The long-term vision of CURE is to develop respiratory phage therapies capable of improving clinical outcomes in asthma. Such accomplishment will undoubtedly be paralleled by an enhanced understanding of microbiome variability in asthma, providing an innovative aspect of disease pheno/endotyping and establishing the basis for precision medicine interventions. Furthermore, the developed paradigm could be straightforwardly expanded to other chronic respiratory conditions, such as chronic obstructive pulmonary disease (COPD). Our vision requires the capacity to predict with accuracy and repeatability the microbiological, immunological and clinical effects of an ecological intervention in the respiratory niche. We envision this approach as an integral part of phage therapy development, able to support decision making in preparation of phages mixes (‘cocktails’) and bridging the gap between the need for personalized treatment and regulatory demands for standardization.
Two unique concepts underpin this vision.
The first is that, in addition to their potential as ‘new age antibiotics’, phages may be used to treat chronic inflammatory disorders such as asthma. Asthma is an ideal choice due to its prevalence, impact, variability, suboptimal therapeutic options and multifaceted association with infection
The second is the notion of eubiosis reinstatement, which suggests that in cases where dysbiosis is prominent, the restoration of healthy symbiotic communities may be therapeutically more appropriate than complete elimination of ‘culprit’ bacteria. Using robust methodologies, CURE will take the essential steps to reach a point where one or more phage cocktails could be ready to be evaluated in clinical trials in asthma.
The key technological breakthrough will be a set of computational tools, based on experimentally validated mathematical models, able to predict the impact of interventions with specific phages on the microbial ecology and associated clinical status in asthma, thus guiding the design of clinically relevant phage cocktails.
On the way to this goal, CURE will greatly advance our knowledge of the characteristics and dynamics of the human respiratory microbiome in health and asthma, by describing in detail the currently unexplored virome, the viral-bacterial interaction network and their perturbations in time. The longitudinal approaches will allow the assessment of causal relationships between microbiome and disease. In addition to our understanding of ecological dynamics, the development of tangible intervention agents is also a key requirement. Therefore, CURE will establish and optimize a novel collection of bacteriophages, selected for the purposes of the intervention.
However, there are several pitfalls that need to be overcome before phage therapy becomes standardized, potentially revolutionizing our medical armamentarium. The pre-optimization of phage cocktails is a major requirement, towards which the CURE models represent an ambitious and concrete step. Our approach will not only predict treatment responses, but also be capable of addressing individual/subgroup variability and aid treatment stratification, thus supporting precision medicine approaches. While phage therapy appears to be safe (in 2006 the FDA gave phages the designation ‘Generally Regarded as Safe (GRAS)), proof of efficacy will require well-designed clinical trials. The CURE Consortium will be excellently placed to initiate such trials, taking into account that in addition to the theoretical prediction, following the successful completion of the project, it will be in possession of a novel collection of relevant phages. Phase I/IIa trials will then provide the opportunity to evaluate the model and further optimize it in a direct in-vivo human setting.