroMemantines. We found that NitroMemantines have superior efficacy to Memantine in several different animal models of neurological diseases. In this proposal, we will begin to investigate the potential of Memantine and NitroMemantine to treat the neurological manifestations of TSC. Thus, we propose to treat TSC mouse models with Memantine/NitroMemantine and examine their effects on these mice.

Since Memantine is an FDA-approved drug, successful treatment of animal models of TSC could expedite clinical trials in human TSC. Additionally, we will draw upon our experience in developing Memantine as an FDA-approved drug in advancing NitroMemantine into human clinical studies. Thus, our proposal holds promise for impacting therapy of the neurological manifestations of TSC.