State University, AR, United States
State University, AR, United States
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The subject invention concerns materials and methods for treating or preventing disease and conditions associated with various sulfatase enzymes that are defective or that are not properly expressed in a person or animal. In one embodiment, the disease is Sanfilippo A (MPS -III A) disease. The subject invention also concerns materials and methods for treating or preventing multiple sulfatase deficiency (MSD) in a person or animal. Compounds of the invention include a fusion protein comprising i) a mammalian sulfatase, or an enzymatically active fragment or variant thereof, and ii) a plant lectin or a binding subunit thereof. In a specific embodiment, the mammalian sulfatase is a human sulfatase, or an enzymatically active fragment or variant thereof. Polynucleotides encoding the fusion proteins are also contemplated for the subject invention. The subject invention also concerns materials and methods for producing proteins of the invention.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 223.35K | Year: 2014

DESCRIPTION (provided by applicant): The long-term goal of this project is to develop an effective protein replacement therapeutic (PRT) for patients affected with rare forms of Osteogenesis imperfecta, OI-VIII (deficiency in prolyl 3-hydroxylase 1; P3H1)and OI-VII (deficiency in cartilage associated protein CRTAP). These PRTs will integrate the safety and cost advantages of plant-based bioproduction with innovations that enhance delivery and disease correction. OI is a group of genetic connective tissue disorders characterized by low bone mass and increased bone fragility. Current treatment options for OI are limited to bisphosphonates treatments, which inhibit bone resorption but are controversial due to the likelihood of deleterious effects in young patients as well as adults. Developing effective PRTs for these patients is challenging since classic enzyme replacement therapies (ERTs) have been relatively ineffective in correcting bone-related pathologies. PRTs for these rare OI diseases will require eff


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 1.49M | Year: 2015

DESCRIPTION provided by applicant The goal of this SBIR proposal is to develop an effective enzyme replacement therapy ERT for Sanfilippo A patients by exploiting safety supply and cost advantages of plant based enzyme bioproduction while integrating novel ERT delivery strategies being development at BioStrategies LC Sanfilippo A MPS IIIA is a rare genetic lysosomal storage disorder affecting less than people in the U S It is caused by a defect in the gene encoding the enzyme heparan N sulfatase SGSH and is characterized by progressive degeneration in normal childhood development especially in brain function leading to death at an early age Current treatment options are limited to symptom management and development of an effective ERT drug has been hindered by challenges of delivering these drugs to the brain and central nervous system CNS If successful this SBIR will lead to an effective ERT based treatment for Sanfilippo A patients a patient population with desperate need and limited options Utilizing BioStrategiesandapos new plant lectin ERT fusion and delivery technology to be further developed during this project this research could lead to a fundamental paradigm shift for ERT based treatment approaches based on innovative alternate cell targeting mechanisms and trans blood brain barrier BBB drug delivery The promise of plant made bio production to be employed in this project has recently been recognized with the FDA approval of Elelyso Protalix Pfizerandapos s plant made glucocerebrosidase ERT for Gaucher Disease The potential for a marketable product is high With the rare disease community showing escalating interest in reducing drug development and production timelines and costs our new ERT drug technology utilizing plant based bio production will be highly attractive and competitive All Phase I objectives of this SBIR project have been met demonstrating a the feasibility of using plant based bio manufacturing for our complex human gene product and b the ability of our lectin carriers to mediate delivery of active sulfamidase into human cells and lysosomes leading to MPS IIIA disease phenotype correction This Phase II SBIR proposal addresses the following follow on objectives To produce bioactive SGSH lectin fusion drug products at scale and purity to support in vivo mouse model animal trials To evaluate in vivo enzyme distribution in normal and MPS IIIA mice and To assess efficacy in disease correction of our lead drug candidate in the MPS IIIA mouse model Success in Phase II will demonstrate the efficacy of our lectin drug candidate to correct in vivo disease phenotype in the mouse model for this disease supporting subsequent preclinical efficacy and toxicology studies required for a successful IND application to FDA to initiate human clinical trials PUBLIC HEALTH RELEVANCE The family of human genetic diseases represented by Sanfilippo A Syndrome MPS IIIA and other lysosomal disorders LDs include some of the most devastating human afflictions known and the most costly to patients their families and the public health system The currently approved enzyme replacement therapeutics ERTs available to treat several of these diseases although effective for many patients still suffer frm problems of safety high cost availability of adequate product supplies to patient populations and product effectiveness in treating all organs of body The new therapeutics technologies for MPS IIIA developed in this SBIR Phase II Randamp D project would address all of these issues by employing new drug delivery technology that more effectively targets affected cell types cellular compartments and organs The need for delivering new treatment options such as that described in this proposal to the central nervous system CNS and brain is particularly critical as current drug options for LDs are generally not effective in the brain The innovative drug delivery technology developed in this project including our use of cheaper plant based manufacturing would further the national goal of reducing the suffering and costs for patients afflicted with these devastating genetic diseases


The current invention involves the use of protein lectins produced by plants including the non-toxic carbohydrate binding subunits (B subunits) of plant AB toxins (PTB lectins) as delivery vehicles for mobilizing associated drug substances for delivery to animal and human cells. The resulting protein fusions or conjugates retain lectin carbohydrate specificity for binding to cells and cellular trafficking activity so as to deliver an associated drug compound to the site of disease manifestation. One embodiment of this invention concerns the ability of ricin toxin B subunit, as a model PTB lectin, to deliver enzyme replacement therapeutic drugs to cells of several organs of the body including the brain and central nervous system, eyes, ears, lungs, bone, heart, kidney, liver, and spleen for treating lysosomal diseases.


The current invention involves the use of protein lectins produced by plants including the non-toxic carbohydrate binding subunits (B subunits) of plant AB toxins (PTB lectins) as delivery vehicles for mobilizing associated drug substances for delivery to animal and human cells. The resulting protein fusions or conjugates retain lectin carbohydrate specificity for binding to cells and cellular trafficking activity so as to deliver an associated drug compound to the site of disease manifestation. One embodiment of this invention concerns the ability of ricin toxin B subunit, as a model PTB lectin, to deliver enzyme replacement therapeutic drugs to cells of several organs of the body including the brain and central nervous system, eyes, ears, lungs, bone, heart, kidney, liver, and spleen for treating lysosomal diseases.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 225.00K | Year: 2016

DESCRIPTION provided by applicant The goal of this proposal is to develop an enzyme replacement therapy ERT approach for rare genetic diseases that is effective in mitigating the problem of immune sensitization that has hindered previous ERT technologies Enzyme replacement therapies remain the most effective treatment for those rare genetic diseases for which approved recombinant enzyme products are available ERTs have been crucial in treating several lysosomal diseases LDs which in their severe forms present with devastating multi organ pathologies in affected children However the induction of patient anti ERT antibodies immune sensitization has emerged as a significant limitation in the effectiveness of ERTs altering enzyme distribution and activity Because early infantile onset forms comprise the most severe mutations the development of immune sensitization is much more prevalent in younger patients These children often show dramatic life saving improvements upon treatment onset However progress stops or quickly declines as these patients develop neutralizing antibodies to the ERT drug Most currently approved ERTs for LDs exploit the same Mannose Phospate M P receptor for uptake into disease cells and the predominant class of anti ERT antibodies interfere with this uptake process However the ERT technology developed by BioStrategies LC uses an alternative ERT RTB fusion mechanism for cell uptake and we have found in preliminary experiments using Hurler MPS I lysosomal disease cell cultures that active ERT RTB was successfully delivered in the presence of neutralizing antibody containing serum from immune sensitized animals Based on these promising in vitro results our goal in this SBIR Phase is to demonstrate in vivo efficacy including enzyme delivery and glucosaminoglycan GAG substrate reduction in ERT sensitized Hurler mice We previously demonstrated that IDUA RTB shows broad bio distribution and corrects GAG substrate levels in the MPS I mouse model Specific aims for Phase I include to Develop MPS I mice that are immune sensitized to the rhIDU ERT product and Compare IDUA activity and GAG levels in selected tissues in rhIDU sensitized mice following treatments with either rhIDU or IDUA RTB Success of these experiments will demonstrate that a significant increase of ERT enzyme activity is delivered to organs of IDUA sensitized Hurler mice after treatment with IDUA RTB verses rhIDU Based on a successful Phase I feasibility study Phase II research will target statistically significant assessments in the MSP I animal model and application of the RTB lectin platform to other diseases such as Pompe and other diseses where immune sensitization problems have most significantly impacted successful ERT treatments The long term goal is to develop new immune mitigating ERTs for patients that will provide sustainable efficacy of these therapies for lysosomal and other protein deficiency diseases PUBLIC HEALTH RELEVANCE The childhood human genetic diseases belonging to the group of lysosomal disorders and bone developmental diseases currently under development at BioStrategies represent some of the most devastating disease afflictions known and the most costly to patients their families and the public health care system Currently available enzyme replacement therapeutics ERTs for several of these diseases although effective for many patients suffer from problems of safety high cost product effectiveness including immune sensitivity problem studied in this project The new therapeutics innovations developed in this SBIR Phase I feasibility project would address many of these issues by developing ERTs that are more effectively targeted to diseased cell types and tissues and that are safer and cheaper to supply to patient populations by virtue of employing newer plant based production technologies The innovative drug delivery technology developed in this project would further the goal of reducing the cost and suffering of patients with these devastating genetic diseases


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 225.00K | Year: 2014

DESCRIPTION (provided by applicant): The goal of this proposal is to develop an effective enzyme replacement therapy (ERT) for patients suffering from GM1 Gangliosidosis by integrating a novel protein fusion ERT cell delivery strategy under development atBioStrategies LC and by exploiting safety, supply, and cost advantages of new plant-based enzyme therapeutics bio-manufacturing systems. GM1 Gangliosidosis is a rare genetic lysosomal storage disorder affecting less than 200,000 people in the U.S. It is caused by a defect in the gene encoding the enzyme ?-galactosidase and is characterized by progressive degeneration of normal childhood development especially in brain function leading to death at an early age. Current treatment options are limited to management of disease symptoms and development of an effective ERT drug has been hindered by challenges of delivering these drugs to the brain and central nervous system. This research project is a collaboration between BioStrategies LC, a company focused


Grant
Agency: Department of Agriculture | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 90.00K | Year: 2010

As the nation attempts to meet the challenges posed by the spread of pandemic influenza there is a need for innovative strategies to produce effective vaccines for humans, poultry and livestock. Interleukin-12 (IL-12) is a potent adjuvant of cell-mediated immunity that has been shown to enhance protection afforded by influenza vaccines. The use of IL-12 adjuvant could improve vaccines for several serious porcine diseases including flu but the high cost of current production methods does not sustain the scaled up product availability necessary for large scale vaccination strategies. Plant-based production offers several potential benefits over conventional production systems including lower startup costs and increased flexibility in terms of scale-up, storage, safety, and cost containment. We have demonstrated that plants can produce fully functional mouse and chicken IL-12 at production levels compatible with large scale commercial applications. This Phase I SBIR proposes to show the feasibility of plant-based bio-production of porcine IL-12 (PoIL-12) by addressing the following specific aims: I. Construct porcine IL-12 gene vectors for expression in plants. II. Test IL-12 gene vectors for protein yield and bioactivity in a tobacco transient expression system. This Phase I feasibility study will establish the ability of plants to produce bioactive porcine IL-12, provide productivity assessments, and establish bio-production protocols for supplying bioactive PoIL-12 to researchers for further R&D. Phase II research will address development of stable transgenic plant lines, IL-12 product characterization and purification, scaled up production, and demonstrations of adjuvancy and protection against flu in porcine vaccine trials.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 151.19K | Year: 2010

DESCRIPTION (provided by applicant): This Small Business Innovation Research Phase I proposal develops a technology that allows bioactive proteins to be synthesized and secreted from cultured plant cells in high yields and with prolonged serum half-life. The innovation of this technology, designated Hyp-Glyco, involves the expression of secreted therapeutic proteins as fusions with a novel hydroxyproline (Hyp)-Glyco tag. The Hyp-Glyco tag also extends serum half-life and facilitates purification of secreted proteins while retaining protein bioactivity. This proposal is focused on scale-up process development of Hyp-Glyco technology in bioreactor cultured tobacco cells expressing interferon 2b and in development of a cost-effective technique for protein recovery/purification. Specific aims of this feasibility Phase I are to 1) Establish bioreactor based high yield interferon protein production in plant cell cultures using Hyp-Glyco technology; 2) Demonstrate that continuous perfusion culture technology will further enhance protein production; and 3) Show that reliable and cost-effective recovery and purification of bioactive interferon protein can be achieved in bioreactor grown plant cell cultures. Success of Phase I will support a follow-up Phase II aimed at establishing cost-effective commercial level production protocols for all phases of this new protein production technology so as to provide the confidence necessary for investing in Phase III commercial development. Protein therapeutics represents a multi-billion-dollar marketplace, but costly manufacturing methods for these drugs currently make them prohibitive for consumers. The broad impact of the proposed work resides in the potential of an alternative less costly platform for enhanced production of therapeutic proteins in plant cells which would, simultaneously, provide the added advantage of improved clinic effectiveness. Because this technology not only produces high-yield secreted proteins but also eliminates the time-consuming and expensive process of chemical derivatization to improve clinic effectiveness, the production costs can be significantly reduced. With the additional safety advantage of substituting plant cells for existing animal cell production, molecular farming could become commercially competitive with current mammalian and microbial cell production systems. Importantly, the interferon with extended serum half-life described here would meet a significant demand from 4 million hepatitis C virus (HCV) infected patients in USA and 3% of population worldwide. This technology is also broadly applicable to a wider range of therapeutically important proteins such as hGH, G-CSF and EPO etc, all of which represent billion-dollar markets. The development and success in commercializing the Hyp-Glyco protein manufacturing technology would create job opportunities in economically disadvantaged regions of the US and drive local economic development. PUBLIC HEALTH RELEVANCE: The growing dual threat of environmental pollution and global warming is considered by most health/medical experts and governments as one of the most dangerous and intransigent potential health problems globally. The need for developing new health positive, cost conscious and environmentally sustainable technologies for production of industrial and pharmaceutical products is a high priority of health related research in the U.S. and abroad. This proposal will target this need directly by developing and testing the feasibility of innovative more cost-effective methods for producing therapeutic proteins by using plant-based cultures and bioreactors which will confer the simultaneously benefits of greater safety, energy conservative and environmental sustainability than traditional manufacturing methods.


Grant
Agency: Department of Agriculture | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 460.00K | Year: 2011

(23) Non-technical Summary: TITLE: Plant Produced Porcine Il-12 Vaccine Adjuvant for Swine Flu and Other Viral Diseases PD: Radin, David N., PhD, BioStrategies LC CoPD: Cramer, Carole L., PhD, Arkansas State University and BioStrategies LC CoPD: Medrano, Giuliana, PhD, Arkansas State University As the nation attempts to meet the challenges posed by the spread of pandemic influenza there is a need for innovative strategies to produce effective vaccines for domestic swine which are a key carrier and incubator for new flu varieties threatening humans and commercial swine herds. Interleukin-12 (IL-12) is a potent adjuvant of cell-mediated immunity that has been shown to enhance protection from influenza pathogens. The use of IL-12 adjuvant could improve vaccines for several serious porcine diseases including flu but the high cost of current production methods cannot sustain the scaled up product availability necessary for large scale vaccination strategies. Plant-based production offers several potential benefits over conventional production systems including lower startup costs and increased flexibility in terms of scale-up, storage, safety, and cost containment. Our Phase I research demonstrated that plants can produce fully functional Porcine IL-12 adjuvant in a transient tobacco expression system. This Phase II SBIR proposes to further develop this plant-produced immune stimulator adjuvant product (PoIL-12) by addressing the following specific objectives: I. Demonstrate CMI-inducing efficacy or porcine IL-12 in vivo. II. Enhance yields of recombinant porcine IL-12 in plants. III. Assess protection and vaccine dose-sparing potential of pIL-12 in SIV vaccination trials. IV. Test the potential of orally administered pIL-12 to provide protective immune stimulation. This Phase II R & D, in addition to developing in vivo vaccine adjuvancy protocols of plant-produced porcine IL-12 in pigs, will focus on enhancing plant-based IL-12 product yields in support of Phase III commercial development.

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