GDF15 is a dynamic biomarker of the integrated stress response in the central nervous system.

AIM: Characterize Growth Differentiation Factor 15 (GDF15) as a secreted biomarker of the integrated stress response (ISR) within the central nervous system (CNS). METHODS: We determined GDF15 levels utilizing in vitro and in vivo neuronal systems wherein the ISR was activated. Primarily, we used the murine model of vanishing white matter disease (VWMD), a neurological disease driven by persistent ISR in the CNS, to establish a link between levels of GDF15 in the cerebrospinal fluid (CSF) and ISR gene expression signature in the CNS. GDF15 was also determined in the CSF of VWM patients. RESULTS: GDF15 expression was increased concomitant to ISR activation in stress-induced primary astrocytes as well as in retinal ganglion cells following optic nerve crush, while treatment with 2Bact, a specific eIF2B activator, suppressed both the ISR and GDF15. In the VWMD model, CSF GDF15 levels corresponded with the magnitude of the ISR and were reduced by 2BAct. In VWM patients, mean CSF GDF15 was elevated >20-fold as compared to healthy controls, whereas plasma GDF15 was undifferentiated. CONCLUSIONS: These data suggest that CSF GDF15 is a dynamic marker of ISR activation in the CNS and may serve as a pharmacodynamic biomarker for ISR-modulating therapies.

Evaluating Antibody Pharmacokinetics as Prerequisite for Determining True Efficacy as Shown by Dual Targeting of PD-1 and CD96.

One important prerequisite for developing a therapeutic monoclonal antibody is to evaluate its in vivo efficacy. We tested the therapeutic potential of an anti-CD96 antibody alone or in combination with an anti-PD-1 antibody in a mouse colon cancer model. Early anti-PD-1 treatment significantly decreased tumor growth and the combination with anti-CD96 further increased the therapeutic benefit, while anti-CD96 treatment alone had no effect. In late therapeutic settings, the treatment combination resulted in enhanced CD8+ T cell infiltration of tumors and an increased CD8/Treg ratio. Measured anti-PD-1 concentrations were as expected in animals treated with anti-PD-1 alone, but lower at later time points in animals receiving combination treatment. Moreover, anti-CD96 concentrations dropped dramatically after 10 days and were undetectable thereafter in most animals due to the occurrence of anti-drug antibodies that were increasing antibody clearance. Comparison of the anti-PD-1 concentrations with tumor growth showed that higher antibody concentrations in plasma correlated with better therapeutic efficacy. The therapeutic effect of anti-CD96 treatment could not be evaluated, because plasma concentrations were too low. Our findings strongly support the notion of measuring both plasma concentration and anti-drug antibody formation throughout in vivo studies, in order to interpret pharmacodynamic data correctly.

Policy recommendations for rare disease centres of expertise.

AIM: Rare diseases are a serious public health concern and are a priority in the EU. This study aims to develop policy recommendations for rare disease centres of expertise (CoEs) in order to improve standards and quality of care. SUBJECT AND METHODS: A modified 3-round Delphi technique was used. Participants included rare diseases patients, carers, patient representatives and healthcare professionals (HCPs) from CoEs in two countries-Denmark and the UK. RESULTS: The results suggest the need to make improvements within current CoE environments, access to CoEs and the need for coordination and cooperation of services within and outside CoEs. It is recommended that CoEs are not overly 'medicalised', while at the same time they should be established as research facilities. The importance of including patient representatives in CoE performance management was also highlighted. Raising awareness and provision of appropriate training amongst non-specialist HCPs is seen as a priority for early and correct diagnosis and ensuring high quality care. Similarly, provision of targeted information about patients' illness and care was considered essential along with access to social assistance within CoEs. CONCLUSIONS: Policy recommendations were developed in areas previously recognised as having gaps. Their implementation is expected to strengthen and improve current care provision for rare disease patients. In member states where national plans and strategies are being developed, it is recommended to replicate the methodological approach used in this study as it has proven to be a helpful tool in rare disease centres of expertise policy development.