Over 30 million people in the US suffer from genetic diseases or cancers caused by mutations of which ~15% disrupt the regulation of splicing. Alternative splicing (AS) errors have been reported in literature to drive 370 genetic diseases out of ~800 described to date. In addition, due to the recent success of FDA-approved splicing modulators like Nusinersen, along with fascinating pre- clinical results underlining the importance of AS as therapeutic targets; splicing research has become of major interest to pharmaceutical companies. Envisagenics is developing SpliceCoreTM, an innovative cloud-based software platform using biomedical big data for AS analysis to discover new therapies and biomarkers for complex diseases. Our breakthrough platform combines algorithms and databases developed and experimentally validated at Cold Spring Harbor Laboratory (CSHL): SpliceTrapTM, for the detection of splicing activity using RNA-seq data; SpliceDuoTM, for the identification of significant splicing variation across biological samples; SpliceImpact2TM, for the prioritization of biologically relevant AS variants with therapeutic potential; and TXdbTM, a splicing isoform database that connects client?s proprietary data to public repositories such as the Cancer Genome Atlas (TCGA). Thanks to the Phase I award SpliceCore was adapted as a cloud-based software, accelerating scalability and adaptation to the fast- evolving market of biomedical Big Data. We now have deployed SpliceCore?s back-end on three cloud-service providers, increased its overall run-time by a factor of 12, developed tools to discover disease-specific AS isoforms, finalized and tested a machine-learning algorithm to predict the biological impact of AS, and experimentally validated some of our new predictions with a success rate of 82.5%. The goal for Phase II is to accelerate client acquisition through the development of user-interactive applications informed from client?s feedback by substantially expanding the platform?s knowledgebase and predictive functions with novel AS isoforms extracted from ~37,000 public datasets. Thus, a new version of SpliceCore will be developed to predict regulatory interactions between RNA-binding proteins and their RNA targets to assist in the interpretation of aberrant splicing factors through a collaboration with world renowned HHMI Professor Dr. Tom Tuschl from Rockefeller University and developer of Nusinersen, Professor Dr. Adrian Krainer from CSHL. Envisagenics is targeting the global bioinformatics market valued at $4 billion in 2014 with a CAGR of over 21%. SpliceCore could capture ~10% of the market, identify novel drug targets, and design RNA therapeutics from aberrant splicing events prevalent in cancer and a multitude of genetic diseases while increasing the efficiency of R&D in biopharma.
In this SBIR Phase II, Envisagenics will advance the development of SpliceCoreTM, a cloud-based software platform for the discovery of drug-targets and biomarkers using biomedical big data. Therapeutic screens are increasingly focusing on Alternative Splicing (AS), a biological process that regulates gene-product structure and function. Strikingly, 50% of genetic diseases described in literature can be triggered by AS errors. The recent FDA approval of RNA-therapeutic compounds to correct AS errors, combined with increasingly available big datasets and groundbreaking cloud-computing provide a unique opportunity for computerized discovery of AS therapeutics. Envisagenics? technology will help biomedical researchers to translate basic science into new therapeutic products for cancer and genetic diseases. By the completion of this project, we will deploy a user-friendly, secured and scalable SpliceCore software, with new functionalities ready for integration into biopharmaceutical Research & Development workflows.