Thematic Priority
Life sciences, genomics and biotechnology for health

Integrated Project
RNA Interference Technology as Human Therapeutic Tool

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Project summary

The RIGHT project aims at exploiting the vast potential of RNA interference (RNAi) for human therapy, based on an advanced understanding of the underlying mechanisms. Rational and selective approaches will be taken to generate efficient RNAi reagents, and strategies will be developed for efficient delivery to cells and tissues of diseased organisms.

RIGHT combines the strengths of 5 synergistic competence domains to reach this ambitious goal and overcome key technological barriers such as undesired interferon response and insufficient delivery, stability and targeting of RNAi to the appropriate cells.

1. The understanding of the molecular processes associated with RNAi and microRNA will be improved as a basis for the development of molecular strategies and tools enabling the successful application of RNAi for human therapy.

2. Improved inhibitors including RNAi mimics and potent delivery reagents will be chemically synthesized and extensively tested in cell culture and living organisms in order to increase sensitivity, specificity and cost-effectiveness and reduce side effects.

3. Potent viral or non-viral RNAi vectors will be generated and their features evaluated in relation to their chemical counterparts.

4. For the development of a drug, synthetic or genetic RNAi reagents will be assessed with pharmacokinetic methods, and extensive phenotyping of treated animals will be performed.

5. Selected disease models will be used for the paradigmatic assessment of RNAi as a therapeutic tool to generate RNAi leads for clinical tests.

The RIGHT partnership of leading research institutions and biotech SMEs will deliver tools such as new enabling technologies, chemically synthesized and genetically generated inhibitors with efficient delivery properties. Within 4 years, the potential of RNAi to diagnose and successfully treat severe unvanquished diseases will be demonstrated and proof of principle for the value of RNAi as a therapeutic tool in living organisms will be provided.

Project objectives

The RIGHT project aims at exploiting and further developing the high potential of RNA interference in order to provide effective therapeutic tools for the treatment of important diseases, such as cancer, degenerative diseases and infections. To achieve this ambitious goal, an integrated, multidisciplinary action is required including basic research and development, chemical and genetic approaches, as well as cell biology and pre-clinical assessment.


The enormous potential of RNA interference (RNAi) has only recently begun to be discovered. RNAi not only is a most efficient tool for functional genomics, but it has been demonstrated to be effective for therapeutic approaches in living mammalian organisms. Thus, RNAi has a ubiquitous potential for the treatment of diseases resulting from the dysfunction of gene expression or regulation, opening up completely new avenues of approaches for the therapy of major human diseases (see Nature 425, 10-12, 2003).

For many severe unvanquished diseases, such as cancer or HIV infection, the main research orientations currently rely on chemical drug development, usually based on an empirical "trial and error" approach. Vaccinology, a key for treatment and prevention of selected diseases, on the other hand, did not reach the general applicability necessary to defeat the majority of human diseases.

RNAi allows now for an entirely novel therapeutic approach with an immense potential for effective human therapies. This approach is (i) extremely versatile and flexible thanks to a predictable drug-target relation, (ii) highly effective and sensitive due to its targeting at an early gene function level (mRNA), and (iii) associated with a minimum of toxic and other side effects due to its sequence specificity at least in theory.

Based on the knowledge of specific gene sequences playing their roles in disease, RNAi molecules can be generated for down-regulating the expression of distinct dysfunctional genes thus enabling a rational, targeted therapy. As compared to current therapy strategies, RNAi prevails by its effectiveness, flexibility, versatility and predictability, with regard to both target assessment and immediate therapeutic application. The availability of RNA based tools would hence impact dramatically the efficiency and development speed of new therapies for severe diseases caused by gene malfunctions such as cancer, or viral diseases, in particular where they are triggered by rapidly mutating viruses such as HIV.

Amongst the variety of previously studied RNA technologies, RNAi has emerged as the most promising and powerful tool for human therapy. Accordingly, the technology of RNAi is a rapidly evolving research area. RNAi is a natural phenomenon which has only recently been exploited as a technology to down-regulate gene functions in higher eukaryotes (mammals). It has been first discovered about 5 years ago in worms where it was subsequently used to knock-down gene function. Only in 2001 the technology could be further elaborated for the use in mammals. Since then, RNAi was not only shown to be effective in cultured cells but also in living animals.

Although European researchers have made substantial contributions to the early development of this technology, Europe is currently lagging behind the US which are heavily investing in RNAi research programmes. Whilst US research even focuses on costly high throughput analyses, Europe should seize the opportunity of enforcing its leadership in further developing RNAi for the use in advanced health applications and therewith contribute to address important European objectives: health care progress regarding efficiency and cost of treatments and strengthened position of European research and biotechnology industry.

Today's applications of the RNAi technology mainly concern the assessment of gene functions in individual limited settings or on larger screens for the identification of relevant targets and functional gene sequences. However, the complex requirements of therapeutic applications, i.e. sufficient delivery as well as stability, targeting and pharmacokinetic behaviour, cannot be met at the present time. Addressing and overcoming these constraints would mean to develop RNAi to the stage of a most effective therapeutic tool. This would enable treatments against many acute and persistent diseases including cancer and other genetic dysfunctions, as well as severe infections.


In the long term, the RIGHT consortium aims at bringing RNAi to a stage where it can be generally applied for treatment of human diseases via the modulation of gene expression.

The objective of RIGHT is to contribute to this aim by generating effective RNA inhibitors and developing suitable delivery strategies that have proven useful in appropriate disease models. This ambitious goal cannot solely be achieved by a single research discipline, but rather requires a highly integrated multidisciplinary effort and the synergistic interaction of specific competence domains.

The RIGHT consortium has formulated a complete technology development plan that, by combining expertise in various areas of basic and applied research, can lead to the improvement of the RNAi technology in disease model systems and, ultimately, to clinical applications. The stepwise progression of technical development here envisaged is summarized as follows: Starting from the basic knowledge of the RNAi mechanism and its principle technological application, RNAi inhibitors need to be synthesised via two complementary routes, i.e. by chemical and genetic means.

Optimised inhibitors need to be delivered to cells and specific organs, and their pharmacokinetic properties need to be investigated in vitro and in vivo. The use of cell biology and disease models will then allow addressing their function and effectiveness for the treatment of representative diseases.

RIGHT will place an emphasis to overcome still existing hurdles to achieve general applicability and improve delivery of RNAi in living animals, and resolve current issues on the potential side effects of siRNA such as interferon response and other non-specific phenomena.

The targeted developments in each of the RIGHT competence domains will be:

Competence Domain 1: RNAi and miRNA: Molecular mechanisms and technologies

In order to successfully apply RNAi for therapy it is necessary to optimise its proficiency on the basis of an improved understanding of the molecular processes associated with RNAi and miRNA, and to develop molecular strategies and tools which enable appropriate therapeutic approaches.

Competence Domain 2: Chemical tools

Development and exploitation of chemical synthesis of improved RNAi inhibitors, including RNAi mimics and their delivery agents, for the use in living organisms is necessary to allow cost-effective and efficient treatment. The use of effective chemically synthesized inhibitors represents one arm of therapeutic RNAi.

Competence Domain 3: Genetic tools

The generation of appropriate genetic vectors for the in vivo synthesis of shRNA is a crucial second approach for the therapeutic delivery of RNAi. A variety of viral or non-viral delivery systems will be generated and tested for their use in therapeutic settings.

Competence Domain 4: Pharmacokinetics

Both chemical and genetic inhibitors need to be assessed for the functionality and specificity in living animals. This requires the generation of appropriate animal models and appropriate pharmacokinetic analysis.

Competence Domain 5: Cell biology and disease models

In order to assess the suitability of RNAi as a therapeutic tool several disease models need to be used as model systems. This is important in order to (i) maximise the chances of success via the diversity of approaches, (ii) learn from the experience in different areas and (iii) gain synergy via integration of different expertise in different experimental systems. These studies will give rise to lead RNAi inhibitors for the treatment of human diseases, such as infectious diseases, cancer and other diseases caused by genetic malfunctions.

The development of a therapy based on RNAi will have different phases:
During the duration of 4 years of the RIGHT project the main research and development activities will be covered and the constructs will be evaluated in vitro and in living animals.Once the main research and development results are available and stabilised, a second validation phase has to start in a clinical environment. Clinical test activities will be performed after completion of the preclinical tests and rely on resources provided by industrial partners outside the scope of this project.

Results and evaluation

Several disease models have been chosen which have been rigorously assessed with regard to their suitability for therapeutic use of RNAi in humans. The RIGHT project will deliver first generation RNAi inhibitors for the initial testing in human patients.

To achieve this goal, the consortium will generate a better understanding of RNAi and miRNA structure and function to evaluate the potential of new therapeutic strategies. It will develop new enabling technologies for the identification of effective RNAi constructs and generate a variety of both chemical and genetically (viral and non-viral) driven RNAi reagents. The RNAi reagents will be optimised with respect to improved effectiveness, optimised targeting specificity, low toxicity and improved delivery for tissue-specific release of compounds.

RIGHT will provide proof of principle for the use of RNAi as a novel therapeutic tool to combat infectious and intrinsic genetic diseases and will develop a pipeline of tools aiming at silencing specific cellular genes (involved either in the pathogenesis of the genetic disease or in the infection process), or genes expressed by the infectious agent. A three-level strategy will be used to demonstrate the efficacy of the RNAi approach:

Level 1:  RNAi silencing of cellular or viral genes and proof of principle for the technology in established cell lines.
Level 2:  Demonstration of the efficacy of the treatment in vitro on cells isolated from patients (collaborations with various clinical groups).
Level 3: Experimentation on animal model systems to demonstrate the efficacy of the RNAi reagents (chemically and virally delivered) and its potency in blocking the pathogenic or the infectious process in vivo.

List of participants

Max Planck Institute for Infection Biology,  Prof. Dr. Thomas F. Meyer
University of Aarhus, Prof. Jørgen Kjems
VTT Technical Research Centre of Finland, Prof. Olli Kallioniemi
University of Southern Denmark, Prof. Jesper Wengel
University of Uppsala, Prof. Jyoti Chattopadhyaya
Centre National de la Recherche Scientifique, Institut André Lwoff, Dr. Annick Harel-Bellan
Institut Gustave Roussy, Dr. Guido Kroemer
University of Torino, Prof. Carola Ponzetto
Max Planck Institute of Molecular Cell Biology and Genetics, Prof. Marino Zerial
BioXtal/Regulon, Dr. Kenneth Lundstrom
Childrens Hospital, LMU, Dr. V. Haunersches
Munich, Prof. Arndt Borkhardt
German Cancer Research Center, Prof. Dr. Volker Schirrmacher
Johann Wolfgang Goethe-Universität, Prof. Joachim Engels
Katholieke Universiteit Leuven, Prof. Piet Herdewijn
Fondazione Centro San Raffaele del Monte Tabor, Prof. Luigi Naldini
Oxford BioMedica Plc, Dr. Pippa Radcliffe
Polish Academy of Sciences, Laboratory of Cancer Genetics, Prof. Wlodzimierz Krzyzosiak
Laboratory of Bioinformatics, Prof. Jacek Blazewicz
RiNA GmbH, Dr. Martina Rimmele
University of Rome "La Sapienza", Prof. Irene Bozzoni
Institut Clinique de la Souris (ICS), Prof. Johan Auwerx
Biomedical Sciences Research Center "Al. Fleming", Dr. George Mosialos
PolyPlus-transfection SA, Dr. Patrick Erbacher