|Inflammatory disease||Neurodegenerative disorders||Anxiety and psychiatric disorders|
The TSPO knockout mouse model (C57BL/6-Tspotm1GuWu) developed at ANSTO is useful in the study of various disease states. It is the most advanced and characterised in vivo method to acquire robust specificity and selectivity data for TSPO-binding compounds.
It enables faster evidence-based decisions in the selection of suitable drug candidates for the TSPO and unique insights into the mechanism of action or off-target effects.
- Accelerated drug development
- Further understanding of the mechanisms of action
- Evidential proof to strengthen end product value
Pathways of the innate immune system have broad relevance for the diagnostics and therapeutics of many acute and chronic diseases. The TSPO knockout mouse model, as shown in Banati et al., (Nature Communications 2014) allows the dissection of the TSPO associated inflammation pathways.
There is increasing recognition that glial responses are underpinning regeneration and more careful separation of inflammatory pathways from neuro-glial interactions is needed to design rational therapeutic strategies.
The TSPO has been under investigation as a drug target for inflammatory conditions, such as arthritis and MS. In the case of MS, activated microglia are involved in the immune response. The TSPO is expressed by microglia and up-regulated in MS, particularly in the case of secondary progressive MS correlating with clinical disability. TSPO ligands have been used experimentally to mitigate the course of auto-immune inflammation.
Obesity, diabetes and metabolism disorders
The use of TSPO null background material, such as the TSPO knockout mouse model, can provide the direct validation of the selectivity and specificity of many TSPO targeting compounds which have so far, been difficult to obtain.
It has recently been reported that TSPO plays a role in modulating energy, obesity and diabetes. After testing the effect of 2,400 bioactive compounds on glucogenesis using a high throughput screen in transgenic reporter zebrafish, it was discovered that TSPO ligands PK11195 and Ro5-4864 decrease glucose levels and reduce energy consumption, suggesting a role for TSPO in glucose metabolism (Gut et al., Nature Chemical Biology 2013, 9: 97–104).
Further, it was demonstrated that PK11195 and Ro5-4864 reduced blood glucose in 24 hour fasted mice, reduced weight gain and improved glucose tolerance in a mouse model of high-fat induced obesity and diabetes.
The effect of PK11195 on glucose homeostasis suggests that TSPO may have a role in cellular energy consumption through modulation of mitochondrial energy production. The utility of this approach has been already demonstrated for a number of ANSTO synthesised-TSPO compounds.
The TSPO knockout mouse model can help in determining the specificity and selectivity of a TSPO ligand, and provide answers in regards to mechanism of action and therapeutic efficacy.
TSPO expression has been used as a diagnostic biomarker of neuro-inflammation, while synthetic ligands for the TSPO are being studied as potential therapeutic drugs that alter the functional state of the brain innate immune effector cell, microglia.
TSPO ligands with a potential to ameliorate or reverse neurodegenerative pathology, such as Alzheimer’s disease, are already under active investigation.
The TSPO knockout mouse model is currently the most advanced approach to determine the specificity and selectivity of anxiolytic TSPO ligands in vivo. Despite new insights into underlying brain mechanisms associated with psychiatric disorders, there has been relatively little progress in the identification of novel pharmacological treatments of anxiety.
TSPO targeting ligands are one of the few novel targets for anxiolysis. A number of studies have demonstrated therapeutic promise in anxiety treatment (Rupprecht et al., Nature Reviews Drug Discovery2010, 12: 971-88), in particular by minimising the risk of tolerance, dependence and sedation which are common with current anxiolytics.
Recent research discoveries implicate the TSPO in antipsychotic response and antipsychotics induced weight gain as well as suggesting that chronic fatigue syndromes are associated with TSPO up-regulation in the brain.