University of Otago Otago Innovation Ltd

Gene Silencing Opportunity

Summary

Otago Innovation is currently investigating a compound (a deliverable conjugate of Peptide Nucleic Acid) that may have application in the treatment of any diseases which could be targeted by PNA such as cancer (e.g. PAX 2) or HIV. The technology describes the delivery of the gene silencing oligonucleotide PNA via a conjugate (TPP-SS-PNA, with TPP = triphenylphosphonium) through cell membranes into the cytoplasm, where the active PNA is released. PNA was discovered in 1991. The major problem in drug development with PNA is the difficulty of delivering the PNA through the blood stream into the tissues, where its action is needed. In previous attempts, PNA accumulation in the liver has been very common. This is why PNA is usually injected into the desired tissue. TPP is currently in clinical trials (Antipodean Pharmaceuticals Inc.) phase 2 for delivery of antioxidants into the mitochondrium. TPP-SS-PNA is stable in plasma. In vitro proof of concept showed delivery through the cell walls, releasing active PNA into the cytoplasm. Recent in vivo experiments showed no negative effects of TPP-SS-PNA injections in mice. Tissue distribution experiments are in progress to give in vivo proof of concept. Otago Innovation is looking for a partner with the resources and expertise to develop and guide this technology through pre-clinical and clinical trials.

The Market and Community Need

Because PNA can target any specific part of information stored in a sequence of about 20 bases on RNA, there are many applications and markets theoretically possible. In the research within the University of Otago, PNA targeting PAX 2 has been used. Recent research has shown that inhibiting expression of PAX 2 or PAX 3 genes (Pair-box genes 1-9, primarily expressed in developing embryonic tissues, also identified in tumour cell lines and thought to be required for growth and survival of cancer cells) in cancer leads to rapid induction of apoptosis. Of particular interest is the expression of PAX 2 in a high proportion (more than 50%) of breast and ovarian cancer. Breast cancer has the highest incidence (32%) and is the second most cause for cancer death (15%) in women in the US. In 1996, US$5.4 billion have been spent on the treatment of breast cancer, which describes together with colorectal cancer the biggest amount spent on cancer. From an antisense therapy market perspective, this is the most important and promising market. The competing treatments for cancer are chemotherapy, radiation, surgery, and gene therapy. There are areas of application where no traditional competition can take place and others where gene silencing drugs will be in competition with traditional pharmaceuticals. E.g. antisense therapy is expected to be effective against Hepatitis C (global market size 2000: US$ 800 million) where no effective therapy exists. The global market size of HIV 2000 was US$ 1 billion and would have to be shared with competing treatments as protease inhibitors and triple drug combination. Research on PNA targeting specifically HIV is progressing. PNAs targeting bacterial infections have also been reported in the literature (antibiotic market of US$ 40 billion).

Systemic Delivery of PNA into Cells for Gene Silencing

PNA is a neutral (non-charged) molecule, which is comparable to a DNA strain (negatively charged molecule) with a modified backbone to enhance its stability. PNA cannot cross cell membranes. The TPP-kation (positively charged) is pulled via a gradient into the mitochondrium in the cell. University of Otago researchers found TPP can transport a relatively short PNA (12-20 bp) into the cytoplasm. The simple but smart thiobutyl linkage dissolves in the cytoplasm, releasing active PNA, before TPP enters the mitochondrium (no toxic side effects). TPP is currently in clinical trials phase 2 for delivery of antioxidants into the mitochondrium (Antipodean Pharmaceuticals Inc.). TPP's use to deliver PNA into the cytoplasm has been patented in the name of Otago Innovation under WO2005035546. TPP-SS-PNA is stable in plasma. In vitro proof of concept showed delivery through the cell walls, releasing active PNA into the cytoplasm. Some of these data have been published in FEBS Letters 556 (2004) 180-186. Recent in vivo experiments showed no negative effects of TPP-SS-PNA injections in mice. Tissue distribution experiments with biotinylated PNA targeting PAX 2 are in progress to give in vivo proof of concept within 2006. PNA was discovered in 1991 and most patents for therapeutic uses are held by Isis Pharmaceuticals. Isis Pharmaceuticals will definitely support this technology by out-licensing its PNA IPR. Depending on the in vivo results, Isis Pharmaceuticals is going to review partnering opportunities with Otago Innovation.

The Investment Opportunity

At present only few antisense products are on the market and other products are in clinical trials. Up- and/or down-regulation or silencing a specific part of a gene completely has been approached on several scientific pathways. One of it is using PNA. The young global antisense market is expected to increase from 2000 US$750 million to 2005 US$3.6 billion. The conjugate TPP-SS-PNA could participate in the near future. The initial application would be for breast cancer with a market size of US$5.4 billion 1996, in the US alone.

Further applications are:

Otago Innovation is looking for a partner with the resources and expertise to develop and guide this technology through pre-clinical and clinical trials.

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Contact

Dr Alexandra Tickle
Otago Innovation,
PO Box 56, Dunedin. New Zealand
Phone: +64-3-4794145
alexandra.tickle@otagoinnovation.com