Copernicus Therapeutics Inc.
Nucleic Acid Nanoparticles for Treating Human Diseases
Copernicus: Delivering the Promise of Nucleic Acids as Therapeutics Nucleic acid-based therapies are a natural progression from development of genetic engineering in the 70's and the Human Genome Project of the late 90's. These emerging therapies introduce nucleic acids into cells to correct or modify genetic information to restore normal functionality. This technology can also silence aberrant or disease-causing genetic sequences. In each of these cases, nucleic acids intervene at the primary control point for cellular activity, gene expression. Nucleic acid therapeutics potentially offer novel therapies that cannot be addressed using conventional small molecule drugs or proteins. Additionally, these therapies provide a high level of cellular targeting with improved specificity of action, which can lower toxicity risks. A whole new way of treating disease is possible.
As stated by Nobel Prize winner Inder Verma, the major hurdle impeding nucleic acid-based therapies is "delivery, delivery, delivery." Dr. Verma is talking about the ability to safely and efficiently deliver nucleic acids to the cells of interest. Most of the initial attempts at delivery have involved the use of engineered viruses. This was a logical path to follow as Nature had already designed viruses to deliver their own nucleic acid into cells. However, many shortcomings have been associated with the use of engineered viruses, both minor and major (including death and causing cancer). Alternatively, non-viral approaches have been attempted and were often found to be inefficient, especially in non-dividing cells, which include essentially most of the cells of the body. Non-viral systems were also transient in their effects and often included toxicity issues.
Copernicus Therapeutics, Inc. ("CTI") has developed an innovative non-viral approach based on condensing nucleic acids into nanoparticles, which has been found to avoid the many pitfalls associated with both viral and previous non-viral approaches. This CTI technology provides a very attractive alternative to prior delivery systems. The Company's nucleic acid nanotechnology platform is validated in humans with the development of a first-in-class therapeutic product for the treatment of Cystic Fibrosis.
Additionally, CTI's collaborative research supports the development of first-in-class therapies to treat other serious diseases that have few therapeutic options, including diseases causing blindness (macular degeneration, diabetic retinopathy, and retinitis pigmentosa), airborne viral diseases (influenza A, SARS, and avian flu), and diseases of the brain (Parkinson's disease, stroke and Alzheimer's). The Copernicus technology addresses the delivery issue and is poised to deliver the promise of nucleic acids as therapeutics.
Copernicus has solved the problem of efficiently and safely delivering a nucleic acid therapeutic to the nucleus of a cell with a novel and simple technology that does not use viruses. We compact single copies of the long strand of DNA into nanoparticles (NPs) that have a minimum cross-section far smaller than 25 nanometers. The compacting agent could be one or more of a variety of polycations, and a preferred polymer is composed of a chain of normal amino acids, lysine, that is modified with a commonly used drug stabilizer, polyethylene glycol (PEG). This compaction of single molecules of nucleic acid sounds like a simple solution to a complex problem, and we believe it is, for no other candidate non-viral DNA medicine has been successful in efficiently and safely entering the nuclei of non-dividing cells, which represent the bulk of cells in the human body. And it is worth noting that compaction of single molecules of DNA (chromosomes) is a normal process in our cells; it is the central mechanism that allows each of our cells to contain a full copy of condensed DNA chromosomes in our nuclei. In this sense, our technology reproduces a normal biologic mechanism to make DNA an effective drug platform.
Figure 1. Figure 1 illustrates the challenges for nucleic acid delivery and uptake into cells following in vivo transfer. These hurdles include (1) degradation by extracellular nucleases after either local administration into target tissues or systemic injection, (2) efficient entry into the cell, (3) degradation by cytoplasmic nucleases and/or export from the cell, (4) efficient intra-cytoplasmic transport to the nucleus (for DNA vectors), (5) uptake via the nuclear membrane pore, and (6) efficient release of biologically functional nucleic acids. (Adapted from Davis 2007).
By exploiting proprietary methods to produce charge-neutral, polyelectrolyte complexes of condensed nucleic acid nanoparticles, Copernicus Therapeutics believes it has developed a superior nucleic acid delivery system to those based either on viral vectors or on other non-viral based strategies. Regardless of whether the molecule is a DNA or RNA nucleic acid, it is “compacted” using patent protected condensing agents and formulation methods, which physically reduces the size of the nucleic acid molecule. Importantly, Copernicus has issued composition-of-matter claims for nucleic acid nanoparticles that contain polycations and essentially a single molecule of nucleic acid; these claims are broad and disruptive, are independent of the specific formulation method and polycation composition, and provide Copernicus highly protected commercialization rights. Moreover, the resulting compacted nucleic acid is highly stable and protected from enzymatic and chemical degradation. It is stable at refrigerator temperatures for years, and at least 1 year at room temperature. Such nucleic acid nanoparticles are efficiently taken up by cells, including non-dividing cells, and in the case of DNA, is subsequently translated into the desired protein or used as a template to produce ribozymes, siRNA, or miRNA. Other non-viral delivery systems, such as liposomes, micelles, or electroporation, have notably lower efficiency in nucleic acid transfer and often fail to deliver nucleic acids to the nuclei of non-dividing cells. Most of the cells in our bodies are non-dividing, such as the epithelial cells lining the airways that are the target for our CF therapeutic. For the many reasons listed above, effective non-viral gene delivery appears to require nucleic acids to be highly compacted to their minimum possible size; the CTI proprietary formulation uniquely accomplishes this objective.
Mechanism of Action
Initial studies indicate that Copernicus Therapeutics’ compacted DNA is taken into cells by membrane-associated nucleolin. Cell surface nucleolin is found on cells lining the airways of the lung, various cells of the eye including those of the retina, neural cells, certain tumors, and newly formed blood vessels.
To date, Copernicus and its collaborators have demonstrated nucleic acid delivery to a variety of these cell types at levels of efficiency similar to viral-based delivery systems. Copernicus’ first generation “non-targeted” formulation is therefore amenable for use to deliver nucleic acid therapeutics to a variety of tissues, each with numerous potential clinical indications. Cystic fibrosis, a disease in which the affected lung airway cells are rich with cell surface nucleolin, provides a number of clinically- and technically-relevant advantages as the first application of the Company’s technology. The flexibility and relative simplicity of the Company’s platform will allow for the development of a broad pipeline of therapies utilizing different types of nucleic acids, e.g., DNA, shRNA, and mRNA. Copernicus Therapeutics expects to develop a number of these applications in partnership with a variety of corporate partners.