By utilizing short, non-coding oligonucleotides to specifically target and up-regulate therapeutic genes, RNAa offers the ability to modulate previously undruggable targets. It represents one of the few available technologies that can be translated into the clinic to treat diseases corrected by stimulating the expression of silenced therapeutic genes.
RNAa uses short, non-coding oligonucleotides to target and ‘turn up’ transcription of an endogenous gene leading to restoration of endogenous protein function. RNAa offers unprecedented advantages:
Expanded disease spaces by targeting nearly any beneficial gene including In theory, any gene could be targeted by RNAa including disease-beneficial genes, instead of disease-causing genes, offering new hope for many diseases undruggable by conventional approaches such as those caused by epigenetic silencing or downregulation of target gene expression.
Faithful restoration of natural gene function.
Persistent expression of target gene.
Pre-established medicinal chemistries and drug delivery platforms developed for gene silencing techniques are readily implemented accelerating in-house drug development.
Our in-house expedited and cost-saving screening process rapidly identifies numerous activating oligonucleotides for targeted genes of choice. Each represents a candidate API.
Additional tweaks improve medicinal properties and maximize transcriptional output for selected lead candidates.
Vector-based systems (e.g., viral, plasmid, etc.) have been the traditional approach to gene therapy. All vector-based systems require large artificial expression constructs that typically do not resemble natural genes. They contain many foreign sequences from viruses or other sources that drive production of modified genes present in the expression construct. Furthermore, vector-based systems (e.g. viral gene therapies) have been linked to major health problems including secondary malignancies and even death.
On the other hand, small oligonucleotides do not encode for any exogenous genes. Rather, their activity is largely based on principles of complementary base pairing. Over the past decade, oligonucleotides have emerged as an important new class of therapeutic molecules. However, nearly all oligonucleotide-based drugs exhibit only an inhibitory mechanism of action in that they silence gene expression.
Our platform is based on RNAa technology that utilizes short, non-coding oligonucleotides to specifically target and up-regulate therapeutic genes rather than silence them. As a consequence, our pharmaceutical development process benefits from the use of already established medicinal chemistry and drug delivery platforms accelerating drug development. In addition, RNAa has the unique ability to enhance transcription of a targeted gene offering for a more natural alternative to gene therapies, as well as the ability to restore expression of silenced genes previously thought of as undruggable targets.
R. J. Britten and E. H. Davidson proposed the gene-battery model in which activator RNA induces gene expression in the nucleus by binding to gene promoter (Britten and Davidson. Science 1969)
RNAa discovered – Li et al. first demonstrated RNAa in human cells and coined the term (Li et al. PNAS 2006)
Janowski et al. reported RNAa in human cells (Janowski et al. Nature Chem Biol 2007)
Place et al. reported RNAa induced by miRNA (Place et al. PNAS 2008)
First in vivo study of RNAa – Turunen et al tested RNAa's therapeutic use in vivo and proposed the concept of epigenetherapy (Turunen et al. Circ Res 2009)
Huang et al. reported conservation of RNAa in mammalian cells (Huang et al. PLoS One 2010)
Huang et al. reported miRNA-induced RNAa in physiological context (Huang et al. NAR 2012)
Long-Cheng Li Lab at UCSF and Alnylam Pharmaceuticals jointly published two preclinical studies of treating prostate and bladder cancer using saRNA (Place et al. Mol Ther-Nucleic Acids 2012; Kang et al. Cancer Res 2013)
Seth et al. reported RNAa in C. elegans (Seth et al. Dev Cell 2013)
Turner et al reported miRNA-mediated RNAa in C. elegans (Turner et al. Cell Cycle 2014)
UK-based MiNA Therapeutics licensed rights of RNAa-related intellectual property created in Long-Cheng Li Lab at UCSF (read the news)
The first clinical trial of RNAa-based therapy — The first-ever saRNA drug developed by MiNA Therapeutics entered clinical trial (NIH clinical trial number: NCT02716012)
Portnoy et al. reported the identification of the RITA (RNA-induced transcriptional activation) complex (Portnoy et al. Cell Res 2016); Meng et al. published new understanding of RNAa mechanism (Meng et al. Nucleic Acid Res 2016)
Ractigen uses a powerful, high-throughput discovery engine to rapidly identify numerous activating oligonucleotides for any single target gene. In combination, we implement a highly refined bioinformatics search engine to identify sequences susceptible to gene activation. Neither process relies on knowledge or function of non-coding RNA transcripts or chromatin structure to identify successful candidates. We are actively generating thousands of oligonucleotides capable of activating an ever-growing list of therapeutic genes to expand our IP estate and actively pushing our lead compound to Phase I clinical trials.
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