From the Valley of Death to Human-Centric Precision Medicine: The REPO4EU Platform and its Transition into REPOSYSTEM

<p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="first" dir="auto" id="d21861250e103">Decades of <b> investment in translational medicine have failed</b> to deliver curative therapies for most chronic diseases. <a data-untrusted="" href="https://paperpile.com/c/ndWE3k/Bki3" id="d21861250e108" target="xrefwindow">1</a> The causes are well known: symptom- and organ-based <b>disease definitions</b>, <a data-untrusted="" href="https://paperpile.com/c/ndWE3k/CEzE+otyd" id="d21861250e114" target="xrefwindow">2,3</a> animal models with poor predictive validity, <a data-untrusted="" href="https://paperpile.com/c/ndWE3k/ay82+pbYd" id="d21861250e117" target="xrefwindow">4,5</a> the scarcity of affordable <b>investigator-initiated trials</b>, <a data-untrusted="" href="https://paperpile.com/c/ndWE3k/MHZU+gQFs+OmRP" id="d21861250e124" target="xrefwindow">6–8</a> and a <b>reproducibility</b> crisis in biomedical research. Together, these factors create the “v <b>alley of death</b>” between basic discoveries and clinical benefit. <a data-untrusted="" href="https://paperpile.com/c/ndWE3k/2tnU" id="d21861250e133" target="xrefwindow">9</a> <p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d21861250e136"> <b>REPO4EU</b> is a Horizon Europe flagship that addresses this crisis by building the first open, pan-European platform for mechanism-based disease re-definition and pairs it—for rapid and safe application—with drug repurposing. At its core lies a multi-agent system powered by applied network medicine <a data-untrusted="" href="https://paperpile.com/c/ndWE3k/RDLA" id="d21861250e141" target="xrefwindow">10</a>, AI <a data-untrusted="" href="https://paperpile.com/c/ndWE3k/DIHS" id="d21861250e144" target="xrefwindow">11</a>, and mechanistic disease modules <a data-untrusted="" href="https://paperpile.com/c/ndWE3k/TcQR+ALqz+kq2q" id="d21861250e147" target="xrefwindow">12–14</a>—small, reversible protein–protein interaction dysfunctions that represent the true causal units of disease. This framework allows patient stratification by mechanism, the rational combination of approved drugs, <a data-untrusted="" href="https://paperpile.com/c/ndWE3k/0DoN" id="d21861250e150" target="xrefwindow">15</a> and adaptive Phase IIa/b proof-of-concept trials that are lean, low-cost, and curative rather than symptomatic. <p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d21861250e153">The <b>platform</b> already integrates: <div xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="list"> <a class="named-anchor" id="d21861250e158"> <!-- named anchor --> </a> <ul> <li id="d21861250e159"> <div class="so-custom-list-content so-ol"> <p class="first" dir="auto" id="d21861250e160">Computational tools (Drugst.One DREAM, AI pipelines for module discovery and prioritisation); </div> </li> <li id="d21861250e162"> <div class="so-custom-list-content so-ol"> <p class="first" dir="auto" id="d21861250e163">Preclinical validation in patient-derived cells and organoids, plus genetic disease model phenotyping via INFRAFRONTIER; <a data-untrusted="" href="https://paperpile.com/c/ndWE3k/TcQR+tmj3+4uBm+qWTt+BthX+Hbmv" id="d21861250e165" target="xrefwindow">12,16–20</a> </div> </li> <li id="d21861250e168"> <div class="so-custom-list-content so-ol"> <p class="first" dir="auto" id="d21861250e169">Companion diagnostics linked to BBMRI biobanks; </div> </li> <li id="d21861250e171"> <div class="so-custom-list-content so-ol"> <p class="first" dir="auto" id="d21861250e172">Investigator-initiated trial templates (based on REPO-HFPEF, REPO-STROKE, and CIPER), atrial-site database,and new pilot trials(REPO-HYPER, REPO-DIPG, REPO-THYROID). </div> </li> </ul> </div><p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d21861250e174">The next step is <b>REPOSYSTEM</b>, a pan-European Research Infrastructure now in preparation to ensure sustainability and scale. REPOSYSTEM will provide a sustainable operations hub—the Brandenburg Institute for Systems Medicine—and integrate seamlessly with existing infrastructures: <div xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="list"> <a class="named-anchor" id="d21861250e179"> <!-- named anchor --> </a> <ul> <li id="d21861250e180"> <div class="so-custom-list-content so-ol"> <p class="first" dir="auto" id="d21861250e181"> <b>INFRAFRONTIER</b> for mechanistic validation in genetic disease models (cellular and animal); </div> </li> <li id="d21861250e186"> <div class="so-custom-list-content so-ol"> <p class="first" dir="auto" id="d21861250e187"> <b>BBMRI-ERIC</b> for access to biobanks and diagnostic pipelines; </div> </li> <li id="d21861250e192"> <div class="so-custom-list-content so-ol"> <p class="first" dir="auto" id="d21861250e193"> <b>ELIXIR</b> for data standards, FAIRification, and large-scale integration of omics and clinical datasets. </div> </li> </ul> </div><p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d21861250e198">This synergy establishes the missing link in the <b>European Research Area</b>: a human-centric precision medicine-enabling ecosystem that moves beyond descriptive, hypothesis-driven “translational medicine” and—in combination with drug repurposing— instead implements a reproducible, mechanistic, and scalable pathway from discovery to rapid cure. <p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d21861250e203">REPO4EU demonstrates feasibility and initiates a paradigm shift in medicine. 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