IP Policy Forum: Intellectual Property Rights (IPR) In Collaborative Drug Development in the EU: Helping a European Public-Private Partnership Deliver - The Need for a Flexible Approach to IPR

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Isolation and characterisation of a locus disrupted in a transgenic mouse mutant exhibiting sex-linked cleft palate

A unique transgenic mouse line displayed the phenotype of sex-linked cleft palate. As no other mouse line expressing this transgene demonstrated a similar phenotype, it is argued that the disorder is due to the disruption of the cellular locus. At the very least this mutation results in redirecting expression of the transgene in a unique fashion, alternatively, a gene(s) at the locus is critical to normal secondary palate development. Therefore 32.8Kb of cellular DNA of the cellular locus disrupted in this mutant has been cloned and characterised. This 32.8Kb of wild type DNA has been characterised at the level of conservation of sequence between species and expression. No potential gene encoding sequences were initially found. Subsequently, using the technique of exon-trapping several exons have been isolated from the wild type locus. When these exons were hybridised to Northern blots of embryonic and post-natal RNAs they revealed a 4.5Kb, a 0.8Kb and a 0.5Kb transcript, each expressed in the head and body during embryonic development. The 0.8Kb message was shown to be expressed post-natally in a tissue specific manner. Five individual exons have been isolated and sequenced. They range in size from 81bp to 446bp. One exon (exon p50, 446bp in size) was found to be composed of repetitive sequence but it did not contain an open reading frame (ORF) that spanned the exon. The other four exons (exon p51, p52, p56 and p57) were found to contain an ORF that spanned the exon. Database analysis with the sequence of the exons revealed that two of the exons (exon p56 and exon p57) showed no homology to nucleotide sequences in databases, and another (exon p52) exhibited a high level of similarity to CaM kinase II at both the nucleotide and amino acid level. Using RT-PCR, two of the exons (exon p52 and exon p57) were shown to be expressed at the RNA level during development in the wild type mouse. Exon p52 and exon p57 were also found to be spliced together. Cloning and sequencing of this exon p52-exon p57 RT-PCR product revealed that this RT-PCR product contained a single ORF that spanned the sequence of both exons spliced together. The amino acid sequence of the putative peptide encoded by this ORF revealed 47% identity to the calmodulin-binding domain of CaM kinase II. Analysis of this RT-PCR product in RNA derived from transgenically positive spleen revealed that several products are present which are absent in the wild type. These novel products hybridise with exon p52 and exon p57 sequences as well as the transgene sequences, indicating that the splicing of the RT-PCR product is aberrant in the transgenic mutant. A human form of heritable sex-linked cleft palate has been well documented. The phenotypes observed in the transgenic mutant and the cloning of the gene from the wild type locus may lead to the identification of the human gene involved in heritable sex-linked cleft palate, as well as provide a model for the analysis of the disorder

The European lead factory—an experiment in collaborative drug discovery

The European Lead Factory (ELF) is a unique collaborative public–private partnership aiming to deliver innovative drug discovery starting points and improving the value generated by ultra-High Throughput Screening (uHTS) approaches. Composed of a unique compound collection derived from private pharmaceutical company collections and complemented with new chemistries from a unique public collection, it offers a unique uHTS platform accessible to both private companies and publicly funded researchers. One of the key challenges in setting up ELF has been to balance access to screening results with protecting the value of compounds in the collection. Through an ‘honest data broker’ data management platform and a royalty reward scheme based on achieved milestones, ELF has been able to overcome these challenges. Set up in 2013, it has already accepted 42 targets for screening, submitted by publicly funded researchers, and generated 12 Qualified Hit Lists. In addition, 55,000 new library compounds have been generated by the public partners and added to the 320,000 compounds made available by the companies. Although it faced many challenges in becoming operational, this unique experiment in collaboration is already generating exciting results that will hopefully, eventually lead to better medicines and tools to advance our biological knowledge, and should act as a template for future approaches in the area

Assessing the Safety of Stem Cell Therapeutics

Unprecedented developments in stem cell research herald a new era of hope and expectation for novel therapies. However, they also present a major challenge for regulators since safety assessment criteria, designed for conventional agents, are largely inappropriate for cell-based therapies. This article aims to set out the safety issues pertaining to novel stem cell-derived treatments, to identify knowledge gaps that require further research, and to suggest a roadmap for developing safety assessment criteria. It is essential that regulators, pharmaceutical providers, and safety scientists work together to frame new safety guidelines, based on “acceptable risk,” so that patients are adequately protected but the safety “bar” is not set so high that exciting new treatments are lost

Murine CASK Is disrupted in a sex-linked cleft palate mouse mutant

A transgenic mouse insertional mutant displayed the phenotype of altered cranial morphology with sex-linked cleft palate. We have cloned the disrupted genomic X-linked locus and report the identification of the mCASK gene. The gene is transcribed to produce two messages of 4.5 and 9.5 kb expressed during development and in adult tissues, particularly the brain. We describe the isolation of two differentially spliced mouse cDNAs from the locus (mCASK-A and mCASK-B). The mCASK-B cDNA probably represents the full-length product of the 4.5-kb transcript. The identical N-termini of the predicted encoded proteins (mCASK-A and -B) are highly homologous to Ca2+/calmodulin-dependent protein kinase II, while the deduced C-terminus of mCASK-B is highly homologous to a family of multidomain proteins containing a guanylate kinase motif, the MAGUK proteins. mCASK-B is a new member of an emerging family of genes in which the encoded proteins combine these domains, termed here, the CAMGUKs, including rat CASK,Caenorhabditis elegans lin-2,andDrosophila caki/camguk.The CAMGUKs are likely to be effectors in signal transduction as regulatory partners of transmembrane molecules, modulated by calcium and nucleotides. The transgene in this mutant mouse line integrated into an intron that bisects the encoded calmodulin-binding domain, a potentially important regulatory domain of the predicted protein, generating hybrid transcripts

Building new models of drug discovery in Europe: The Innovative Medicines Initiative

The discovery and development of a new medicine is time-consuming, risky and expensive. It often takes 10-15 years and an investment of on average >$1 billion for a compound to navigate its way along the drug discovery and development process - and only 8% of drug candidates entering clinical development make it to market and benefiting the patient1,2. To mitigate the risk and investment, but also to increase efficiency by pooling resources, experience and expertise, more and more collaborative partnership/open innovation models of R&D have emerged. Founded by the European Commission (EC) and the European Federation of Pharmaceutical Industries and Associations (EFPIA), one such joint undertaking is the Innovative Medicines Initiative (IMI). IMI supports collaborative research projects and builds networks of industrial and academic experts in order to boost pharmaceutical innovation in Europe. Collaborative approaches such as IMI have traditionally focused on pre-competitive areas. Recently, however, we have seen the emergence of projects focused on more competitive areas of research, particularly early drug discovery and hit and lead optimisation.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Mapping and expression analysis of the human CASK gene

No abstract available

Diet restriction inhibits apoptosis and HMGB1 oxidation and promotes inflammatory cell recruitment during acetaminophen hepatotoxicity (Retraction of Vol 16, Pg 479, 2010)

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s10020-020-00262-

Diet restriction inhibits apoptosis and HMGB1 oxidation and promotes inflammatory cell recruitment during acetaminophen hepatoxicity (Expression of Concern of Vol 16, Pg 479, 2010)

The Editors-in-Chief would like to alert readers that this article [1] is part of an investigation being conducted by the journal following the conclusions of an institutional enquiry at the University of Liverpool with respect to the quantitative mass spectrometry-generated results regarding acetylated and redox-modified HMGB1