Nucleic Acid Drug Discovery
Marina Biotech’s versatile drug discovery platform allows us to pursue the most appropriate nucleic acid-based therapeutic approach necessary to effectively modulate targets for a specific disease indication. Many of these targets are considered undruggable by traditional methodologies. Such nucleic acid-based therapeutics and their respective mechanism of action include:
- siRNAs directed at RNA interference
- MicroRNA mimics directed at microRNA replacement
- Antagomirs directed at microRNA inhibition
- Antisense compounds directed at mRNA translational inhibition, steric blocking or exon skipping
Each of these approaches, i.e. siRNA, miRNA mimic, antagomir and antisense oligonucleotide, has certain advantages and disadvantages. We can utilize our diverse capabilities to screen across multiple mechanisms of action to identify the most effective therapeutic. We believe this capability is unique in the development of compounds to treat rare and orphan diseases.
Proprietary Chemistry and Delivery Technologies for Development of Nucleic Acid-based Therapeutics
Unique and proprietary chemistries are required to synthesize stable, highly active single and double-stranded oligonucleotides. Marina Biotech’s chemistries include:
- Unlocked Nucleobase Monomers (UNA) – UNA are acyclic monomers that are distinguishable from RNA nucleotides because they do not contain a ribose sugar ring. This important difference instructure creates a unique and proprietary monomer and provides us the freedom-to-operate necessary to develop double-stranded oligomers that can replace siRNAs and other constructs.
- Conformationally Restricted Nucleotides – CRN are novel nucleotide-like structures in which the flexible ribose sugar is locked into a rigid conformation by a chemical linker. CRNs can be used to create unique single-stranded anti-sense oligonucleotides and antagomirs with new properties.
The need for efficient and cell-specific delivery of oligonucleotides is critical for the successful development of nucleic acid therapeutics.
Marina Biotech has both internally developed and acquired numerous diverse delivery technologies in order to maximize the therapeutic opportunity of nucleic acid mechanisms of action. We undertake a SMARTICLES® approach to delivering nucleic acid therapeutics developing the best and “smartest” vehicles for the most efficient and effective delivery of RNA and DNA cargoes..
We base our approach on novel lipid and novel lipid compositions spanning both cationic and anionic lipid formulations as well as engineered bacteria. This approach allows us to develop intravenous, subcutaneous, local, topical and orally administrated therapeutics directed at various tissue systems. Currently, we are the only company in the sector with two distinct delivery technologies in clinical development (a lipid-based and a bacterial-based system). Furthermore, our lipid-based system is versatile enough to deliver both a single-stranded and double-stranded nucleic acid to both the cell nucleus and the cell cytoplasm, respectively.
We offer potential partners the opportunity to license our proprietary lipid- and bacterial-based delivery formulations or, through a SMARTICLES-type collaboration, develop new proprietary formulations for exclusive ownership. The breadth of our delivery technologies include:
- SMARTICLES – Our SMARTICLES research and development collaborations as well as our SMARTICLES-based technologies revolve around both:
- Amphoteric liposomes composed of unique combinations of lipids having anionic and cationic groups that work together to enable cell uptake, to provide serum stability, and to provide pH-triggered endosomal escape; and
- Di-terminal Amino Acid Lipids (DILA2) which are proprietary molecules composed of unique combinations of head groups and terminal groups on a central amino acid having unique cone angles for formation of small, cargo-carrying liposomes.
- tkRNAi – TransKingdom RNAi (tkRNAi) are non-pathogenic bacteria engineered to produce, deliver and release various therapeutic molecules including interfering RNA mediators, such as short hairpin RNA and microRNA mimics, as well as other therapeutics to targeted tissue.
- Trp Cage Phage Display Library – The Trp Cage library possesses 20 x 10^7 unique peptides in a high copy number phage library that can be utilized to biopan for cell-penetration and cell-targeting peptides.