Sierra Sciences: Achievements and Intellectual Property

1. INTRODUCTION

Sierra Sciences, an 11-year-old biotech company from Reno, Nevada, is the only company in the world that has developed a sensitive and reliable high-throughput assay to screen chemicals to determine whether they induce telomerase activity.

Telomerase induction technology holds incredible promise. Proof-of-concept experiments suggest that such a therapy could extend and improve our healthspans and lifespans, that it could prevent the physical and mental decline associated with aging, and that it could allow humans to live healthy beyond our theoretical maximum age of 125 years. For more details on the science of telomerase induction and these proof-of-concept experiments, please see our associated document, "Potential Therapeutic Applications of Telomere Biology."

Telomerase induction promises to be one of the great medical advances in history, and undoubtedly has the potential to quickly develop into a multi-billion dollar industry once a successful product is brought to market. Although it is expected to take years to bring a pharmaceutical telomerase inducer through FDA approval, there are several markets for this technology that are potentially very profitable in the short term, including the nutraceutical market and the pet market.

Sierra Sciences is well-positioned to enter the nutraceutical market. Our assay is capable of screening not only random chemicals for telomerase induction, but also extracts of plants, bacteria, and other small organisms that are not regulated by the FDA because they are generally recognized as safe ("GRAS"). Any given organism contains thousands of small-molecule compounds, each of which is potentially as powerful as any pharmaceutical drug. In essence, nutraceuticals can provide a "shortcut" to a marketable drug that does not require FDA approval.

Sierra Sciences has screened more than 1,000 nutraceutical extracts, and, so far, we have found five confirmed extracts that induce telomerase at weak levels. These products are likely to have some effect on human health and aging, and are in a position to be marketed immediately.

The second early market for telomerase induction will be the pet market. Pet medicines are more heavily regulated than nutraceuticals, but not as heavily regulated as FDA-approved pharmaceuticals. Based on our early experiments with animal cells and our review of the scientific literature, we believe that drugs that induce telomerase in humans will have the same effect on dogs, cats, and horses. Market research has demonstrated that people with pets won't hesitate to purchase products that could keep their pets healthier longer. Even better, the pet market will undoubtedly help prepare people for the concept of human health extension and life extension, thus expanding the pharmaceutical market for telomerase inducers even before final FDA approval is reached.

Considering that we are the only biotech company actively pursuing telomerase induction technology, the intellectual property and experience our team has accumulated over the last eleven years puts us significantly ahead of any competitors who would try to enter the market now.

II. ACHIEVEMENTS OF SIERRA SCIENCES

Sierra Sciences was founded in 1999 by Dr. William H. Andrews, shortly after his team at Geron Corporation successfully discovered and cloned human telomerase. After this discovery, Geron decided to focus their efforts on developing telomerase inhibitors as potential cancer treatments. Dr. Andrews' focus on telomerase induction led him to split with Geron and subsequently found Sierra Sciences to work on the development of a telomerase inducer.

For the last eleven years, Sierra Sciences has been virtually the only company pursuing this line of research. We have made significant progress in understanding the underlying science behind telomerase induction, developing tools to discover telomerase-inducing drugs, and discovering active telomerase inducers with the potential to be turned into pharmaceuticals.

Sierra Sciences currently possesses the only high-throughput screening system in the world that is capable of screening for telomerase inducers, which we call the "hTERT RT-PCR HTS assay." Using this assay, Sierra Sciences has screened approximately 4,000 chemicals per week from random compound libraries for the last two years.

Prior to the development of the hTERT RT-PCR HTS assay, we employed a "Brute Force assay," where we spent several months screening chemicals using the same techniques as the hTERT RT-PCR HTS assay. Initially, we were restricted to doing our screening by hand, rather than using robots, because the system was not sensitive enough to screen in the small volumes that robots require.

The Brute Force assay led to the discovery of our very first telomerase-inducing compound, C0057684. At the time, C0057684 gave us a signal that was barely detectable above background. By using C0057684 as a positive control, we were able to vastly improve our screen. By automating our assay, we can now accomplish in one day what it took us four months to screen in the Brute Force assay. In other words, our proprietary technology enables us to screen for telomerase inducers approximately 120 times faster than any emerging competition would initially be capable of.

Not only have we been able to screen in smaller volumes, but our screen has become far more sensitive. We have established a "Telomerase Induction Scale" from 0 to 100, where 0 represents a chemical that does not induce telomerase, and 100 represents a chemical that induces as much telomerase as a HeLa cancer cell generates. We believe that a score of 100 would represent approximately the amount of telomerase necessary to cause a human cell to become immortal.

On the Telomerase Induction Scale, C0057684 rates a 6. Our Brute Force assay was initially incapable of detecting any hits weaker than a 6. We have re-screened many of the chemicals that we originally screened in the Brute Force screen, and we have found several telomerase inducers with lower scores.

As of October 2010, we have screened more than 250,000 chemicals, over 600 of which have been confirmed telomerase inducers. These chemicals fall into 38 chemical families, based on their chemical structures and what we know of their mechanisms of action. We have enforceable patent applications on these chemicals.

The discovery of these chemical families has allowed us to perform medicinal chemistry and structure-activity relationship studies, leading to the design of drug-like chemicals that are significantly more active than the best hits from our primary screen. In conjunction with Federico Gaeta, Ph.D. and NanoSyn, Inc., Sierra Sciences has synthesized 426 compounds in our six most promising chemical families. The strongest of these chemicals rates 16 on our Telomerase Induction Scale.

We believe that, if we can secure the funding to do further mechanism of action studies, structure-activity relationship studies, and synergy studies, our medicinal chemists can raise that score significantly above 16.

In September 2010, Sierra Sciences began screening natural products that are generally recognized as safe for human consumption ("GRAS"). Using the hTERT RT-PCR HTS assay, Sierra Sciences has screened 5,364 extracts of natural products and discovered 42 extracts that cause weak levels of telomerase induction. We have recently signed an agreement to start screening 1,000 more natural products per week.

These extracts are not as potent as our synthesized chemicals; the best one we have found to date rates a 1.2 on our Telomerase Induction Scale. However, GRAS extracts can be brought to market without FDA approval. There is currently only one telomerase activator on the market: TA-65, a nutraceutical distributed by TA Sciences.

TA-65 is the first natural product that has ever shown activity in the Telomerase Activity assay (TRAP assay). Until there is something much better, we highly recommend that everyone take TA-65. We do.

III. SIERRA SCIENCES' INTELLECTUAL PROPERTY

Sierra Sciences currently holds 5 issued U.S. Patents and 4 pending, enforceable U.S. Patent Applications, two of which are published.

A. Repressor binding sites

The human genome contains the gene for telomerase, but in our non-reproductive cells, that gene is repressed by one or more repressors. Sierra Sciences' initial strategy was to identify the repressor binding sites, identify the repressor proteins binding to the sites, and engineer a drug that would bind to the repressor proteins, preventing them from binding to the repressor sites.

In 2001, Sierra Sciences discovered a repressor binding site that blocks the expression of telomerase and named it Site C. Sierra Sciences has patented this discovery as U.S. patent #6,686,159. In 2004, we discovered another repressor bind site, "GC-Box 5," and patented this discovery as U.S. patent #7,279,328.

B. Repressor proteins

Sierra Sciences spent several years researching the repressor proteins involved in the repression of the telomerase gene, although we have since shifted our focus entirely to our screening efforts. Sierra Sciences has patented the proteins we consider most likely to be involved in repression, for which we hold U.S. patents #7,211,435 and #7,795,416.

C. Telomerase assays

Sierra Sciences has developed several assays besides the Brute Force and RT-PCR assays in our attempt to discover whether chemicals modulate the telomerase promoter and/or repressor to increase telomerase induction within a human cell. We have abandoned our intellectual property rights on most of these, because they ultimately did not produce useful results.

The exception is our "Mutant hTR assay," an assay in which we created a mutant template sequence of the telomerase RNA component ("hTR") that caused cells to produce mutant telomerase that was toxic to them, and compared the effects of compounds on cells containing this hTR template against the effects on cells containing the wild-type hTR template. We hold U.S. patent #7,226,744 for the Mutant hTR assay, and believe that there could be possible future applications of our proprietary knowledge of toxic variants of hTR.

D. C0057684 and other telomerase-inducing chemical compounds

Sierra Sciences holds an unpublished, enforceable patent application on C0057684, the first moderate-strength telomerase inducer ever discovered. Initially, the discovery of C0057684 was met with some skepticism, since there were many scientists at that time who believed that the telomerase gene could not be de-repressed by use of a drug.

This skepticism was overcome when the ability of the compound to induce telomerase activity was validated by three independent labs: Woody Wright and Jerry Shay at the University of Texas Southwestern; Judy Campisi at Berkeley Lab's Life Sciences Division; and Richard Allsopp at the University of Hawaii. Sierra Sciences has not shared the chemical structure of C0057684 with these labs.

Disappointingly, DNA Array Analysis has suggested that C0057684 has too global an effect on the genome to be useful as a pharmaceutical candidate, and additional medicinal chemistry is needed to eliminate these global effects while retaining the telomerase-inducing effect. In addition, as discussed above, discovering this positive control allowed us to design the HTERT RT-PCR HTS assay.

Sierra Sciences also holds enforceable patent applications on the compounds we have created through medicinal chemistry, which are significantly stronger than C0057684. These are the strongest telomerase-inducing chemicals ever discovered by any company.

 

Poster Presentations

Scientists at Sierra Sciences created posters summarizing their research in the field of telomerase biology for the UABBA Conference, June 2008.

Click on the links at the bottom left to view individual posters that were presented. The posters are meant to be interactive: click on the links to view an individual poster at a larger size.