December 23, 2012

Gold Nanorods against cancer and Protein- and peptide-based therapeutics

Launched in November 2011, Breakout Labs provides early-stage companies with the means to pursue their most radical goals in science and technology. To date Breakout Labs has awarded a total of twelve grants of up to $350,000 each.

Breakout Labs grants were recently awarded to General Genomics and Siva Therapeutics. General Genomics uses ancestral DNA sequence reconstruction to radically improve the efficiency with which protein- and peptide-based therapeutics, as well as industrially-relevant enzymes, can be developed. Siva Therapeutics is developing therapies with the potential to be more effective, safer, less expensive, and less invasive by exploiting the biophysical properties of gold nanorods engineered to capture infrared light and emit heat that destroys diseased tissue.

Siva Therapeutics

Siva’s approach will be to use SivaRodsTM - engineered gold nanorods - and infrared light with the goal of destroying solid tumors and improving patient health and outcome.

Electron micrographs of SivaRods™ (each rod is approximately 12 x 50 nm).

Siva Therapeutics is researching ways to target and destroy cancer cells from within by using gold nanoparticles that we term SivaRodsTM combined with near-infrared light. The light heats the SivaRodsTM in a process called hyperthermia.

Our technology employs:
1) the injection of a suspension of precision gold nanorods manufactured in a size, shape, and surface chemistry that cause them to selectively infiltrate growing, abnormally vascularized cancer tissues

2) hyperthermia, in which infrared light is used to heat the nanorods, thereby destroying tumors while leaving surrounding tissue unharmed. Initial preclinical studies have established proof of concept (toxicology and efficacy) in mice, and additional animal studies are underway. Early testing has been very successful, eliminating tumors in mice in as few as 25 days.

Hyperthermia can destroy cancer cells. The challenge in using hyperthermia effectively has been directing the heat to the tumors without damaging adjacent healthy tissue. Precision nanorods solve this problem. Nanorods are preferentially absorbed and retained by vascular tumors, and animal studies indicate that Siva Therapeutics' treatment will work not only on the primary tumor, but also on spreading and early metastases of tumors.

Why SivaRods?

1. SivaRodsTM can be manufactured with a higher degree of precision than other gold particles, resulting in a much narrower size distribution of SivaRodsTM, and much higher uniformity of SivaRodsTM dimensions.

2. SivaRodsTM absorb infrared radiation, and re-emit this radiation as heat, permitting photothermal heating of targeted tissues. Conventional gold particles are roughly spherical in shape, and they absorb (and re-emit) shorter wavelengths of light, rather than infrared, eliminating photothermal capabilities. In fact, the wavelength at which SivaRodsTM absorb and re-emit light can be precisely tuned by regulating the length of the rods.

General Genomics

General Genomics intends to radically improve the efficiency with which protein- and peptide-based therapeutics, as well as industrially-relevant enzymes, can be developed. Founder Eric Gaucher’s research on ancestral sequence reconstruction, which traces the evolutionary pathway of functional proteins, has been published in the top scientific journals of the world. Now, he intends to use this bioinformatics technology to derive functional insights that will speed the design and development of proteins for applications ranging from agriculture to therapeutics.

General Genomics engineers proteins useful for industrial processes, agriculture and biomedicine.

The technology represents a platform approach to understanding evolutionary changes in biomolecules as a means to derive new therapeutic and industrial agents with unique profiles of activity. Our technology is first applied to the development of novel proteins designed to reduce abnormally high levels of uric acid, a natural breakdown product of DNA, in patients suffering from Gout and other uric acid-related diseases. This project has been active for nearly two years. The goals of the current project consist of developing a therapeutic molecule through pre-clinical studies allowing us to file an investigational new drug application and applying for federal funding (viz. SBIR)The overall goal of General Genomics, LLC is to generate a novel platform that exploits evolutionary analyses to guide the engineering of biomolecules (e.g., proteins) that have therapeutic and industrial utility. The first application of our platform is applied to the uricase gene family. The product of this application is intended to treat human Gout effectively while eliminating the problematic allergic responses elicited by many currently-marketed medications. The scientific, business-supporting goals of funding periods IA and IB are to synthesize engineered uricase proteins (i.e., new chemical entities, NCEs) using an evolutionary-based methodology developed by Prof. Eric Gaucher and test these proteins in vitro (IA) and in vivo in mice (IB). The business goals of this funding period are to incorporate General Genomics, LLC and secure federal funding (SBIR) and better understand the Gout market we are trying to penetrate (IB). The engineered uricases will be developed by uniquely exploited evolutionary models to reconstruct ancient uricase genes in the laboratory. This is necessary because humans (and all other apes) have a mutation in their uricase gene that prevents them from making functional, active uricase. As such, we cannot degrade the substrate of uricase (uric acid is highly insoluble and builds up in the joints and kidney) into the more soluble product (5-hydroxyisourate) that can ultimately be further converted and excreted from the body through the kidneys in urine. One way to treat Gout is to inject a foreign uricase protein (most commonly purified from fungus or pig) into the human body to degrade the uric acid crystals that are causing Gout. Unfortunately, injecting foreign proteins into human bodies often elicits strong immune responses that (at least) attack and degrade the foreign protein or (at most) lead to death via anaphylactic shock in patients. Our goal is to engineer uricases that minimize immune responses when injected into humans. This may be possible using resurrected uricases from ancient apes that are less foreign to the human body than fungal and pig uricases. The process of resurrecting ancient proteins follows a present-day-backwards approach whereby uricase gene sequences from modern organisms are analyzed in an evolutionary framework to infer the sequences of the ancient genes. These genes are then synthesized in the laboratory, recombinantly expressed in a modern organisms, the ancient protein is then purified from that organism and characterized in the laboratory. The Gaucher group has expertise in this field and has published in many high profile journals such as Nature, Science, etc.

General Genomics first Market Gout

Worldwide sales of Gout management products totaled approximately $650 million in 2007. These products are comprised of predominantly generic drugs and therefore the sales data likely under-represent the size of the Gout market. A better indication of market size is based on the number of prescriptions and/or patients receiving Gout management therapy. Gout currently affects 3-5 million adults in the U.S., and the prevalence of Gout is increasing, as illustrated by the rise in patients prescribed the conventional Gout medication, allopurinol. Within the span of 6 years from 1996 to 2002, patients receiving allopurinol therapy rose from 1.2 to 1.6 million. Additionally, the increase in Gout prevalence is corroborated by several studies that suggest that the number of Gout cases in the U.S. has doubled within the last three decades

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