This proposal responding to RFA-OD-10-005, """"""""Recovery Act Limited Competition: NIH Director's Opportunity for Research in Five Thematic Areas (RC4)"""""""" fully addresses Research Area 2: Translating Basic Science Discoveries into New and Better Treatments, but also Research Areas 3 (Using Science to Enable Health Care Reform) and 4 (Focusing on Global Health). Infantile spasms (IS) represent a devastating epilepsy syndrome of childhood. IS usually develops between 3-12 months with an incidence of approximately 1 case per 3225 live births. Thus, in the US only there are about 1500 NEW cases of IS, i.e., children who newly require diagnosis and treatment, every year. Worldwide estimate is about 50,000 new patients with IS annually. About 85% of patients with IS become mentally retarded and 67% suffer from intractable epilepsy despite treatment, which is currently mostly hormonal (ACTH, corticosteroids) or vigabatrin, with emergence of new seizure types. IS are associated with significant mortality: about 30% of the patients with IS die mostly during the first 3 years of life. Improvements in therapy of the IS have been severely limited by absence of appropriate animal models for testing new drugs and to study IS mechanisms. Our recently developed model of IS consisting of prenatal priming with betamethasone and postnatal trigger of spasms with NMDA remarkably mimics the human condition: The spastic seizures are age-dependent, associated with EEG electrodecrement and interictal large-amplitude EEG waves, and respond to both acute and long-term treatment with ACTH in a similar way the human IS do. Our follow-up studies revealed several mechanisms that may contribute to the condition of IS: (1) Prenatal priming upregulates expression of melanocortin MC4 receptors in the hypothalamic arcuate nucleus (Arc) one of the brain structures closely linked to the expression of flexion spasms. (2) Prenatal priming upregulates expression of corticotropin releasing factor (CRF) in the Arc. (3) Prenatal priming accelerates developmental switch in replacing NR2B subunit of the NMDA receptor with the NR2A subunit. This proposal will build on these mechanisms to propose three new classes of drug treatment for IS with better efficacy, fewer side effects, and better long-term outcome compared to current IS treatments, with additional substantial cost improvement.
Specific aims of this proposal will determine: (1) Activation of MC4 receptors is an effective therapeutic tool against IS. (2) Blockade or downregulation of CRF receptors-1 is effective against IS. (3) Blockade or downregulation of the NR2A subunit of the NMDA receptor will suppress IS. Methods use prenatal priming with betamethasone and postnatal triggering of spasms with NMDA to model IS. Intracranial microinfusions (icv. and intraparenchymal) of specific siRNAs or receptor agonists/antagonists will determine comparative efficacy versus systemic treatment with ACTH or vigabatrin confirmed by EEG/video monitoring. Behavioral assays will evaluate side effects of new treatments and long-term cognitive outcome.
This proposal fully addresses Research Area 2: Translating Basic Science Discoveries into New and Better Treatments, specifically the infantile spasms (IS), which are a devastating epilepsy syndrome of childhood (about 1500 new cases in the USA per year) currently treated either hormonally (ACTH) at tremendous costs or with vigabatrin with significant side effects but neither treatment improves long-term cognitive outcome, thus over 80% of children become mentally retarded. We have developed and validated a model of IS and determined some basic mechanisms that may contribute to the occurrence of IS. Utilizing these mechanistic findings it is proposed to investigate three new classes of drugs and to develop mechanistic IS therapies, which would become superior in efficacy to the current treatment together with fewer side effects and significant improvement in long-term cognitive outcome, and finally would be incomparably cheaper and safer than currently used drugs.
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