CHASKA, MN, United States
CHASKA, MN, United States

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Unger G.M.,Genesegues, Inc. | Kren B.T.,University of Minnesota | Korman V.L.,Genesegues, Inc. | Kimbrough T.G.,University of Minnesota | And 6 more authors.
Molecular Cancer Therapeutics | Year: 2014

Improved survival for patients with head and neck cancers (HNC) with recurrent and metastatic disease warrants that cancer therapy is specific, with protected delivery of the therapeutic agent to primary and metastatic cancer cells. A further objective should be that downregulation of the intracellular therapy target leads to cell death without compensation by an alternate pathway. To address these goals, we report the utilization of a sub-50-nm tenfibgen (s50-TBG) nanocapsule that delivers RNAi oligonucleotides directed against the essential survival signal protein kinase CK2 (RNAi-CK2) in a cancer cell-specific manner. We have evaluated mechanism and efficacy of using s50-TBG-RNAi-CK2 nanocapsules for therapy of primary and metastatic head and neck squamous cell carcinoma (HNSCC). s50-TBG nanocapsules enter cancer cells via the lipid raft/caveolar pathway and deliver their cargo (RNAi-CK2) preferentially to malignant but not normal tissues in mice. Our data suggest that RNAi-CK2, a unique single-stranded oligonucleotide, co-opts the argonaute 2/RNA-induced silencing complex pathway to target the CK2αα′ mRNAs. s50-TBG-RNAi-CK2 inhibited cell growth corresponding with reduced CK2 expression in targeted tumor cells. Treatment of three xenograft HNSCC models showed that primary tumors and metastases responded to s50-TBG-RNAi-CK2 therapy, with tumor shrinkage and 6-month host survival that was achieved at relatively low doses of the therapeutic agent without any adverse toxic effect in normal tissues in the mice. We suggest that our nanocapsule technology and anti-CK2 targeting combine into a therapeutic modality with a potential of significant translational promise. ©2014 AACR.


Trembley J.H.,University of Minnesota | Chen Z.,National Institute on Deafness and Other Communication Disorders | Unger G.,Genesegues, Inc. | Slaton J.,University of Minnesota | And 3 more authors.
BioFactors | Year: 2010

Protein kinase CK2, a protein serine/threonine kinase, plays a global role in activities related to cell growth, cell death, and cell survival. CK2 has a large number of potential substrates localized in diverse locations in the cell including, for example, NF-κB as an important downstream target of the kinase. In addition to its involvement in cell growth and proliferation it is also a potent suppressor of apoptosis, raising its key importance in cancer cell phenotype. CK2 interacts with diverse pathways which illustrates the breadth of its impact on the cellular machinery of both cell growth and cell death giving it the status of a "master regulator" in the cell. With respect to cancer, CK2 has been found to be dysregulated in all cancers examined demonstrating increased protein expression levels and nuclear localization in cancer cells compared with their normal counterparts. We originally proposed CK2 as a potentially important target for cancer therapy. Given the ubiquitous and essential for cell survival nature of the kinase, an important consideration would be to target it specifically in cancer cells while sparing normal cells. Towards that end, our design of a tenascin based sub-50 nm (i.e., less than 50 nm size) nanocapsule in which an anti-CK2 therapeutic agent can be packaged is highly promising because this formulation can specifically deliver the cargo intracellularly to the cancer cells in vivo. Thus, appropriate strategies to target CK2 especially by molecular approaches may lead to a highly feasible and effective approach to eradication of a given cancer. © 2010 International Union of Biochemistry and Molecular Biology, Inc.


Patent
Genesegues, Inc. | Date: 2013-03-21

The present invention relates to compositions and methods for concurrently activating antisense and double-stranded RNase (dsRNase) mechanisms for inhibiting expression of a targeted gene, by delivering a single stranded bifunctional chimeric DNA/RNA oligonucleotide optimized for siRNA activity as well as antisense activity, into the nucleus of a target cell.


Patent
Genesegues, Inc. | Date: 2015-08-05

The present invention relates to compositions and methods for concurrently activating antisense and double-stranded RNase (dsRNase) mechanisms for inhibiting expression of a targeted gene, by delivering a single stranded bifunctional chimeric DNA/RNA oligonucleotide optimized for siRNA activity as well as antisense activity, into the nucleus of a target cell.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 600.00K | Year: 2013

DESCRIPTION (provided by applicant): The ultimate goal of this project is to develop a safe and effective topical vaccine against the dengue virus (DENV). DENV causes an estimated 30 to 50 million cases of debilitating fever leading to over 20,000 deaths worldwide every year. DNA-based vaccines have great potential against DENV because they can more quickly generate a balanced immune response, are less expensive to produce, and have greater temperature stability than current DENV vaccine candidates in clinical trial. However, DNA vaccines have historically suffered from low immunogenicity. The vaccine that we propose is engineered to overcome this barrier-to- success in three key ways. First, the US Centers for Disease Control and Prevention (CDC) vaccine incorporates advances that redirect humoral immunity away from the production of non-protective and potentially pathogenic antibodies to increase the production of potently neutralizing and protective antibodies. Second, the vaccine is delivered directly tothe network of immune effector cells in the skin via GeneSegues' (GSI's) topically administered sub-50 nanometer (s50) capsules. Third, the s50 encapsulated vaccine exploits the efficient, size-sensitive lipid raft uptake pathway to traffic directly to thenucleusof immune effector cells, addressing a major hurdle to DNA delivery. In this Phase 1 study, we propose to develop a topical DENV DNA vaccine by focusing on serotype-2 (DENV-2), with four specific aims. First, we will build upon pilot in vivo s50 DENV-2 vaccine delivery studies to determine optimal topical delivery site parameters in a mouse model. Second, for the selected delivery and application site, we will mechanistically assess differential adjuvants and dosing parameters, by comparing early percent effector cell transfection and antigen expression with subsequent neutralizing antibody response and persistence. Third, using the two best s50 vaccine candidates identified in Aims 1 and 2, we will characterize cell-mediated immune responses by examining the establishment and persistence of DENV-2 specific immunological memory. Fourth, in a separate study arm, we will compound the s50 DENV-2 DNA vaccine in a panel of semisolid vehicles (lotions and/or gels) to obtain maximum and uniform dose delivery, and execute a proof-of-principle study in mice with the best compounded candidate, with a key goal of achieving equivalent or superior protective neutralizing antibody titers vs. naked DNA delivered via electroporation and via intramuscular injection. Future work will expand and transition to the three remaining dengue serotypes (DENV-1, -3 and -4) and determine the optimum formulation to elicit tetravalent balanced, protective, and long lasting immunity within two to three months. Vaccine efficacy and safety will be assessed by using the DENV vaccine and disease AG129 mouse model, including lethal challenge and sublethal antibody-dependent enhancement of infection studies. We will also conduct manufacturing scale-up and other tasks necessary to progress to IND submission and human clinical trials. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: The dengue viruses (DENV) cause an estimated 30 to 50 million cases of debilitating fever leading to more than 20,000 deaths worldwide every year, yet commercial DENV vaccines remain unavailable. DNA-based vaccines offer great potential against DENV because they induce balanced immune responses, are relatively inexpensive and easy to produce, and are temperature stable. However, DNA vaccines have historically suffered from low immunogenicity, in large part due to inability to deliver these large, charged molecules into target cells. This Phase 1 project aims to develop a safe and efficacious, topically-applied, DENV DNA vaccine encapsulated in GeneSegues'novel sub-50 nanometer capsules that deliver the expression plasmid directly to the nucleus of target antigen-presenting cells of the immune system in the skin.


Patent
Genesegues, Inc. | Date: 2011-03-24

Disclosed are drug delivery systems and methods for extravascular administration of drug, vaccine, and/or diagnostic agents, for use in research and medical applications.


Disclosed are targeted sub-50 nanometer nanoparticles suitable for delivering bioactive agents of interest, and related compositions, methods, and systems, which improve the manufacturing, stability, efficacy and other aspects of therapeutic nanoparticles.


Patent
Genesegues, Inc. | Date: 2011-08-25

Disclosed are drug delivery systems and methods for extravascular administration of drug, vaccine, and/or diagnostic agents, for use in research and medical applications.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 158.98K | Year: 2012

DESCRIPTION (provided by applicant): Diseases such as age related macular degeneration (AMD), other retinal dystrophies, and glaucoma cause a large proportion of blindness worldwide. A critical barrier in treating these diseases is the inability to efficaciously, economically, and safely deliver drugs and gene therapy DNA constructs to the retina and the retinal pigment epithelium (RPE). Topical delivery by eye drops has been ineffective because of permeability and absorption barriers of the anterior segment of the eye. Thus, current delivery approaches for these diseases entail costly injections of the eye using viral vectors that in some clinical trials have demonstrated dangerous side effects. The broad, long-term objective of this project is to develop asafe, economical, and effective gene delivery approach using novel, nonviral sub-50 nanometer (s50) capsule technology that is cell-specific and traffics to the nucleus without endosomal entrapment. Our preliminary data indicate that these nanocapsules administered as topical eye drops onto the tear film of living rats result in delivery and expression of gene vectors in cells of the retina and RPE. Topical application resulting in DNA delivery to posterior ocular targets is surprising and potentially transformative. If brought to the clinic, it should provide safe and economical treatment for many blinding diseases. In this Phase 1 study, we propose to optimize the topical s50-capsule dosing regimen in terms of safety and efficacy using easily-assessed fluorescent plasmid DNA expression vectors. We then will compare expression levels and inflammatory markers of the optimized topical s50-capsule dosing regimen, with an ocular injection protocol that we have previously optimized. We will use the LCA2 mouse model of retinal degeneration. LCA2 mouse models are useful because they have severe vision deficits due to simple lack of a single gene product (RPE65), yet they have delayed morphological degeneration. Thus, successful delivery of replacement gene vector results in creation of visual function and prevention of degeneration. If the results of this Phase I study are encouraging, we will propose Phase II studies using the novel s50 capsule technology to deliver therapeutic RPE65 expression vectors to mice deficient in RPE65, and assess target gene expression and function, visual function, and morphology. PUBLIC HEALTH RELEVANCE: The relevance of this research to public health is potentially very high. A large proportion of blindness is caused by retina and retinal pigment epithelium (RPE) pathologies. Several therapeutic DNA constructs and drugs are effective treatments for these diseases in animal and cell culture models, but are of limited use in the clinic because they cannot be delivered to target tissue and cells efficiently and safely. The aim of this project is to develop a safe and effective way to deliver these treatments.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 200.00K | Year: 2013

The design, fabrication, characterization, and preclinical evaluation of novel nanoparticle-based drug formulations capable of delivering candidate RNAi therapeutics for the treatment of cancer. PUBLIC HEALTH RELEVANCE

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