Select Page
Inhibition of MEK-ERK signaling reduces seizures in two mouse models of tuberous sclerosis complex Lena H.Nguyen, Steven C.Leiser, Dekun Song, Daniela Brunner, Steven L.Roberds, Michael Wong, Angelique Bordey Tuberous sclerosis complex (TSC) is a monogenic disorder characterized by hyperactivation of the mTOR signaling pathway and developmental brain malformations leading to intractable epilepsy. Although treatment with the recently approved mTOR inhibitor, everolimus, results in clinically relevant seizure suppression in up to 40% of TSC patients, seizures remain uncontrolled in a large number of cases, underscoring the need to identify novel treatment targets. The MEK-ERK signaling pathway has been found to be aberrantly activated in TSC and inhibition of MEK-ERK activity independently of mTOR rescued neuronal dendrite overgrowth in mice modeling TSC neuropathology. Here, we evaluated the efficacy of MEK-ERK inhibition on seizures in two mouse models of TSC. We found that treatment with the MEK inhibitor PD0325901 (mirdametinib) significantly reduced seizure activity in both TSC mouse models. These findings support inhibiting MEK-ERK activity as a potential alternative strategy to treat seizures in TSC.
Use of Phenotypic Screening in Mice in the Development of a Novel Non-D2-Receptor-Targeting Drug for the Treatment of Schizophrenia E. Leahy, M. Varney and D. Brunner

SEP-363856, a novel, first-in-class drug treatment being developed by Sunovion Pharmaceuticals, showed robust therapeutic effects in patients diagnosed with schizophrenia across a broad range of disabling symptoms including positive, negative, depressive, and general psychopathology symptoms, with a safety profile similar to placebo. SmartCube® – PsychoGenics’ proprietary mouse-based phenotypic platform, in combination with anti-target screening, was used as part of a phenotypic screening effort that identified SEP-363856. SmartCube® employs computer vision and artificial intelligence to extract and analyze behavioral data for central nervous system disorders. SEP-363856 does not interact with dopamine D2 nor with 5HT2A receptors that mediate the effects of currently available antipsychotic agents. The SmartCube® platform thus represents an effective approach to the discovery and development of the next generation of breakthrough treatments for schizophrenia and other neuropsychiatric disorders.

Elevation of brain magnesium with Swiss chard and buckwheat extracts in an animal model of reduced magnesium dietary intake Bassem F. El-Khodor, Karma James, Qing Chang, Wei Zhang, Yvette R. Loiselle, Chinmayee Panda & Taleen Hanania Nutritional Neuroscience, DOI: 10.1080/1028415X.2021.1995119,   Objectives: Inadequate dietary magnesium (Mg) intake is a growing public health concern. Mg is critical for diverse metabolic processes including energy production, macromolecule biosynthesis, and electrolyte homeostasis. Inadequate free Mg2+ ion concentration ([Mg2+]) in the brain is associated with several neurological and behavioral disorders. Elevating [Mg2+]in the brain using oral Mg supplementation has proven to be challenging due to the tight regulation of Mg2+ transport to the brain. This stu[pdfjs-viewer url="" viewer_width=100% viewer_height=800px fullscreen=true download=true print=true]dy explored the effect of short-term moderate reduction in dietary Mg intake (87% of normal Mg diet for 30 days) on [Mg2+] in the cerebrospinal fluid (CSF) ([Mg2+]CSF) and red blood cells (RBCs) ([Mg2+]RBC) in adult male rats. In addition, we investigated the effectiveness of magnesium-rich blend of Swiss chard and buckwheat extracts (SC/BW extract) in increasing brain [Mg2+] compared to various Mg salts commonly used as dietary supplements.
Novel brain permeant mTORC1/2 inhibitors are as efficacious as rapamycin or everolimus in mouse models of acquired partial epilepsy and tuberous sclerosis complex Theilmann, W,Gericke,B,Schidlitzki, A, Anjum, S,Borsdorf, S, Harries, T, Roberds, S.L., Aguiar, D,Brunner, D, Leiser, S,Song, D, Fabbro, D,Hillmann, P, Wymann, M,Loscher, W. Neuropharmacology.
Mechanistic target of rapamycin (mTOR) regulates cell proliferation, growth and survival, and is activated in cancer and neurological disorders, including epilepsy. The rapamycin derivative (“rapalog”) everolimus, which allosterically inhibits the mTOR pathway, is approved for the treatment of partial epilepsy with spontaneous recurrent seizures (SRS) in individuals with tuberous sclerosis complex (TSC). In contrast to the efficacy in TSC, the efficacy of rapalogs on SRS in other types of epilepsy is equivocal. Furthermore, rapalogs only poorly penetrate into the brain and are associated with peripheral adverse effects, which may compromise their therapeutic efficacy. Here we compare the antiseizure efficacy of two novel, brain-permeable ATP-competitive and selective mTORC1/2 inhibitors, PQR620 and PQR626, and the selective dual pan-PI3K/mTORC1/2 inhibitor PQR530 in two mouse models of chronic epilepsy with SRS, the intrahippocampal kainate (IHK) mouse model of acquired temporal lobe epilepsy and Tsc1GFAP CKO mice, a well-characterized mouse model of epilepsy in TSC. During prolonged treatment of IHK mice with rapamycin, everolimus, PQR620, PQR626, or PQR530; only PQR620 exerted a transient antiseizure effect on SRS, at well tolerated doses whereas the other compounds were ineffective. In contrast, all of the examined compounds markedly suppressed SRS in Tsc1GFAP CKO mice during chronic treatment at well tolerated doses. Thus, against our expectation, no clear differences in antiseizure efficacy were found across the three classes of mTOR inhibitors examined in mouse models of genetic and acquired epilepsies. The main advantage of the novel 1,3,5-triazine derivatives is their excellent tolerability compared to rapalogs, which would favor their development as new therapies for TORopathies such as TSC.
Mouse model systems of autism spectrum disorder: Replicability and informatics signature

Kabitzke, P, Morales, D, He, D, Cox, K, Sutphen, J, Thiede, L, Sabath, E, Hanania, T, Biemans, B, Brunner, D. Genes, Brain and Behavior. 2020;e12676.
Phenotyping mouse model systems of human disease has proven to be a difficult task, with frequent poor inter‐ and intra‐laboratory replicability, particularly in behavioral domains such as social and cognitive function. However, establishing robust animal model systems with strong construct validity is of fundamental importance as they are central tools for understanding disease pathophysiology and developing therapeutics. To complete our studies of mouse model systems relevant to autism spectrum disorder (ASD), we present a replication of the main findings from our two published studies of five genetic mouse model systems of ASD. To assess the intra‐laboratory robustness of previous results, we chose the two model systems that showed the greatest phenotypic differences, the Shank3/F and Cntnap2, and repeated assessments of general health, activity and social behavior. We additionally explored all five model systems in the same framework, comparing all results obtained in this three‐yearlong effort using informatics techniques to assess commonalities and differences. Our results showed high intra‐laboratory replicability of results, even for those with effect sizes that were not particularly large, suggesting that discrepancies in the literature may be dependent on subtle but pivotal differences in testing conditions, housing enrichment, or background strains and less so on the variability of the behavioral phenotypes. The overall informatics analysis suggests that in our behavioral assays we can separate the set of tested mouse model system into two main classes that in some aspects lie on opposite ends of the behavioral spectrum, supporting the view that autism is not a unitary concept.

ANAVEX®2-73 (blarcamesine), a Sigma-1 receptor agonist, ameliorates neurologic impairments in a mouse model of Rett syndrome

Kaufmann W E, Sprouse J, Rebowe N, Hanania T, Klamer D, Missling C U Pharmacol Biochem Behav. 2019, December 187:172796. doi: 10.1016/j.pbb.2019.172796.
Rett syndrome (RTT) is a severe neurodevelopmental disorder that is associated in most cases with mutations in the transcriptional regulator MECP2. At present, there are no effective treatments for the disorder. Despite recent advances in RTT genetics and neurobiology, most drug development programs have focused on compounds targeting the IGF-1 pathway and no pivotal trial has been completed as yet. Thus, testing novel drugs that can ameliorate RTT's clinical manifestations is a high priority. ANAVEX2-73 (blarcamesine) is a Sigma-1 receptor agonist and muscarinic receptor modulator with a strong safety record and preliminary evidence of efficacy in patients with Alzheimer's disease. Its role in calcium homeostasis and mitochondrial function, cellular functions that underlie pathological processes and compensatory mechanisms in RTT, makes blarcamesine an intriguing drug candidate for this disorder. Mice deficient in MeCP2 have a range of physiological and neurological abnormalities that mimic the human syndrome. We tested blarcamesine in female heterozygous mice carrying one null allele of Mecp2 (HET) using a two-tier approach, with age-appropriate tests. Administration of the drug to younger and older adult mice resulted in improvement in multiple motor, sensory, and autonomic phenotypes of relevance to RTT. The latter included motor coordination and balance, acoustic and visual responses, hindlimb clasping, and apnea in expiration. In line with previous animal and human studies, blarcamesine also showed a good safety profile in this mouse model of RTT. Clinical studies in RTT with blarcamesine are ongoing.

SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D2 Receptor Mechanism of Actions Dedic N, Jones P.G, Hopkins S.C, Lew R, Shao L, Campbell J. E, Spear K. L, Large T. H, Campbell U. C, Hanania T, Leahy E, Koblan K Journal of Pharmacology and Experimental Therapeutics. August 1, 2019 jpet.119.260281.
For the past 50 years, the clinical efficacy of antipsychotic medications has relied on blockade of dopamine D2 receptors. Drug development of non-D2 compounds, seeking to avoid the limiting side effects of dopamine receptor blockade, has failed to date to yield new medicines for patients. In this work, we report the discovery of SEP-363856 (SEP-856), a novel psychotropic agent with a unique mechanism of action. SEP-856 was discovered in a medicinal chemistry effort utilizing a high throughput, high content, mouse-behavior phenotyping platform, in combination with in vitro screening, aimed at developing non-D2 (anti-target) compounds that could nevertheless retain efficacy across multiple animal models sensitive to D2-based pharmacological mechanisms. SEP-856 demonstrated broad efficacy in putative rodent models relating to aspects of schizophrenia, including phencyclidine (PCP)-induced hyperactivity, prepulse inhibition, and PCP-induced deficits in social interaction. In addition to its favorable pharmacokinetic properties, lack of D2 receptor occupancy, and the absence of catalepsy, SEP-856’s broad profile was further highlighted by its robust suppression of rapid eye movement sleep in rats.
Allele-selective transcriptional repression of mutant HTT for the treatment of Huntington’s disease Zeitler B, Froelich S, Marlen K, Shivak D.A, Yu Q, Li D, Pearl J.R, Miller J.C, Zhang L, Paschon D.E, Hinkley S.J, Ankoudinova I, Lam S, Guschin D, Kopan L, Cherone J.M, Nguyen B.H.O, Qiao G, Ataei Y, Mendel M.C, Amora R, Surosky R, Laganiere J, Vu B.J , Narayanan A, Sedaghat Y, Tillack K, Thiede C, Gärtner A, Kwak S, Bard J, Mrzljak L, Park L, Heikkinen T, Lehtimäki K.K , Svedberg M.M, Häggkvist J, Tari L, Tóth M, Varrone A, Halldin C, Kudwa A.E, Ramboz S, Day M, Kondapalli J, Surmeier D.J, Urnov F.D, Gregory P.D, Rebar E.J, Sanjuán I.M, Zhang H.S Nature Medicine. July 25, 2019. Vol. 25, 1131–1142.
Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the huntingtin gene (HTT), which codes for the pathologic mutant HTT (mHTT) protein. Since normal HTT is thought to be important for brain function, we engineered zinc finger protein transcription factors (ZFP-TFs) to target the pathogenic CAG repeat and selectively lower mHTT as a therapeutic strategy. Using patient-derived fibroblasts and neurons, we demonstrate that ZFP-TFs selectively repress >99% of HD-causing alleles over a wide dose range while preserving expression of >86% of normal alleles. Other CAG-containing genes are minimally affected, and virally delivered ZFP-TFs are active and well tolerated in HD neurons beyond 100 days in culture and for at least nine months in the mouse brain. Using three HD mouse models, we demonstrate improvements in a range of molecular, histopathological, electrophysiological and functional endpoints. Our findings support the continued development of an allele-selective ZFP-TF for the treatment of HD.
Validated Phenotypic Approach to Neuropsychiatric Drug Discovery Leahy E Drug Development & Delivery March 2019 Vol 19 No 2: 46-49.
At the recent American College of Neuropsychopharmacology (ACNP) meeting, Sunovion Pharmaceuticals and PsychoGenics Inc. announced positive Phase 2 results for SEP-363856, a novel, first-in-class treatment that has the potential to offer patients with schizophrenia the chance to live a near-normal life. Available treatment options fail to treat all schizophrenia symptoms, and their side effects result in non-compliance and relapse. SEP-363856, by contrast, shows robust effects across a broad range of disabling symptoms, including positive, negative, depressive, and general psychopathology symptoms, with a safety profile similar to placebo. Discovered via SmartCube®, PsychoGenics’ target-agnostic platform, SEP-363856 does not interact with the dopamine D2 or other neuroreceptors thought to mediate the effects of currently available antipsychotic agents. The SmartCube platform thus represents a novel approach to discovering the next generation of breakthrough treatments for schizophrenia and other neuropsychiatric disorders.