[nanoPost] DNA nanoparticle technologies to produce safe and effective DNA drugs

Company USA

Most attempts to prepare non-viral DNA for gene therapy involve mixing DNA with positively charged molecules, or “polycations,” that condense the DNA and reduce its charge. However, these complexes contain too many molecules of DNA, making them far too large to enter through the nuclear membrane of human cells, where they must be delivered to be effective.

In an important break-through, the company has discovered how to compact DNA into complexes containing only a single molecule of DNA, resulting in a volume 30-1000 times smaller than other complexes. This simple difference makes the company’s “DNA nanoparticles” highly stable and uniquely able to deliver DNA to the nuclei of non-dividing human cells – which includes most cells in the body.

The company believes that the size of the compacted DNA complex is important. Nature compacts DNA. Below is a figure of a bacteriophage which has been breached in the “head” portion so that the DNA contained in the head can spill out. As can be seen, the long thread-like DNA must have been highly compacted to be contained in the head.

The company also believes that each compacted DNA complex should contain one copy of the therapeutic gene. Again nature has set the example. The bacteriophage contains a single copy of DNA. Similarly, the company's DNA nanoparticles contain only a single copy of DNA. They are smaller than the size of the pores in the membrane of the nucleus of cells.

These nuclear pores are widely recognized to be about 25 nM in size, and the company’s DNA nanoparticles are smaller than this dimension. Experiments have shown the company’s  DNA nanoparticles to be 1,000 to 10,000 times more effective than “naked DNA” in being expressed in cells with intact nuclear membranes.

Most of the cells of the human body have intact nuclear membranes during the time course of gene transfer. The company feels it is important to consider the size and state of DNA used for gene therapy. The figure below depicts golfers playing golf either with the company’s DNA nanoparticles (golf ball) or with the competition’s condensed DNA aggregates (soccer ball).

The company has established proprietary processes to produce DNA nanoparticles using raw materials readily amenable to pharmaceutical quality control measures. The compacted particles can be stored at 4C for years. Preliminary data show the complexes are stable for months when stored at room temperature. We have also shown that our material may be lyophilized.

The company’s technology is not subject to the difficulties and expense associated with the biological manufacturing systems required for viral vectors. Our manufacturing process and its raw materials are well-characterized and highly reproducible. The company feels secure in its ability to consistently manufacture a high quality product.

Compacted DNA can be administered a variety of ways. Compacted DNA has been tested in rodents by intrapulmonary administration and by direct injection into muscle. The expression of aerosolized compacted DNA is many times higher than “naked” DNA, even “naked” DNA formulated with lipids. These results suggest gene delivery utilizing the company’s compaction technology could be more effective and more efficient than seen with other non-viral gene therapy methods.

Based on current information, we foresee that non-targeted DNA nanoparticles may be used for pulmonary diseases, including asthma and cystic fibrosis; hemophilia and other genetic deficiency disorders; anti-angiogenesis (cancer), vaccines (intra-muscular, subcutaneous, intra-dermal, intra-nasal or aerosolized), and direct injection or application into diseased tissues such as joints, skin, eyes or tumor nodules. By adding targeting ligands to DNA nanoparticles, these complexes can be directed to specific tissues, including the liver, epithelial cells, endothelial cells, and tumors.

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