Thota Ganesh - US grants

Lay Summary Alzheimer's disease (AD), a neurodegenerative disorder, is a leading cause of dementia in elderly. AD leads to progressive loss of cognitive functions. Currently about 5.4 million Americans (1 in 8 persons 65 or older) are living with AD, and the number is expected to triple by the year 2050. Approximately $200 billion per year is spent on all aspects of caring for AD patients, yet there is no therapy on the horizon that clearly alters the disease progression and inevitable cognitive decline. The small molecule drugs that have been developed based on amyloid cascade hypothesis have not shown a clear clinical benefit so far. Thus it would be very important to focus on identification of novel drug targets and small molecules that work through novel mode of biological action for future AD therapy. COX-2 levels are increased at the early stage of AD, and its levels are correlated with levels of A?-peptides. Clinical studies suggest that COX-2 inhibitors may be useful as preventative for AD if they were given at asymptomatic stage of the disease, but they may offer little or no benefit to clinically diagnosed patients with cognitive deficits. However, chronic use of COX-2 drugs (examples, Vioxx and Bextra) resulted in adverse cardiovascular events, which is worrying for the AD patients who already are at increased risk for heart disease. Thus, future use of COX-2 drugs on patients will be limited. COX-2 catalyzes the first-step towards synthesis of five prostaglandins; PGD2, PGE2, PGF2, PGI2, and TxA2, which activate eleven prostanoid receptors, DP1, DP2, EP1, EP2, EP3, EP4, FP?, ?, IP and TP?, ? respectively. We hypothesize that targeting EP2, a specific prostanoid receptor downstream of COX-2, rather than a generic block of the entire COX-2 signaling is a superior therapeutic strategy for AD with an EP2 specific antagonist. In this study, we propose to develop an EP2 selective antagonist, to demonstrate a proof of concept whether EP2 antagonist suppresses inflammation, neurodegeneration and cognitive deficits in 5XFAD model of AD, and to establish a preliminary safety package for using EP2 drugs potentially on AD patients.

Program Director/Principal Investigator (Last, First, Middle): Ganesh, Thota Lay summary Epilepsy is associated with significant mortality and morbidity, with an estimated annual cost of $15 billion to the USA. About 150,000 new cases of epilepsy are diagnosed in the United States each year. The anti-seizure drugs, which blunt seizures in epilepsy patients, do not prevent the development of epilepsy. Posttraumatic epilepsy (PTE) arises in patients due to traumatic brain injury (TBI). The incidence of epilepsy in adults after a penetrating TBI is about 50%. Thus, it is very important to identify novel adjunct therapeutic agents which can be administered along with anti-seizure drugs to delay the progression and prevent the development of PTE and other types of epilepsy. Induction of COX-2 and PGE2 were found in the brain of patients and rodent models after TBI and seizures. Recently, we have shown that COX-2 deletion restricted to forebrain neurons is beneficial in pilocaprine induced model of status epilepticus (SE). A selective antagonist of PGE2 receptor EP2 recapitulated many features of conditional COX-2 deletion in SE model by blunting several proinflammatory mediators, gliosis and neurodegeneration, suggesting that most of the COX-2 proinflammatory effects are mediated through EP2 receptor in a brain injury model. Thus, we hypothesized that targeting EP2 receptor, downstream of COX-2, will be a superior strategy for the development of anti-epileptogenic therapy. In this study, we propose to test a proof-of-concept whether targeting EP2 receptor with small molecule antagonist will be anti-epileptogenic in rat rostral parasagittal fluid percussion injury (rpFPI) model of posttraumatic epilepsy. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) Page Continuation Format Page

Program Director/Principal Investigator (Last, First, Middle): Dingledine, Ray Abstract Epilepsy, the 4th most prevalent neurological disorder after stroke, Alzheimer's and migraine with an incidence of 1 in 26 individuals, is often accompanied by cognitive deficits. Cognitive comorbidities substantially reduce quality of life in people with epilepsy. Although a number of anti-seizure drugs are available, no approved drugs mitigate either the cognition problems or progression of the disease. Inflammation is a component of all chronic diseases including epilepsy, and is the consequence of several broad signaling cascades including cyclooxygenase-2 (COX-2). We have shown that activation of the EP2 receptor for prostaglandin E2 is responsible for blood-brain barrier leakage and much of the inflammatory reaction, neuronal injury and cognitive deficit that follows seizure-provoked COX-2 induction in brain. We have synthesized and tested >500 compounds as competitive antagonists of the human EP2 receptor, and demonstrated in vivo efficacy in three animal models of epilepsy. We now wish to progress one of our EP2 antagonists, TG11-77?HCl, through phase 1 clinical trials. This compound, TG11-77?HCl, is potent (Schild Kb 10 nM against EP2), >300-fold selective against the other eight prostanoid receptors, orally active with acceptable plasma half-life (2.4 hr) and brain-to plasma ratio (0.4) in mice. The SAR for potency and selectivity are well understood. Our compounds show therapeutic efficacy in rodent models of seizure-induced brain injury and memory deficits, and lack common forms of toxicity after 30 days exposure to doses higher than the efficacious dose. The compound series is protected by three awarded and two pending patents. In specific aim 1 we will complete all requirements to enter the Development phase. In specific aim 2 we will submit an IND. In specific aim 3 both single and multiple ascending dose phase 1 clinical trials will be completed. Successful completion of this project would lay the groundwork for the first clinical test of the hypothesis that EP2 receptor modulation after seizures can provide the first preventive treatment for one of the chief comorbidities of epilepsy. OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Page Continuation Format Page