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Patent
AM Biotechnologies, LLC | Date: 2015-03-11

Chemically modified small interfering RNAs (siRNAs) that include both phosphorodithioate modifications (PS2-RNA) and 2-O-methyl modifications (MePS2) provide improved RNA silencing. Specific chemically modified siRNA that show enhanced silencing of RNAs involved in resistance to chemotherapeutic agents are provided.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 1.26M | Year: 2015

DESCRIPTION provided by applicant The X Aptamer Selection Kit XASK makes aptamers much more accessible to the life science market The low priced kit greatly minimizes the expertise and equipment required to perform aptamer selections thus enabling virtually any scientist with basic laboratory skills to rapidly develop his or her own synthetic next generation X Aptamer XA affinity reagents The Phase I SBIR successfully answered several fundamental questions associated with the bead based selection technology underlying the XASK It also conclusively demonstrated the feasibility of the kit as a commercial product Several independent users successfully selected X Aptamers using XASK prototypes which far exceeded the anticipated outcome from Phase I X Aptamers are chemically modified DNA affinity agents that utilize amino acid functional groups and even small molecules to enhance interaction with targets XAs routinely exhibit nanomolar to picomolar binding affinity as well as excellent specificity making them a promising synthetic alternative to antibodies AM Biotech has developed a rapid single cycle XA discovery process that is not based on SELEX The process is performed in two easy steps using bead based oligonucleotide libraries and standard laboratory equipment that enable packaging the discovery processes into XASK The Phase II SBIR will focus on enhancing the quality of the critically important bead based libraries and optimizing the bead based selection process to improve the success rate to andgt The XASK is a revolutionary product that will disrupt the aptamer market and will begin to make inroads into the antibody market AM Biotech believes that the XASK and X Aptamers are poised for strong market penetration that will help to pull aptamers into many commercial applications PUBLIC HEALTH RELEVANCE The X Aptamer Selection Kit XASK is a revolutionary product that minimizes the expertise and equipment required to perform aptamer selections which will make aptamers much more accessible to the life science market Synthetic affinity molecules like aptamers have many desirable characteristics that could solve numerous problems that are associated with the antibodies that they are intended to replace This is expected to lead to better diagnostic tests and to novel drug candidates for a wide range of diseases and conditions


Grant
Agency: National Aeronautics and Space Administration | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 600.00K | Year: 2010

AM Biotechnologies (AM) in partnership with Sandia National Laboratories will develop a Thioaptamer Diagnostic System (TDS) in response to Topic X10.01 Reusable Diagnostic Lab Technology. The TDS will quickly quantify clinically relevant biomarkers in flight using only microliters of virtually any complex sample. The system combines ambient-stable, long-shelf-life affinity agent assays with a handheld microfluidic gel electrophoresis affinity assay quantification technology. The system is easy to use, compatible with operation in microgravity, and designed to permit simultaneous quantification of 32 or more biomarkers from a single astronaut sample. Phase 1 of this project demonstrated that a thioaptamer assay used in the microfluidic instrument can quantify a specific biomarker in serum in the low nanomolar range. AM also successfully identified novel affinity agents to bone specific alkaline phosphatase (BAP) and demonstrated their use to detect BAP using the microfluidic instrument. Phase 2 will expand the number of ambient stable affinity agents and demonstrate a TDS prototype to NASA. AM anticipates that the TDS at the end of Phase 2 will be at TRL 4 to 5. In Phase 3, AM and Sandia will produce flight units for NASA research use on the International Space Station (ISS) as well as for diagnostic use on future long duration missions.


Grant
Agency: Department of Defense | Branch: Defense Advanced Research Projects Agency | Program: SBIR | Phase: Phase I | Award Amount: 99.97K | Year: 2014

AM Biotech proposes to develop X-Aptamer-functionalized NanoSponges (XANS) as a multi-valent snakebite antidote using synthetic, ambient-stable affinity molecules (X-Aptamers) coupled to nanoporous silica microparticles (nanosponges). XANS would be ambient-stable, universal, available in remote locations, and would not cause anaphylactic reactions. The antidote would be injected in the field at the site of a suspected envenomation enabling the X-Aptamers attached to the vast surface area of the nanosponges to bind with high affinity to many, if not all, of the toxins present in venom. Once injected, the XANS would rapidly absorb a large quantity of the toxins present and sequester them. After several hours, the XANS would either be excreted with the sequestered toxins or collect in the liver (primarily) and degrade slowly over weeks, allowing the victim?s immune system and serum proteases to effectively deal with the toxins without significant side effects.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 180.12K | Year: 2012

DESCRIPTION (provided by applicant): Functional RNA molecules such as aptamers, siRNAs, miRNAs, and related compounds have enormous potential as human therapeutics and as tools for elucidating gene regulation in vivo. To reach this potential, such molecules must be highly potent and highly nuclease resistant. Unmodified RNAs typically do not meet these requirements. A variety of chemical modifications have been explored to overcome these limitations. In particular, some success has been achieved in varioussystems using 2'-F-ribose and phosphorothioate backbone modifications, alone or in combination. However, further improvements are highly desirable. In addition, phosphorothioate modifications are chiral, resulting in two distinct isomers at each backbonesubstitution. Thus, there is a need for improved chemical modifications that can be incorporated into functional RNAs. AM Biotechnologies will address these critical issues by developing 2'-F-ribonucleoside thiophosphoramidites (2'-F-thioamidites) to enable synthesis of phosphorodithioate 2'-F-RNA (PS2-2'-F- RNA). We have previously shown that PS2 modifications at selected backbone positions of DNA aptamers enhance binding affinity to target proteins without loss of specificity. In addition, selected PS2 modifications in siRNAs significantly improve gene silencing activities. Thus, selected PS2-2'-F-RNA modifications will significantly increase binding affinity and potency of 2'-F-RNA aptamers, and will offer new avenues for synthesis of highly potent siRNAs. PS2-2'-F-RNAs will also be achiral at phosphorus, eliminating the variable biochemical, biophysical, and biological properties of diastereomeric phosphorothioate substituted RNAs. This Phase I project will: 1) develop the chemistry to produce four 2'-F-thioamidites (ABz, CBz, GIbu and U); 2) optimize the synthesis of PS2-2'-F-RNAs; 3) evaluate the effects of PS2-2'-F modifications on the binding affinity of a model 2'-F-RNA aptamer; and 4) evaluate the effects of PS2-2'-F modifications on the gene silencing activities of siRNAs targeting 2-secretase. In Phase II, AM will (a) scale reagent production up to commercial quantities and purity; (b) optimize a robust protocol for synthesis of PS2-2'-F-RNA; (c) evaluate the effects of PS2-2'-F modifications on aptamers and siRNA activity in vivo; and (d) fully characterize the pharmacokinetic properties of PS2-2'-F-RNA. AM in Phase II may also offer for sale limited quantities of research-grade reagents for market beta testing. Upon successful completion of PhaseII, AM will work with its existing industry partners to commercialize the 2'-F-thioamidites and enable the entire life science community to use these unique reagents in developing improved high-potency RNA drugs for a wide variety of human disease applications. PUBLIC HEALTH RELEVANCE: Functional RNA molecules such as aptamers and siRNAs have exciting potential as therapeutics in areas such as viral infections, cancer, genetic disorders, and neurological diseases. However, these potential RNA drugsrequire chemical modifications to achieve the necessary potency and stability. AM Biotechnologies (AM) will develop 2'-F-ribonucleoside thiophosphoramidite reagents that will allow the life science community to produce high potency, highly stable phosphorodithioate 2'-F-RNA-based drugs. The unique reagents that AM will develop under this project could have a profound impact on public health.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 156.73K | Year: 2011

DESCRIPTION (provided by applicant): Functional RNA molecules such as aptamers, siRNAs, miRNAs, and related compounds have enormous potential as human therapeutics and as tools for elucidating gene regulation in vivo. To reach this potential, such molecules must be highly potent and highly nuclease resistant. Unmodified RNAs typically do not meet these requirements. A variety of chemical modifications have been explored to overcome these limitations. In particular, some success has been achieved in varioussystems using 2'-O-methyl-ribose and phosphorothioate backbone modifications, alone or in combination. However, further improvements are highly desirable. In addition, phosphorothioate modifications are chiral, resulting in two distinct isomers at each backbone substitution. Thus, there is a need for improved chemical modifications that can be incorporated into functional RNAs. AM Biotechnologies will address these critical issues by developing 2'-O-methyl-ribonucleoside thiophosphoramidites (2'-OMe-thioamidites) to enable synthesis of phosphorodithioate 2'-OMe-RNA (PS2-2'- OMe-RNA). We have previously shown that PS2 modifications at selected backbone positions of DNA aptamers enhance binding affinity to target proteins without loss of specificity. Similarly, selected PS2 modifications in siRNAs significantly improve gene silencing activities. Thus, selected PS2-2'-OMe-RNA modifications will significantly increase binding affinity and potency of 2'-OMe-RNA aptamers, and will offer new avenues for synthesis of highly potent siRNAs. PS2-2'-OMe-RNAs will also be achiral at phosphorus, eliminating the variable biochemical, biophysical, and biological properties of diastereomeric phosphorothioate substituted RNAs. This Phase I project will: 1) develop the chemistry to produce four 2'-OMe-thioamidites (ABz, CBz, GIbu and U); 2) optimize the synthesis of PS2-2'-OMe-RNAs; 3) evaluate the effects of PS2-2'-OMe modifications on the binding affinity of a model RNA aptamer; and 4) evaluate the effects of PS2-2'-OMe modifications on the gene silencing activities of siRNAs targeting 2-secretase. In Phase II, AM will (a) scale reagent production up to commercial quantities and purity; (b) optimize a robust protocol for synthesis of PS2-2'OMe-RNA; (c) evaluate the effects ofPS2-2'-OMe modifications on aptamers and siRNA activity in vivo; and (d) fully characterize the pharmacokinetic properties of PS2-2'-OMe-RNA. AM in Phase II may also offer for sale limited quantities of research-grade reagents for market beta testing. Uponsuccessful completion of Phase II, AM will work with its existing industry partners to commercialize the 2'-OMe-thioamidites and enable the entire life science community to use these unique reagents in developing improved high-potency RNA drugs for a widevariety of human disease applications. PUBLIC HEALTH RELEVANCE: Functional RNA molecules such as aptamers and siRNAs have exciting potential as therapeutics for viral infections, cancer, genetic disorders, and neurological diseases. However, thesepotential RNA drugs require chemical modifications to achieve the necessary potency and stability. AM Biotechnologies (AM) will develop 2'-O-methyl-ribonucleoside thiophosphoramidite reagents that will allow the life science community to produce high potency, highly stable phosphorodithioate 2'-O-methyl-RNA-based drugs. The unique reagents that AM will develop under this project could have a profound impact on public health.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 949.24K | Year: 2010

DESCRIPTION (provided by applicant): New Reagents for Synthesis of High Potency siRNAs Abstract Since the discovery of short interfering RNA (siRNA) molecules in the late 1990s, siRNA technology has developed rapidly as a powerful tool for functional genomic analysis, target validation and therapeutic purposes. However, the potency and persistence of unmodified siRNAs is dramatically limited by their sensitivity to nuclease degradation. Developing chemically modified siRNA duplexes with higher potency and improved nuclease resistance is essential, especially for therapeutics applications in vivo. In Phase I of this project, we demonstrated proof of principle for a new approach using phosphorodithioate siRNAs (PS2- siRNAs), prepared using novel ribonucleoside thiophosphoramidite reagents (R-thioamidites). We successfully synthesized the four ribonucleoside thiophosphoramidites (A, C, G, and U) at small scale and used them to synthesize a variety of PS2-siRNAs. Importantly, we showed that PS2-siRNAs had increased gene silencing activity against multiple different gene targets in cultured cells. These results demonstrate that PS2-siRNAs have the potential to greatly improve siRNA-based research and drug development. To achieve that potential, Phase II of this project will achieve the following aims: (1) increase the scale of R-thioamidite production; (2) optimize protocols for solid-phase synthesis of PS2-siRNA for in vitro and in vivo applications; (3) synthesize and screen several PS2-siRNA libraries to identify design rules that maximize the gene silencing activity of PS2-siRNAs; (4) demonstrate increased potency and antitumor efficacy of unformulated PS2-siRNAs in a murine model of metastatic colorectal cancer; (5) develop formulated PS2-siRNAs that provide increased potency and antitumor efficacy in a murine model of metastatic ovarian cancer. Successful completion of this project will demonstrate the value of PS2-siRNAs in vivo, and enable AM and its commercial partners to proceed with full commercialization of the R-thioamidite reagents and contribute toward the realization of effective siRNA-based therapeutics. PUBLIC HEALTH RELEVANCE: New Reagents for Synthesis of High Potency siRNAs Narrative The possible therapeutic applications of small interfering RNA (siRNA) are broad and far reaching for many diseases. However, chemically unmodified siRNA molecules are rapidly degraded by nucleases, and often have inadequate potency, especially in animals. The need to develop nuclease resistant siRNAs with improved activity in vivo is critical to the development of novel siRNA-based therapies, as well as for many research applications of siRNA. AM is developing a novel type of chemically-modified siRNA that is expected to significantly improve siRNA potency and stability, which may lead to improved treatments for multiple human diseases.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 200.00K | Year: 2010

AM Biotechnologies (AM) will develop renewable thioaptamer protein capture reagents to ten proteins related to drug addiction. Thioaptamers are a type of aptamer containing phosphorodithioate linkages and other modifications that have excellent affinity and specificity for proteins. Because of the unique chemical composition of thioaptamers, they cannot be developed using the Systematic Evolution of Ligands by Exponential (SELEX) amplification method.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 449.82K | Year: 2013

DESCRIPTION: AM Biotechnologies (AM) is developing an easy-to-use kit that enables a technician in a life science laboratory to rapidly develop renewable X-Aptamer (XA) affinity reagents at a reasonable price. Affinity reagents are widely used in research, diagnostic, and clinical applications. Antibodies are currently the most common affinity reagents; however, every aspect of the life science market has experienced problems with them including aggregation, precipitation, difficult quality control, batch-to-batch reproducibility issues, short shelf life, eed for cold storage, costly production, and permanent denaturation. X-Aptamers address every antibody limitation. The X-Aptamer Selection Kit has three basic components: 1) a microbead-based oligonucleotide library; 2) a set of reagents for selecting XAs to a target of interest; and ) a few simple hardware items used for XA selection. X-Aptamers are comprised of a DNA scaffold that incorporates non-DNA functional groups such as amino acid side chains andsmall molecules that interact with a target more robustly than standard DNA. XAs are developed in a proprietary, single-round, bead-based selection process using equipment found in virtually any life science laboratory. The process enables the selection ofchemically-modified affinity reagents that cannot be enzymatically generated, which clears the way for a wide array of chemical functional groups that have never before been used in aptamer-based affinity agent selections. Several chemical functional groups have been tested to date and have resulted in X-Aptamers with low picomolar binding affinity. In addition, using XA processes, the binding affinity of a small molecule was improved by a million-fold. While extraordinary results have been obtain to date,there is a strong need to evaluate and optimize combinations of functional groups that hold the potential for creating protein affinity reagents with unmatched affinity, specificity, physical stability, and robust manufacturability. In this project, AM will develop and evaluate multiple chemically-modified library designs for selecting XAs to diverse protein targets and will develop robust methods for selecting ligand-modified XAs to ligand-binding protein targets. Successful completion of this Phase I project will set the stage for a Phase II project to optimize the X-Aptamer Selection Kit processes for commercialization in Phase III. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: The X-Aptamer Selection Kit will enable the life science market to quickly and easily develop chemically-synthesized, renewable affinity reagents that rival the performance of the best biologically-produced antibodies. X-Aptamers will address almost all limitations associated with widely-used antibodies and have the potential to lead to more effective diagnostics as well as new classes of therapeutic drugs.


Patent
AM Biotechnologies, LLC and Board Of Regents Of The University Of Texas System | Date: 2013-10-10

Provided herein are methods for a novel bead-based next-generation X-aptamer selection scheme that extends aptamer technology to include X-modified bases, thus resulting in X-aptamers, at any position along the sequence because the aptamers are chemically synthesized via a split-pool scheme on individual beads. Also provides are application to a wide range of commonly used DNA modifications, including, but not limited to, monothioate and dithioate backbone substitutions. This new class of aptamer allows chemical modifications introduced to any of the bases in the aptamer sequence as well as the phosphate backbones and can be extended to other carbohydrate-based systems.

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