Drug repurposing and discovery multidisciplinary training network

Project Information

DRUGtrain

Grant agreement ID: 955879

DOI

10.3030/955879

Project closed

EC signature date 16 July 2020

Start date 1 January 2021

End date 31 December 2024

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 2 394 816,84

EU contribution

€ 2 394 816,84

Coordinated by

ACADEMISCH ZIEKENHUIS LEIDEN
Netherlands

Periodic Reporting for period 2 - DRUGtrain (Drug repurposing and discovery multidisciplinary training network)

Reporting period: 2023-01-01 to 2024-12-31

Summary of the context and overall objectives of the project

Drug repurposing (or repositioning) is the application of previously identified drugs or compounds to treat new indications. In general, repurposing forms an accelerated approach for finding new therapies. Repurposing may comprise new therapeutic use for marketed drugs, for drug candidates that are currently in clinical development, or for drugs that have been abandoned/failed for a particular indication due to efficacy problems. Other aspects include the development of different formulations or drug delivery systems for an approved drug, or establishing new combinations of individual drugs.
Identifying compounds for repurposing requires a broad variety of approaches including mining of existing scientific databases, in silico bio- and cheminformatics strategies to link drug to disease, in vitro (high-throughput) drug screenings, in vivo experiments, toxicity and pharmacokinetic/dynamic studies. Formulation in drug delivery systems may be used to reduce adverse events.

The International Rare Diseases Research Consortium (IRDiRC) set as main goal for 2027 that 1000 new therapies for rare diseases will be approved. One of the levers to achieve this goal includes the repurposing of already existing and marketed drugs. An example suitable for repurposing is Autosomal Dominant Polycystic Kidney Disease (ADPKD). ADPKD is an inherited kidney disorder with a prevalence of 3:10.000 characterised by the development of renal cysts, slowly progressing towards end-stage renal disease at the age of 50-60 years. Current therapies are directed towards limiting morbidity and mortality from complications of ADPKD . Therefore, there is a need for drugs that specifically target the formation and growth of cysts to slow down or halt disease progression. Given the complexity of altered signalling in cyst-lining epithelium, a phenotypic testing approach to repurpose drugs that are on the market for other diseases is the most logical approach to swiftly bring new therapies to the clinic.

In this context, DRUGtrain (DRUG repurposing and discovery multidisciplinary training network) offers a timely paradigm for multidisciplinary research, ideal for improving drug repurposing and discovery strategies of compounds, with Autosomal dominant polycystic kidney disease (ADPKD) as example. ADPKD is one of the most common causes of renal failure. Currently, only the vasopressin V2 receptor antagonist tolvaptan (Jinarc®) is approved as treatment in a number of countries, to slow disease progression in patients. Unfortunately, this drug is accompanied by side effects, including polyuria and liver toxicity, restricting its use to a subset of ADPKD patients. The difficulty in identifying drugs for ADPKD treatment can be partially attributed to the lack of understanding of the functions of the PKD1- and PKD2-proteins, and on how inactivation of these two trans-membrane proteins leads to cyst development. The identification of more and better drugs for ADPKD requires a multidisciplinary and macro-level approach. Therefore, repositioning of drugs that are on the market for other diseases is probably the fastest approach to bring new therapies to the clinic. ADPKD is a good paradigm for the development of new drugs combining various approaches, including repurposing and drug discovery.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

In DRUGtrain, 6 academic, 4 private sector and 1 patient organisation from 7 European countries are joining forces to intensify network activities between academia, industry and a patient organisation.
9 young researchers from all over the world will be trained through state-of-the-art research projects, intra- and intersectoral secondments as well as local and network-wide training. This will prepare them to: a) Address future challenges of drug repurposing and drug development and find innovative solutions; b) Think differently, taking advantage of network multidisciplinary expertise and intercultural diversity; and c) Move from drug screenings and in silico analyses to molecular mechanisms and in vitro/in vivo preclinical testing, thereby transforming knowledge and ideas into potential treatment.

The research objectives of DRUGtrain are:
1. To identify potential drug targets and drug candidates for repurposing using innovative bio/cheminformatics approaches.
2. To perform drug testing/drug screenings in advanced in vitro and in vivo models, ultimately leading to testing of new treatment strategies.
3. To clarify drug mechanisms and to identify and reduce adverse events using state-of-the-art technologies from in silico and wet lab methodologies.

Final results are confidential, not to be made public yet.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

DRUGtrain will train and educate young researchers in the area of drug repurposing and discovery, with the ambition to create a new generation of creative, entrepreneurial and innovative leaders, as there is a continuous need for highly qualified personnel in the field of multidisciplinary pharmaco/medical research.

The network is combining practical and theoretical aspects of drug repurposing and drug development research from knowledge mining of databases, in silico bioinformatics strategies and high-throughput drug screenings to pharmacodynamics, drug toxicity, drug delivery and (pre)clinical studies to molecular pathway elucidation. The use of this multi-disciplinary knowledge enables to address relevant research questions in drug repurposing/discovery and the translation to a disease (e.g. polycystic kidney disease).

Repurposing of already existing/marketed drugs, that have already gone through toxicology, accelerate clinical implementation. A phenotypic testing approach to repurpose drugs that are on the market, is a first approach to swiftly bring new therapies to the clinic. Other (rare) diseases and acute diseases will also benefit from the drug repurposing approach.

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