AMPA receptor attenuation as a new therapeutic approach for Batten disease

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DESCRIPTION (provided by applicant): The juvenile onset form of Batten disease (Juvenile Neuronal Ceroid Lipofuscinosis, JNCL), a fatal neurodegenerative disorder, results from mutations in the CLN3 gene. No specific treatment is currently available that could halt or slow the progression of the disease. The Cln3-loss-of-function (Cln3 ?ex1-6) mouse model of juvenile Batten disease exhibits many characteristic features of the human disorder including a deficit in motor coordination. Exploring the possible cause(s) of the motor incoordination in Cln3 ?ex1-6mice , we have found that Cln3?ex1-6 cerebellar granule cells in dissociated cultures and in organotypic cerebellar slice cultures are significantly more sensitive to AMPA-type, but not NMDA-type, glutamate receptor-mediated toxicity than their wild type counterparts (Kovacs et al., 2006), indicating an abnormally enhanced AMPA receptor activity. Attenuation of AMPA receptor activity in one-month-old Cln3 ?ex1-6 mice by a single intraperitoneal injection of the specific AMPA antagonist, EGIS-8332, resulted in an immediate improvement of their motor skills confirming that an abnormally increased AMPA receptor activity contributes to the motor coordination deficit at this early stage of the disease. At a later stage of the disease, in 6-7-month-old Cln3 ?ex1-6 mice, acute inhibition of AMPA receptors by EGIS-8332 did not have an immediate effect. Instead, it induced a delayed enhancement of motor learning and a long-lasting improvement of motor skills. These results suggest that temporary inhibition of AMPA receptors can induce a long-lasting correction of the pre-existing abnormal glutamatergic neurotransmission in vivo for juvenile Batten disease. The non-competitive AMPA receptor antagonist, EGIS-8332, we used in our in vivo studies, has not been tried in humans, and its owner, a small pharmaceutical company (EGIS Pharmaceuticals Plc.) does not plan any clinical trials with EGIS-8332 for financial reasons. Novartis, however, has a competitive AMPA receptor antagonist, NVP-AMP397, that was found safe in humans in clinical phase I testing and it is now in clinical phase II trials as a treatment for epilepsy. The goal of this proposal is to test the therapeutic efficiency of NVP-AMP397 (a generous gift of Novartis) in the Cln3 ?ex1-6 mouse model of juvenile Batten disease and provide preclinical pharmacological data that would support an immediate clinical trial with NVP-AMP397 in patients with juvenile Batten disease. PUBLIC HEALTH RELEVANCE: A beneficial effect of acute and chronic treatment with NVP-AMP397 in Cln3 ?ex1-6 mice would strongly argue for and support a clinical trial with this AMPA receptor antagonist in patients with juvenile Batten disease.