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. Source
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.
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.
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.
Genesegues, Inc. | Date: 2015-09-03
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.