Executive Summary – Reporting Period 2

Project rationale and overall objectives of the project

The ULTRA-DD project’s goal is to deliver new tools and resources to speed up the development of truly innovative medicines, especially in the areas of autoimmune and inflammatory diseases, where new treatments are urgently needed. Through the partner Structural Genomics Consortium (SGC), ULTRA-DD has strong ties with similar initiatives elsewhere in the world, and this, coupled with the project’s strong open access policy ensures that the tools, resources, and knowledge generated by the project benefit the entire scientific community and enable new drug discovery and development projects within the industrial biomedical sector.

Overall deliverables of the project

A summary of all deliverables for ULTRA-DD is found in Figure 1 below

Figure 1. Overview of all deliverables for ULTRA-DD during the period 2015-2020

Summary of progress versus plan since last period

All Work-Packages (WPs) have met their milestones and deliverables during the period M13-M24. Further, all WPs are on track towards upcoming major milestones and deliverables due in reporting period 3 (M25-36). There have been no deviations from plan other than that certain WPs have over-delivered or reached certain milestones ahead of plan.

Significant achievements since last report

WP1 – Target Prioritization

All milestones and deliverables were met. The in-house generated computational tool for target prioritization, the Priority Index, was launched to the public and has also been presented at two major conferences. The tool is now being used by ULTRA-DD scientists to prioritize targets within specific inflammatory and auto-immune diseases, such as ankylosing spondylitis.

WP2 – Protein and Antibody Production

All milestones and deliverables were met. The protein production team at Oxford has produced recombinant samples for assay development, protein structures, biophysical and biochemical characterization studies, and as antigens for antibody production. A series of novel vectors for bacterial and mammalian expression of secreted proteins have also been developed. The antibody team at Karolinska has launched an ambitious project to generate biological probes (functional antibodies) for interleukin receptors and for poorly characterized interleukins, currently lacking publicly available antibody research tools.

WP3 – Cell Assays

All milestones and deliverables were met. In vitro screening has been performed on 20 targets and approximately 60,000 data points have been generated. Efforts were mainly focused on epigenetic targets including the development of new HTS assays for the YEATS domain epigenetic reader protein family as well as the NUDIX hydrolase family. A new group leader for the cell assay team at Oxford was recruited (Gillian Farnie, from the Manchester Cancer Research Centre, UK)

WP4 – Protein Structures and Proteomics

All milestones and deliverables were met. In total 32 protein 3D structures were approved, and in addition >70 protein-fragment ligand complex structures were deposited in the protein structures data bank (PDB). Novel structures for the integral membrane protein TRP channel Polycystin-2/PC2 were successfully solved, deposited into the PDB, and published. A new group leader for membrane protein structural work was recruited to Oxford (Katharina Duerr, from the Vollum Institute, US). Our mass spectrometry team at the ETH in Zürich continues their work analysing disease relevant protein complexes and has in addition initiated a number of collaborative efforts with our tissue platform teams for clinical proteomics studies.

WP5 – Chemical Probes

All milestones and deliverables were met. In close cooperation with the EFPIA partners, the chemistry team at Oxford has generated four chemical probes for novel targets linked to inflammation. These probes are now available to the public through SGC and ULTRA-DD, as well as from chemical vendors. In total, ULTRA-DD has generated six novel chemical probes since start of the project.

WP6 – Patient-Derived Cell Assays

All milestones and deliverables were met. The teams at Karolinska and in Oxford have now established the infrastructure and logistics required and recruited the majority of team members. Focus for the first two years of operations has been on the diseases ankylosing spondylitis, hand fibrosis, lupus and myositis, and from 2017 we are also targeting systemic sclerosis. We have developed and put into production four new assays during reporting period 2. New potential target-disease association have been discovered.

WP7 – Informatics

All milestones and deliverables were met. The team has implemented new functionalities in the database Scarab to also be able to capture outputs from the tissue platform (patient-derived cell assays) and antibody teams, and installed and trained staff in its use. Further, with the tissue platforms, a first public data-dissemination interface has been built, which soon will be released to the general scientific community through ULTRA-DD and SGC websites. A new version of Chromohub – a resource tool to disseminate information regarding the gene specific reagents generated – was developed and released.

WP8 – Outreach and Network

All milestones and deliverables were met. Our work to attract collaborations with Disease Foundations and Patient Organizations has expanded. We have now, in partnership with SGC, established a number of directly supported collaborations with e.g. the FOP patient groups, the Brain Tumour Charity and Myeloma UK. We have distributed ULTRA-DD derived chemical probes to >35 international research groups; and arranged a number of open conferences, e.g. Drug Discovery: Creating a New Ecosystem, June 2016 in Oxford.

WP9 – Management

All milestones and deliverables were met. Overall, the management of the project is working well, with established informal and formal channels for governance and interactions. Project finances are coordinated from SGC Toronto, and research activities are running according to budget, with few exceptions, where we still are underspending to a certain extent.