Testing various pharmacotherapeutic approaches in mouse models of infantile, late infantile and juvenile Batten diseases

As outlined in Project 1, the novel nonsense mutant mouse models of infantile, late infantile and juvenile Batten diseases will be used to test nonsense suppression therapy. It has recently been demonstrated that the anticancer drug, 5-azacytidine, by inhibiting nonsense-mediated decay, increases the level of nonsense mutant mRNA transcripts (Bhuvanagiri et al., 2014) and could greatly enhance the therapeutic efficiency of a nonsense suppressive drug. We will test if 5-azacytidine increases nonsense mutant CLN1,CLN2 and CLN3 mRNA expression in the mouse models, and if it does, combinatorial treatment (5-azacytidine + nonsense suppressive drug) will be applied to achieve a maximum therapeutic effect.

Accumulated evidence indicates that glutamate neurotransmission is dysregulated (abnormally enhanced or decreased) in several pediatric lysosomal storage disorders including infantile, late infantile and juvenile Batten diseases. The aberrant glutamate neurotransmission may cause the neurological deficits and progressive neurodegeneration observed in these diseases. Indeed, we have previously shown that attenuation of AMPA- or NMDA-type glutamate receptors improves the motor coordination in the Cln3-knockout (Cln3-/-) mouse model of juvenile Batten disease (Kovács and Pearce, 2008; Kovács et al., 2011; Kovács et al., 2012). Furthermore, our results in primary neuronal cultures from Cln1-knockout (Cln1-/-)and wild type mice indicate that AMPA receptor function is abnormally decreased, whereas NMDA receptor function is abnormally enhanced in Cln1-/- neurons. Based on our findings, the therapeutic efficiency of various glutamate receptor ligands (AMPA receptor antagonists; a positive AMPA receptor modulator, S18986, and the FDA-approved NMDA receptor blocker, memantine) will be tested in our mouse disease models (Cln1-/- ,Cln2-/- and Cln3-/- mice, and also in the new nonsense mutant CLN1,CLN2 and CLN3 models).

Related Publications

Miller, JN, Kovács, AD, Pearce, D.A. (2015) The novel Cln1R151X mouse model of infantile neuronal ceroid lipofuscinosis (INCL) for testing nonsense suppression therapy. Human Molecular Genetics 24: 185-196.

Thada, V, Miller, JN, Kovács AD, Pearce DA. (2016) Tissue-specific variation in nonsense mutant transcript level and drug-induced read-through efficiency in the Cln1R151X mouse model of INCL. Journal of Cellular and Molecular Medicine 20: 381-385.

Cárcel-Trullols, J, Kovács, AD, Pearce DA (2015) Cell biology of the NCL proteins: What they do and don't do. Biochimica et Biophysica Acta 1852: 2242-2255.

Kovács, AD, Hof, C, Pearce, DA (2015) Abnormally increased surface expression of AMPA receptors in the cerebellum, cortex and striatum of Cln3-/- mice. Neuroscience Letters 607: 29-34.

Kovács, AD, Pearce, DA (2015) Finding the most appropriate mouse model of juvenile CLN3 (Batten) disease for therapeutic studies: the importance of genetic background and gender. Disease Models & Mechanisms 8: 351-361.

Bhuvanagiri, M, Lewis, J, Putzker, K, Becker, JP, Leicht, S, Krijgsveld, J, Batra, R, Turnwald, B, Jovanovic, B, Hauer, C, Sieber, J, Hentze, MW, Kulozik AE (2014) 5-azacytidine inhibits nonsense-mediated decay in a MYC-dependent fashion. EMBO Molecular Medicine 6:1593-1609.

Kovács, AD, Saje, A, Wong, A, Ramji, S, Cooper, JD, Pearce, DA (2012) Age-dependent therapeutic effect of memantine in a mouse model of juvenile Batten disease. Neuropharmacology 63: 769-775.

Finn, R, Kovács, AD, Pearce, DA (2012) Altered glutamate receptor function in the cerebellum of the Ppt1-/- mouse, a murine model of infantile neuronal ceroid lipofuscinosis. Journal of Neuroscience Research 90: 367-375.

Kovács, AD, Saje, A, Wong, A, Szénási, G, Kiricsi, P, Szabó, E, Cooper, JD, Pearce, DA (2011) Temporary inhibition of AMPA receptors induces a prolonged improvement of motor performance in a mouse model of juvenile Batten disease. Neuropharmacology 60: 405-409.

Finn, R, Kovács, AD, Pearce, DA (2011) Altered sensitivity of cerebellar granule cells to glutamate receptor overactivation in the Cln3Δex7/8-knock-in mouse model of juvenile neuronal ceroid lipofuscinosis. Neurochemistry International 58: 648-655.

Finn, R, Kovács, AD, Pearce, DA (2010) Altered sensitivity to excitotoxic cell death and glutamate receptor expression between two commonly studied mouse strains. Journal of Neuroscience Research 88: 2648-2660.

Kovács, AD, Pearce, DA (2008) Attenuation of AMPA receptor activity improves motor skills in a mouse model of juvenile Batten disease. Experimental Neurology 209: 288-291.

Kovács, AD., Weimer, JM, Pearce, DA (2006) Selectively increased sensitivity of cerebellar granule cells to AMPA receptor-mediated excitotoxicity in a mouse model of Batten disease. Neurobiology of Disease 22: 575-585.