Project: Gene Inactivation through Chromatin Engineering: An innovative approach to a therapeutic pipeline.
This project has four principal goals:_x000D_1) Identification of specific genomic DNA sequences associated with proven cancer targets._x000D_2) Design and optimisation of an antigene system to silence the aberrant genes_x000D_3) Evaluation of desired and potential off target effects _x000D_4) Preclinical development of an optimised lead therapeutic against a selected target_x000D__x000D_A strong internationally diverse consortium has been assembled to meet these goals bringing expertise in the design and synthesis of antigene therapeutics and diagnostics, and bioinformatics._x000D_The consortium leader, ValiRx PLC, is a UK biotech company with a novel gene knockdown technology platform, GeneICE. Gene Inactivation through Chromatin Engineering, works by selectively targeting specific sequences of DNA in aberrant (diseases associated) genes. The DNA is then collapsed by recruiting a natural gene regulatory enzyme so that it cannot be read and translated into RNA and subsequently proteins. _x000D_This approach to gene inactivation at the DNA level, rather than at the RNA level (such as antisense and RNA interference approaches) is potentially highly efficacious and long lasting with high specificity. The company has a strong IP position and will have optimised aspects of the linking chemistry prior to commencement of this project. Critical aspects to this approach include identification of the target sequence, to avoid modifying non disease associated genes, and design modifications to the triplex forming sequence to optimise binding to the target sequence._x000D_GenoSyst is a Finish bioinformatics company with expertise in advanced data analysis for genomic, transcriptomic and proteomic research and drug development. Proven algorithms and software for functional genomics and proteomics applications have already been used to identify unknown (disease related) gene networks and to predict regulatory/binding sites within genes. Genosyst’s proprietary mathematical solutions, developed to interpret genetic data and further understand human disease will facilitate the discovery new therapeutic targets for the GeneICE technology. Global transcriptomics profiling of the functional effects of the targeted gene silencing will be performed to analyse the epigenetic regulation of gene expression as a result of the GeneICE activity and to probe for non specific effects._x000D__x000D_Pentabase is a Danish Diagnostics company with expertise in the design and synthesis of modified oligonucleotides. It will bring its nucleic acid synthesis expertise to the consortium and synthesise the new GeneICE constructs._x000D__x000D_The primary market for Gene knockdown based therapeutics will initial focus in the oncology sector. The business model will be to license/P clinical development beyond phase Ib. This strategy is supported by the growing appetite for new technologies from large pharma to address dwindling product pipelines and imminent patent losses from blockbuster products. Michael Harris, Executive Editor of BioWorld magazine recently commented that the “imminent reality of gene therapy technologies and drugs” is seen as a key factor in turning bioPing activities between innovative biotech companies and large pharma into “a permanent drug development market core dynamic”. Development of a detailed preclinical data package will allow progression to first in man clinical studies, a major value inflection point, and a critical step towards attracting interest from large Pharma. Several headline deals between big Pharma and companies with gene silencing technologies have taken place over the last few years. Both Roche and Takeda have announced development deals with Alnylam with potential values of $1Bn and Merck and Co. aquired Sirna for $1.1Bn in 2006. Validation of the technology in a specific disease model will open further opportunities for collaborative development in additional “non-core” disease states outside of the oncology field. ValiRx has in-vitro data in several models including Alzheimer’s._x000D__x000D_Earlier opportunities exist for the development of knockdown reagents for use in the life science industry. Gene silencing is a valuable tool for studying effects of specific genes and proteins as well as drug target validation. This market is currently served COly by RNA interference (RNAi) approaches and is expected to exceed $240M by 2012. ValiRx has already initiated discussions with a leading supplier of reagents for the life science community and is carrying out validation work. Improvements to the GeneICE constructs envisaged as part of this programme will support development of this market. Further opportunities exist in the development of knockdown cell lines and animals._x000D__x000D_In-vitro and in-vivo development will be carried out at Imperial Colledge (London) and make use of state of the art imaging facilities whilst preclinical evaluation of the selected lead therapeutic will be carried out by the Spainish company Vivotecnia.
| Acronym | GeneICE (Reference Number: 4838) |
| Duration | 01/06/2009 - 01/06/2012 |
| Project Topic | Silencing genetic anomalies has widespread application in the development of therapeutics. We propose a rational bioinfomatic driven approach to identify potential disease specific genes, design effective gene silencing systems and take a lead system through preclinical testing. |
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Project Results (after finalisation) |
We have successfully manufactured and developed new synthesis routes and quality control procedures of modified oligo nucleotides for clinical testing. We have tested several different chemistries and found strengths and weaknesses of these. The oligo nucleotides have been used for optimization and validation in in vitro and animal studies. The clinical outcome of these studies is not known to us._x000D__x000D_The project summary is: The established cell lines and tumour models have been grown up for testing the various GeneICE II constructs and the equivalent first generation GeneICE constructs for comparative purposes. PentaBase has manufactured sufficient amounts of the GeneICE constructs first and second generation has been completed. This follows on from the reported completion of the new synthetic procedures, and the preliminary in vitro testing has been completed. The wide scale testing and in vivo studies has begun and is in the final completion will occur during 2013 following the full relocation of the primary laboratory and the reestablishment of the animal facilities with the relevant xenograft models at the new location. |
| Network | Eurostars |
| Call | Eurostars Cut-Off 2 |
Project partner
| Number | Name | Role | Country |
|---|---|---|---|
| 3 | GenoSyst | Partner | Finland |
| 3 | Pentabase | Partner | Denmark |
| 3 | ValiRx PLC | Coordinator | United Kingdom |