Method for predicting a subjects response to SLC modulator therapy

Example 11

Proline may function as a neuromodulator via stimulation or alteration of neuronal glutamate and/or GABA signaling, which may underlie its effect on negative and other neuropsychiatric symptoms (Clelland et al., 2016; Crabtree et al., 2016). Molecules that can modulate neuronal glutamate signaling including NMDA receptor and/or glutamatergic signaling functions, and have been considered and/or tested in clinical trials in psychiatric disorders include glycine, D-serine, D-cycloserine and bitopterin (Roche RG1678; RO-4917838), sarcosine, SSR103800, Org 25935 and betaine. These are thought to alter glutamate receptor activity or function either directly or indirectly via modulation of the concentration of glycine and/or function of the glycine binding site.

Considering that clinical studies of molecules also thought to influence glutamate signaling have had mixed results, an initial exploratory analysis was performed of fasting plasma glycine and I-serine and an interaction with COMT genotype on negative symptoms of schizophrenia. Plasma glycine concentrations reflect CNS levels (Jiménez-Jiménez et al., 1998; Scholl-Bürgi et al., 2008; Luykx et al., 2013) and CSF D-serine, which is derived from L-serine via serine racemase, is significantly correlated with plasma L-serine (Luykx et al., 2013; Hashimoto et al., 2003).

In a sample of schizophrenia patients (n=95), fasting plasma glycine and I-serine significantly predicted increased negative symptoms in those subjects with the COMT Val/Met or Met/Met genotypes (glycine r=0.48, p=0.0003, n=53; I-serine r=0.32, p=0.02, n=53), but not in Val/Val carriers (glycine r=−0.05, p=0.78, n=42; I-serine r=−0.12, p=0.46, n=42). Following on from this, in regression analysis any significant effect of glycine was tested for after adjusting for the potential confounding effect of proline. A significant effect of glycine on negative symptoms remained (p=0.013) with medium effect size (partial eta²=0.116). As for proline, as glycine increased, so did negative symptoms in Met allele carrier patients.

In addition, analysis of valproate versus non-valproate-treated subjects indicated that valproate significantly upregulates fasting glycine levels (268 uM no valp n=64, 361 uM valp n=31, p=0.0007) and L-serine levels (103 uM no valp n=64, 117 uM valp n=31, p=0.004).

Given these findings of glycine and serine interactions with COMT, the interaction of COMT Val^158/108Met genotype with glycine on negative symptoms therefore also likely occurs when glycine modulators, including those listed above, are used in psychiatric and neuropsychiatric disorders.

As some of the molecules listed above have been extensively tested in clinical trials, reanalysis of the trial data and/or new trials accounting for COMT genotype when determining efficacy, may lead to evidence of therapeutic efficacy that has been previously undetected.

Trials of the molecules listed above for the treatment of psychiatric, neuropsychiatric, psychotic, mood and personality disorders, and symptoms thereof such as negative symptoms, should therefore be analyzed to account for the interaction of individuals' COMT Val^158/108Met genotype with glycine and (L- and/or D-) serine levels (and/or with potentially glutamate and/or GABA), with the expectation that COMT Val/Val genotype individuals will respond differently from Met allele carriers, and the failure of clinical trials to achieve efficacy may be due to patients not being chosen based on their COMT genotype (and thus whether they would benefit or be harmed by such treatment).

A further embodiment of the invention is that for patients treated with an SLC modulator, for example, LX-6171, inhibition of glutamic acid decarboxylase (GAD) activity will be decreased via decreased transport of synaptic proline across the pre- and/or post-synaptic membrane and relaxation of proline-mediated GAD inhibition, thus increasing gabaergic signaling (Crabtree et al. 2016). This may lead to increased inhibition of dopamine signaling to the prefrontal cortex and worsened negative symptoms for COMT Val/Val carriers. Conversely, for COMT Met allele carriers, LX-6171 may alleviate negative symptoms.

Proline concentration is also influenced by (one or more of) the genes and/or gene variants, and/or gene RNA and protein products of the following genes: PTPRE, AC089984.3, RAB21, DGCR2, MYL7, TBC1D7, KCNQ5, STK32A, NCAM1, LINC01288, DGCR5, DGCR6, DGCR9, FAM230F, AC007326.4, PRODH, ASPG (Rhee et al. 2013; Imaizumi et al. 2019). One or more of the above may interact for patients treated with one or more SLC modulator, for example LX-6171, inhibition of glutamic acid decarboxylase (GAD) activity will be decreased via decreased transport of synaptic proline across the pre- and/or post-synaptic membrane and relaxation of proline-mediated GAD inhibition, thus increasing gabaergic signaling (Crabtree et al. 2016). This may lead to increased inhibition of dopamine signaling and worsened symptoms (e.g., Negative symptoms) for COMT Val/Val carriers. Conversely, for COMT Met allele carriers, LX-6171 may alleviate negative symptoms.

Proline modulating molecules, e.g., upregulators including valproate, ethanol etc. and/or downregulators, e.g., Vitamin D and/or thiazolidinediones including, e.g., rosiglitazone and/or pioglitazone will interact with (one or more of) the above genes and/or gene variants, and/or gene RNA and protein products, and/or along with SLC genes, and/or gene variants, and/or gene RNA and protein products and/or SLC modulators (e.g., LX-6171), to regulate pre-synaptic and/or synaptic and/or post-synaptic proline, and its concomitant effects on neurotransmission and/or neuromodulation. These effects and/or interactions may cause proline upregulation and/or downregulation to have differential effects on symptoms, dependent upon COMT genotype, and may be associated with increased symptom severity or decreased symptom severity for COMT rs4680 V/V and/or V/M and/or M/M carriers, dependent upon optimal or ideal or beneficial proline level for individuals.