CliniGene - NoE

Clinigene-NoE: Goals & presentation

European Network for the Advancement of Clinical Gene Transfer and Therapy: EC funded network of excellence fostering interaction of all stakeholders in the field in order to facilitate and help harmonise Ethical, Quality, Safety, Efficacy and Regulatory issues. This NoE prolongs and extends the action of the former Euregenethy1 & 2 networks supported by EC-DG research FP4 & FP5 programmes.

 

What is Clinigene ?

The role of the European Network for the Advancement of Clinical Gene Transfer and Therapy (CLINIGENE) is to mobilise efficiently all interested parties, mostly involving academic research and production centers together with companies, patients' groups and regulatory bodies. Our main goal is to integrate multidisciplinary research in order to decipher the key elements which can lead to improved safety and clinical efficacy of gene transfer / therapy medicinal products, i.e. for clinical applications. Control and test methods may be applied as platforms for particular gene transfer products. Besides quality control, safety is of germane concern since in the event where the treatment would be proven safe, it could be administered early enough in the course of the disease to achieve genuine cure, so that clinical gene transfer may be called therapy.

 

The general objectives of Clinigene-NoE thus are the following:

1. Foster interaction between all stakeholders: regulators, pre-clinical & clinical investigators, scientists, companies (otherwise competitors), patients’ groups, in order to streamline integration of multidisciplinary expertise.
2. Establish quality, safety, efficacy and morally acceptable standards for clinical gene transfer products.
3. Identify the “critical path” to accelerate the transit phase from preclinical to clinical phase by integrating expertise and generating new knowledge.
4. Improve European competitiveness by spreading of excellence and disseminating knowledge.
5. Obtain clinically significant improvement in the treatment of some human diseases by gene therapy.

 

After running 4 years, the NoE achievements are as follows:

The added value of CliniGene:

1. Defragmentation and integration of EU-wide research and facilities: accelerating the pace at which scientific issues are being taken up and eventually solved;
2. Scientific progress and breakthrough: overcoming almost if not all scientific bottlenecks that were initially identified and targeted by the six technology platforms which have extensively interacted instead of working in parallel; For more information, please refer to the Technology Platform section
3. Central to these successes and their acceleration is the flexibility funds internal collaborative and exchange programme (with 66 projects funded to date targeting novelty and involving international collaborations between more than 40 laboratories and companies);
4. Implementation of a reliable and validated vector biosafety platform focussing on the translational and clinical aspects addressing safety and efficiency of current and newly developed systems in vitro and in vivo. This platform is aiming at comprehensiveness so as to not leave out newest developments, developed either inside or outside CliniGene
5. An important ethical, legal and regulatory component which makes CliniGene a germane European Medicines Agency stake-holder with expert advisory potential
6. Facilitation of clinical trials, with as many as 17 ongoing clinical trial and 12 about to begin while the initial target was in the 10 range at most;
7. High-level training and technology transfer to Industry;
8. Integration of the private sector to the EU-effort towards advancement of clinical gene transfer .
9. Quality management together with the creation and broad use of a tailored scientific & strategic management software; data-sharing: In order to be able to integrate its efforts - given the bredth of both the technological approaches and applications encompassed inside CliniGene - a scientific and strategic management software, named Clinisoft, has been developed which is used on a daily basis by both partners and the management team.

The CliniGene outreach

1. CliniGene web-site displaying unique information, currently being reshuffled;
2. Patients'associations: meeting and publication;
3. CliniGene public meeting in April 2011 (Please refer to the appropriate webpage)

 

What are the future prospects of CliniGene

The CliniGene Network of Excellence, funded by the European Commission’s 6th Framework programme, has created both critical mass and momentum towards high quality gene transfer research at the level of basic science and its translation into well-designed clinical trials. Like all EU funded NoEs, it is time-limited, and will finish in its present format mid-2011. However, plans are underway to create a sustainable not-for profit structure that will preserve the expertise that CliniGene has created and master the momentum underpinning gene transfer research and its safe, effective clinical applications. This would result in the eventual formation of a non-profit “European Institute for Clinical Gene and Cell Therapy” to promote good practice and develop standards that will define good manufacturing practice (GMP) in gene transfer research. This Institute could implement and streamline European and international exchange of information and experience, the holding of workshops, seminars, conferences and other events, as well as the setting-up and editing, promotion and distribution of publications in any form, submission of expert advisory opinions, and cooperation with European and international public and non- government organisations. Such an Institute would be well positioned to respond quickly to the changing demands of a rapidly developing area of science. This would provide the opportunity not only to incorporate novel scientific and technical possibilities, but also to create the appropriate ethical, regulatory and public communication frameworks necessary to secure public endorsement and legitimisation for gene transfer research.

 

A special attention has been brought to the field of emerging technologies, translating into new collaborations funded through flexi-funds as a start-up mechanism intended for feasibility studies. In fact, the opportunities for joint applications between two (or more) labs and compete for flexifunds, has resulted in a huge number of high-quality original programmes. Over 66 collaborative projects have now been successfully funded following a stringent review process. The NoE will continue to encourage interaction in the main emerging fields which have been identified. Altogether, with this internal collaborative flexi- funds programme, an emerging vector platform has build up addressing the bottleneck problem of translational gene therapy research towards improved safety/efficacy.

In order to streamline the clinical translation of the most advanced technologies, the Joint Research Programme has developed and concentrates on four main directions:

• Continue the pre-clinical evaluation of new generation of safer and more efficacious gene transfer vectors which have been developed. Besides the NoE would like to include new partners in order to address transposons derived non-viral integrating vectors and compare them to already available technologies

 

• Safety and efficacy improved integrating vectors since predicting or even controlling the fate of transgenes integration is a major priority in the field [Gabriel et al, 2009; Montini et al, 2009; Mödlich et al, 2009; Hacein-Bay et al, 2008; Howe et al, 2008, Ott et al, 2006; Stein et al, 2010). Progress in this regard is likely to pave the way to the treatment of numerous conditions, noticeably accessible by ex-vivo gene-manipulation of stem cells, whether intended at repairing the cell defect like with hemoglobinopathies, Wiskott-Aldrich syndrome or Fanconi's anemia (Cohen-Haguenauer & al, 2006), or with view to enzyme replacement therapy like with adrenoleukodystrophy (Cartier N & al, 2009) or ADA-deficiency (Aiuti & al, 2009).

 

• Improvement of the therapeutic index of viral and non-viral vectors noticeably via direct in vivo administration routes is another key issue in gene therapy related to the immune responses directed at the vector particles, the transduced cells and/or the therapeutic proteins themselves, that can curtail long-term gene expression (Manno et al., 2006). Such an improvement will likely facilitate the clinical implementation of these vectors and expedite First-in man clinical trials. The risk of inadvertent immune responses can be minimised in avoiding vector uptake and gene expression in antigen-presenting cells (Annoni et al, 2009; VandenDriessche et al., 2007, Matsui et al., 2009), including modified administration routes (Toromanoff et al, 2009). This can also be based on targeting of cell-entry (Buchholtz et al, 2009) and tight transcription regulation taking advantage of miRNAs (Brown et al, 2007 and 2009); in this latter case, concertation with the EC- funded collaborative programme PERSIST will be sought. In addition, the NoE would like to attract new partners developing in vivo selected miRNAs libraries, cloned into AAV shuttles.

• A new iPS technology platform (WP4.7) has been created which will be chaired by Marc Peschanski. This WP will mostly be addressing gene transfer technologies towards induction of iPS together with characterisation and differentiation. Besides experimental research and flexi- funded collaborations including regenerative medicine related projects with stem cells expansion and genetic modification, the activity is planned along two main lines:

i. Organisation of a “hands-on” exchange programme in order to allow scientists who are directly involved in the iPS technical activity to visit collectively each others’ laboratories and benefit from each other’s expertise at the bench;

ii. Holding a main EU-based conference: e-CHIP

 

Finally, the paramount issue of vector production and manufacture has translated into a vision for the building of a Pan-European Vector infrastructure (PEVI) the description of which appears under GeneCellPro in the section dedicated to Facilities below. In fact, one key bottleneck of translating innovative technologies from bench-to-bedside is related to the production of the retargeted cell-type specific vectors or alternative serotypes (Cattaneo et al, 2008; Ciron et al, 2009; Duke et al, 2009). As high-titre vector preparation strongly depends on the capsid or envelope, the production efficiency substantially varies in between different vector types and according to the design of the transgene cassette (Funke et al, 2009). The ability to produce high-titer vectors that are capable of achieving increased gene transfer efficiency and expression in the desired target cells while preventing expression in non-target cells and genotoxicity, are measurable outcomes and addresses a current unmet need in the field of gene therapy. The primary focus of PEVI will be to fine-tune engineering in order to maintain the ability to produce improved vectors at high-titers. This is an essential requirement for translating vectors with improved safety features in confronting advanced technologies to the compulsory scale-up phase.

Plan for using and disseminating the Knowledge

The NoE has adopted an integrated approach aiming at a high level education, training and human mobility of post-doctoral scientists, doctors and pharmacists in order to support a European dimension of highly specialised researchers, health professionals and managers with a view to fostering the clinical development process in collaboration with the ESGCT (European Society of Gene & Cell Therapy) with which a robust and mutually rewarding collaboration has been settled. In addition, contacts have been established with other EC-funded Gene Therapy –related research programme in order to streamline novelty and optimise dissemination.

More details:

• Download the Clinigene flyer (2 pages version) here
• Download the CliniGene brochure (8 pages version) here