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Displaying Available Technologies results for Therapeutics

ADENO-ASSOCIATED VIRAL VECTORS FOR AMD TREATMENT

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Contrary to advances in treating wet AMD, dry AMD continues to elude modern therapeutics and there are no effective or established treatments despite dry AMD comprising 90% of all AMD incidences.

Researchers at the University of Utah have recently developed a potential gene therapy for the treatment of wet and dry AMD using adeno-associated viral vectors that inhibit the generation of reactive oxygen species (ROS). ROS have been linked to the disease progression of AMD. The inventors have shown that the activation of an enzyme, Rap1a, in retinal pigment epithelium (RPE) can reduce ROS generation.  Sub-retinal injections of the viral vector into mice result in a modest improvement in the expression of Rap1a after immunostaining of mouse retinal tissue.  Further validation of the vector could enable the creation of the first effective therapeutic for dry AMD and an alternative treatment option for wet AMD.


NON-NUCLEATED CELLS FOR DRUG DELIVERY

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Platelets are anucleated cells that play vital roles in clotting and maintaining internal body functions. Platelet disorders require time-consuming and resource-intensive transfusions. Donated platelets have a shelf-life of just five days and require HIV and blood-borne disease testing.

Synthetic biology has been used to create engineered megakaryocyte (MK) cells that differentiate into platelets in vitro. This creates a new source of platelets independent of donors to treat diseases associated with low platelet counts. This platform biotechnology/bioengineering technology has additional applications in systemic and targeted cell therapy. Of note, the MK cells are capable of being engineered to produce the non-nucleated platelets carrying therapeutic agents as well as to express specific receptors enabling targeted delivery.


COPOLYMER DRUG DELIVERY SYSTEM FOR ANTIANGIOGENETIC THERAPIES

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Recent studies show that amino bisphosphonates, such as alendronate (ALN), inhibit angiogenesis. Additionally, polymer-drug conjugates have been shown to increase the half-life of low molecular weight drugs, water solubility, and tumor accumulation.

The proposed technology is a combined targeted therapy made by conjugating angiogenesis inhibitors ALN and TNP-470 to a copolymer backbone. In vitro studies provide evidence that this copolymer-drug conjugate targets both tumor epithelial and endothelial compartments. These results indicate that the proposed technology represents a promising therapy for osteosarcomas and bone metastases.


TRANSLATION-TARGETED RNA INHIBITORS WITH ANTI-FLAVIVIRAL AND ANTI-CANCER PROPERTIES

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Anti-flaviviral application:

There is no FDA-approved vaccine for either Zika or dengue virus. Additionally, Dengvaxia, which is under FDA priority review, has been linked to a more severe form of dengue fever in some patients not previously infected by dengue.

A University of Utah researcher has developed a class of pan-viral small molecule inhibitors for the treatment of Flaviviruses. These molecules offer a novel mechanism of action and could potentially be active against a very broad group of RNA viruses based on in vitro testing.

 

Anti-cancer application:

The MYC oncogene is deregulated in >50% of human cancers, and MYC deregulation is central to oncogenic processes. MYC deregulation is frequently associated with poor prognosis and patient survival rates. Although MYC inhibition is recognized as a powerful approach for the treatment of many types of cancers, direct targeting of MYC has been a challenge for decades owing to its “undruggable” protein structure.

The RNA inhibitors have demonstrated anti-cancer activity in several oncology cell lines. Potent synergistic activity with mTOR inhibitors and with cisplatin has been demonstrated in cancer cell lines, suggesting that combination therapies are possible for development.


TARGETED IMMUNE CELL DEPLETION FOR TREATING AUTOIMMUNE DISORDERS

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Current treatment regimens for autoimmune diseases indiscriminately target healthy and diseased immune cells, causing patient immunodeficiency. In disorders like type 1 diabetes, multiple sclerosis, and rheumatoid arthritis, there is systemic depletion of healthy cells and tissues due to the failure of regulatory checkpoints in the immune system, like the PD-1 receptor.

University of Utah researchers have developed a unique approach to specifically deplete pathogenic autoreactive immune cells that cause organ destruction. This approach uses a targeted therapeutic with a PD-1-receptor-targeting moiety conjugated to a unique exotoxin. The exotoxin enters only offending autoimmune cells to begin depletion, without targeting or affecting healthy cells. This approach has been shown to limit healthy cell exposure to the toxin and reduce autoimmune deficiency in mouse models for type 1 diabetes and experimental autoimmune encephalomyelitis.


VIRUS-LIKE NANOCARRIER FOR CELL-SPECIFIC LARGE CARGO DELIVERY

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University of Utah researchers have created a vector system in which capsids from non-enveloped viruses are modified to produce quasi-enveloped viruses. The system is engineered to direct self-release within the vesicle and contains three modular activities: (1) membrane binding, (2) self-assembly, and (3) ability to recruit ESCRT machinery to catalyze membrane fission for release from the cell. Vesicles with internal capsids do not display any antigenic viral properties and are inaccessible to neutralizing antibodies. Specific receptor ligands can be included for cell-specific targeting. Additionally, different genetic elements could be split among multiple capsids, increasing the overall drug payload and overcoming size limitations of enveloped viruses.


RON KINASE INHIBITOR FOR PREVENTING AND TREATING BONE LOSS

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Over 70 percent of breast cancer patients develop bone metastasis, which causes severe pain, nerve compression, hypercalcemia, and debilitating bone fractures. Development and growth of bone metastases depend on the interactions between cells in the bone-tumor microenvironment that increase survival and proliferation of tumor cells. Current treatment options for osteolytic bone metastasis are limited to bisphosphonates and expensive RANKL-blocking antibody therapy with many adverse side effects.

A new, cost-effective treatment method utilizes a novel mechanism of action involving a RON kinase that activates macrophage-stimulating protein (MSP) which is a key driver of osteoclast activation in vivo. The pathway is independent of RANKL signaling. Inhibiting RON prevents both the development of osteolysis and the progression of existing osteolysis. Inhibiting this method also shows potential for treating bone loss due to osteoporosis.


GAL KINASE INHIBITOR TO TREAT GALACTOSEMIA

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Galactosemia is a rare, inherited condition where people cannot metabolize galactose due to mutations in GALT, GALE, and GALK1. The disorder appears in 1 in 40,000 live births and can be fatal if left untreated, but no long-term treatment exists. Although removal of galactose from the diet can prevent death, galactosemia patients still experience intellectual and speech deficits, motor function loss, ataxia, and infertility due to galactose accumulation.

Accumulation of Gal1-p results in a unique form of endoplasmic reticulum stress in fibroblasts of patients with Galactosemia. A small molecule GALK inhibitor can alleviate symptoms of Galactosemia by reducing accumulation of human galactose. GALK inhibitor leads have been identified for testing in animal models. Patient cell lines, crystal structure data, and animal models for Galactosemia are available for rapid development of an IND enabling candidate.


COMBINATORIAL GENE CONSTRUCT AND NON-VIRAL DELIVERY FOR ANTI-OBESITY

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Obesity is a risk factor for a variety of conditions, including diabetes, cancer, and heart disease. Single target protein therapies demonstrate poor efficacy as the body adapts quickly, activating alternate mechanisms to maintain its original state. Combinatorial approaches produce better results, but also greater side effects, leading to increased costs that limit patient compliance.
A novel combinatorial gene construct delivered using a non-viral vector demonstrates improved ability against obesity without significant side effects. The gene construct utilizes two genes that have key roles in the regulation of feeding inhibition, gastric emptying, and energy expenditure. These genes are administered with non-viral polymeric vector linear polyethylenimine, which is less toxic than other polymer vectors and not recognized by the immune system. The therapeutic efficiently transports DNA throughout the blood when administered weekly via intraperitoneal injections.


OPTIMIZED p53 PEPTIDES WITH MITOCHONDRIAL TARGETING SIGNALS

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p53 is a transcription factor that also stimulates apoptotic signaling through death receptors and the mitochondria. Over half of all cancer express p53 mutations and recombinant p53 is often introduced into cancer cells for treatment. Mutated p53, however, interacts with the introduced p53 rendering it ineffective at suppressing tumors.
p53 peptides with mitochondrial targeting signals (p53-MTS) can be introduced into tumor cells, which does not interact with mutant p53. The mitochondrial p53 works as a monomer with pro- and anti-apoptotic proteins at the mitochondrial outer membrane, causing a rapid apoptotic response. The p53-MTS and DNA binding domain constructs are active in cancer cells independent of their p53 status.


COILED COIL p53

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p53 is a transcription factor that also stimulates apoptotic signaling through death receptors and the mitochondria. Over half of all cancer express p53 mutations and wild-type p53 is often introduced into cancer cells for treatment. Mutated p53, however, interacts with the wild-type p53 rendering it ineffective at suppressing tumors.
A novel form of p53 that contains a coiled-coil suppresses tumor activity without interacting with mutant p53. The coiled-coil causes the new p53 to interact only with itself, preventing dimerization. The p53 coiled-coil can be introduced into tumor cells without causing dominate-negative effect. It triggers a rapid apoptotic response and maintains full tumor suppression properties.


OCA-B PEPTIDE INHIBITORS FOR THE TREATMENT OF TYPE-1 DIABETES

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Type-1 diabetes (T1D) is a chronic autoimmune disorder in which host immune system is directed towards antigens associated with insulin generating pancreatic β-cells. Life-long insulin therapy alleviates symptoms of T1D, but treatment complications and affiliated conditions, such as cardiovascular disease, continue to affect patients’ health.

Guided by extensive target discovery and GWAS studies, along with a mouse model, a proprietary OCA-B peptide inhibitor has been developed as a treatment for T1D and Multiple Sclerosis. This approach reduces infiltrating T-cell numbers and alleviates T1D-associated elevated glucose levels without impairing T cell development, base-line function or T-cell memory function.


INHIBITION OF HERPES VIRUS REPLICATION

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Available antiherpesvirus drugs target viral DNA polymerases. These drugs are usually highly effective, although toxicity and development of resistance limit their use. Derivatives of Spironolactone, an existing drug used to treat congestive heart failure, cirrhosis, and kidney problems, inhibit replication of Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpesvirus (KSHV), and Herpes Simplex Virus (HSV). These derivatives exhibit decreased anti-mineralocorticoid activity and increased antiviral activity. The proposed therapeutic degrades cellular transcription factors related to virus production, lytic replication and gene expression. Use of this therapeutic has the potential to prevent KSHV and treat infectious mononucleosis, CMV, and HSV infections.


NOVEL TREATMENT FOR GALACTOSEMIA

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Galactosemia is a rare, inherited condition where people cannot metabolize galactose due to mutations in GALT, GALE, and GALK1. The disorder appears in 1 in 40,000 live births and can be fatal if left untreated, but no long-term treatment exists. Galactosemia patients also experience intellectual and speech deficits, motor function loss, ataxia, and infertility.

The inventors have discovered that accumulation of Gal1-p results in a unique form of endoplasmic reticulum (ER) stress in fibroblasts of patients with Galactosemia. The proposed invention repurposes known ER stress inhibitors, such as Salubrinal, which have been shown to reduce phosphorylation of several intracellular proteins involved in ER stress for the treatment of Galactosemia.


STAUFEN-1 TARGETING THERAPEUTIC FOR TREATMENT OF FATAL NEURODEGNERATIVE DISEASES

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Neurodegenerative diseases represent an ever-increasing societal and economic burden with World Health Organization estimates indicating that they will replace cancer as the 2nd leading cause of death by 2040.

Spinocerebellar ataxia type 2 (SCA2) is a part of a family of progressive, often fatal neurodegenerative diseases with no known treatments or cures. Dominantly-acting mutations lead to expansion of a polyQ domain in the ataxin-2 (ATXN2) protein. Assembly of RNA-binding protein Staufen-1 (STAU1) with mutant ATXN2 in stable inclusions is causative, resulting in aberrant RNA processing in SCA2 and other neuronal diseases such as ALS. The proposed technology identifies STAU1 as an interventional target with STAU1 antisense therapeutic alleviating the severity of the disease in a mouse model of SCA2.


NEXT GENERATION MULTI-PAYLOAD ANTIBODY DRUG CONJUGATE

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ADCs are empowered antibodies designed to harness the targeting ability of monoclonal antibodies by linking them to cell-killing agents to overcome toxicity issues. One of the major limitations of ADCs is having an appropriate linker.

The proposed technology improves the linker, making it possible to create an ADC that possesses high specificity and the advantages of macromolecular therapeutics. The technology involves a controlled living polymerization technique that results in a well-defined HPMA polymer-drug conjugate, followed by specific attachment to an antibody to generate a homogenous ADC with an adjustable amount of payload. Lead ADC, RTX-P-EPI (Rituximab conjugated to Epirubicin) has been well characterized for high linker stability, homogenous ADC mixture, and ADC internalization.


IMMUNO-CELL THERAPY FOR BLOOD DISORDERS WITH NOVEL TARGETS

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Multiple Myeloma (MM) is an incurable plasma cell malignancy with significant morbidity and mortality. While proteasome inhibitors and immunomodulatory agents have improved treatment outcomes, most patients eventually relapse.

The Cancer Immunotherapy program at Huntsman Cancer Institute has established a comprehensive portfolio of novel immuno-oncology therapeutic candidates for hematologic malignancies and solid tumors. The proprietary biologics discovery platform includes a fully human antibody phage display library with a diversity of greater than 1010 clones. A number of monoclonal antibodies and CAR T cells against surface antigens, blocking antibodies against cytokines, and immune checkpoints are being advanced. The lead immunotherapy candidate is a monoclonal antibody and CAR T cell therapy targeting a novel surface receptor CD229. CD229 is selectively expressed on MM chemotherapy resistant precursor cells making it attractive for clinical development as a potential cure for MM. Extended applications include B-cell malignancies.


METHODS TO TREAT DRY MOUTH ASSOCIATED WITH SJOGREN’S SYNDROME

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Sjogren’s Syndrome is a condition that causes immune cell infiltration into the salivary and lacrimal glands, leading to dry mouth and dry eyes. No cure exists and treatments only somewhat alleviate symptoms.

Two novel methods for treating, and potentially curing, Sjogren’s are under development. The first uses Resolvin D1 to improve salivary gland epithelial integrity in cytokine-damaged cells through localized or systemic delivery into glands to treat dry mouth and dry eye. The second uses a fibrin-based hydrogel to regenerate salivary glands. The hydrogel is combined with functional groups, which are chemically conjugated to fluorescent FH to form new salivary tissue and eliminate dry mouth.


BENZONORBORNADIENE DERIVATIVES AND REACTIONS

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Biorthogonal dissociative reactions boast diverse potential applications in chemical biology and drug delivery. Specific cargo molecules within cells are released when benzonorbornadienes react with tetrazines to release amines from carbamate leaving groups. These carrier molecules are highly stable at physiological conditions, but react rapidly with tetrazines and near-quantitatively release cargo molecules such as drugs and optical reporters. The reactions are designed to take place without interfering with the existing cell chemistry and could serve a number of different purposes including DNA sequencing, cell imaging, drug delivery systems, and reaction protection groups.


PROTEIN-BASED PLATFORM TO GENERATE CHIMERIC ANTIGEN RECEPTOR-IMMUNE CELLS

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Antigen specific T cells and Natural Killer (NK) cells generated by virus- mediated gene transfer of Chimeric Antigen Receptors (CAR) has drastically advanced cancer immunotherapy. However, virus-mediated redirection typically results in permanent CAR gene expression and off- tumor toxicity. The recombinant CAR fusion protein (rCAR) developed is mixed with isolated T and NK cells in vitro, resulting in temporarily activated cells ready for infusion in a matter of hours, rather than days or weeks from traditional methodologies. The rCAR technology is a promising advancement for treating solid and hematological malignancies.


PEPTIDES FOR CLEARING DEGRADED AND UNFOLDED COLLAGEN

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Collagen is a major structure protein found in almost all human tissue. Degraded collagen is present in damaged tissues and is highly associated with many critical human diseases and injuries.

The collagen hybridizing peptide (CHP) can bind to these degraded collagens without affecting intact collagen. The proposed CHP has a high affinity to denatured collagen molecules for use in imaging, diagnosing, and treating diseases and injuries that cause collagen damage. The presence of Aza-Glycine residues from collagen mimetic peptide sequence increases stability of bonding to degraded collagen. The peptide can be paired with existing diagnostics and therapeutic agents to provide highly specific and targeted delivery of therapeutics or imaging markers to damaged collagen. Potential applications range from treating cancer to stabilizing blood clots and treating skin conditions.


BH4 (KUVAN) FOR TREATMENT OF SYSTEMIC SCLEROSIS VASCULOPATHY

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Systemic Sclerosis (SSc) is a multisystem autoimmune disorder with a progressively devastating course. Increased fibroblast activity results in abnormal growth of connective tissue that causes vascular damage and fibrosis. Fibrosis occurs in the skin, the gastrointestinal (GI) tract, and other internal organs. There is no cure, effective therapy, or gold standard measurement for disease progression. Delay in diagnosis increases morbidity and mortality.

BH4 is a novel approach for treating SSc by targeting vasculopathy that precedes fibrosis. BH4 (KUVAN) is currently approved to treat phenylketonuria (PKU). Short term study results indicate that BH4 (KUVAN) alleviates SSc symptoms in patients.


ACUTE MYELOID LEUKEMIA COMBINATION THERAPY

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Acute Myeloid Leukemia (AML) is an aggressive cancer with a five-year survival rate under 50 percent. In fact, only about one-third of AML patients are considered healthy enough to safely undergo chemotherapy, which leaves many patients without treatment options.

The proposed technology combines known AML drugs with HPMA polymers to prolong the active half-life of the drugs. This improves targeting of the tumor site and reduces off-target side effects. As each drug works through a different mechanism, the cancer cells are eliminated more completely, meaning lower doses of the drug may be used. This therapy provides treatment options for patients too sick to undergo chemotherapy or who prove non- responsive to existing, first-line treatments.


CRISPRi EPIGENOME MODIFICATION TO TREAT MUSCULOSKELETAL DISEASE

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Musculoskeletal diseases are a leading cause of disability worldwide. Current treatments for osteoarthritis and low back pain (LBP), however are largely palliative and fail to prevent disease progression. Stem cell delivery treatment to the intervertebral disc in clinical trials may work, albeit on a short-term basis as cells succumb to inflammatory responses.

The proposed technology is an innovative CRISPR-based approach that temporarily silences specific pro-inflammatory genes to regenerate the disc to full functionality. This approach promotes cell survival, stem cell differentiation, and immunomodulation under inflammatory conditions. The epigenome editing vector package can be locally injected, or autologous cells can be modified and delivered to replace the lost disc tissue. Studies with dorsal root ganglion demonstrate inhibition of degenerative intervertebral disc neuron activity and preservation of non-pathologic activity.


CELL SPECIFIC IMMUNE CHECKPOINT THERAPY

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Almost 80 percent of patients undergoing immunotherapy experience toxicity complications that reduce drug efficacy and over 10 percent of patients experience life-threatening infections.

New immune-tolerant elastin-like polypeptides (iTEPs) can be used as drug carriers without triggering an immune response in both mice and humans (Journal of Drug Targeting. Vol.24, p328-339). This technology has been applied to both drug delivery and immunology. The technology improves delivery of vaccines by conjugating the drug to the iTEP, which then self-assembles into highly stable, non-toxic nanoparticles with improved efficacy (Theranostics. Vol. 6(5), p666-678). The iTEPs are also utilized to target cytotoxic T lymphocytes and improve innate immune response as defense against cancer and infection. An iTEP-delivered CTL vaccine containing a metalloproteinase-9 (MMP-9)-sensitive peptide and a CTL epitope peptide has been developed. The MMP-9-sensitive vaccine increased epitope presentation by 7-fold, increasing the T-cell response by as high as 9.6-fold (Molecular Pharmaceutics, 14(10), 3312-3321). It has also been applied using αPD-1 antibody for checkpoint inhibition. A fusion protein consisting of a recombinant single-chain variable fragment of αPD-1 and an amphiphilic immune-tolerant elastin-like polypeptide self-assembles into a nanoparticle, which blocks the PD-1 immune checkpoint in vitro and in vivo (Molecular Pharmaceutics, 14(5), 1494-1500).


DRUG-FREE TARGETED TUMOR KILLING WITH MULTIMERIC ANTIBODY CONJUGATE

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Monoclonal antibodies show limited clinical efficacy as a single agent therapy for solid and blood cancers. The requisite high doses result in undesired adverse immunogenicity and toxicity. Conjugating antibodies to cytotoxic drug shows durable clinical response. However, antibody drug conjugate designing is complex, with knowledge of linkers, drug and antibody combinations in the context of a specific cancer.

University of Utah researchers are developing a new approach for modifying and improving antibody avidity by using graphene oxide (GO) as a targeted delivery scaffold. The GO-based aqueous composition allows non-covalent association of multiple antibody molecules on individual GO molecules, resulting in high efficacy antibodies.


ANTIBODY-DRUG COMPLEX: ENHANCED DELIVERY OF ANTI-CANCER THERAPY

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The American Cancer Society states breast cancer is the second most common cancer and second leading cause of death among women in the United States, despite improvements in early detection, treatment, and survival. The preferred treatment involves targeted therapy, which uses selective antibodies and leaves normal cells relatively unharmed.

Conventional antibody-drug conjugate technology for breast cancer, however, is limited due to safety concerns about bonding that leads to low antibody concentration. A novel drug-delivery system combines cancer- specific targeting mechanisms with anti-cancer agents without chemical modifications. The conjugate is comprised of an ATP binding domain (ABD), an anti-cancer drug, and a scFv antibody that targets a specific receptor on the surface of a cancer cell. The fused protein captures an anti- cancer agent without creating a chemical bond and then delivers it to a cancer cell. The drug carrier also has intrinsic anti-proliferative properties that increase drug efficacy by depriving the cancer cell of ATP.


PLGA AND PEI BASED PARTICLES FOR DELIVERY OF MESENCHYMAL STEM CELLS

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Mesenchymal stem cells (MSCs) can regenerate tissue and treat many debilitating diseases, including cardiovascular disease. Human MSC, however, requires lengthy ex vivo expansion times to prepare a sufficient amount of cells. This reduces transfectability, while increasing costs and contamination risk. MSCs also have poor survivability and short lifespans, further limiting their use. A new mechanism using poly(lactic-co-glycolic acid) (PLGA) and poly(ethylenimine) (PEI) porous particles to deliver MSCs increases the efficiency of MSC treatment. The polymer is optimized for MSC bonding affinity, and constructs an anchoring and supporting system for MSC-loading. The particles are loaded with MSCs and injected into the body to treat damaged tissues, specifically damage from myocardial infarction.


GENE THERAPY FOR RETINOPATHY OF PREMATURITY

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Retinopathy of prematurity (ROP) is a leading cause of childhood blindness worldwide. It is becoming more common as emerging countries develop technology to save preterm infants, but lack resources to provide optimal care. In the United States, 14 percent of childhood blindness is attributed to ROP, while in some developing nations estimates surpass 20 percent. Treatments of severe ROP include 1) laser ablation of peripheral avascular retina, which destroys developing retina; or 2) intravitreal anti- VEGF agents, which can lead to persistent avascular retina and even blindness.

The University of Utah is developing a gene therapy based novel approach by targeting STAT3, that unlike anti-VEGF treatment, will not interfere with physiologic retinal vascular development. This approach would stop the growth of abnormal blood vessels in the eye, prevent retinal detachment, and preserve vision.


ERYTHROPOIETIN GENE DELIVERY FOR MYOCARDIAL INFARCTION TREATMENT

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Myocardial infarction is the leading cause of morbidity and mortality worldwide. Although cardiac remodeling can maintain normal function initially, it gradually becomes maladaptive, leading to adverse outcomes, including heart failure. A novel approach for delivering plasmid human erythropoietin gene through an Arginine-grafted Bioreducible Polymer shows promise as a gene therapy tool for treating myocardial infarction. This treatment reverses post-infarct cardiac remodeling and restores heart function. Research suggests that this bioreducible delivery vector can revive the therapeutic potential of erythropoietin and other cardioprotective genes, allowing use as an effective treatment.


β-CATENIN/T-CELL FACTOR (TCF) FOR TARGETING CANCER AND IMMUNE TOLERANCE

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Irregular activation of the Wnt/β-catenin pathway leads to initiation and progression of many cancers, such as colorectal cancer, leukemia, and multiple myeloma. Cancer stem cells, which are resistant to conventional therapies, are also controlled by Wnt signaling. Recent studies indicate Wnt/β-catenin signaling provides therapeutic benefits as a molecular switch between opposing immune functions to treat autoimmune diseases, cancer, and infectious diseases.

The proposed technology describes design and synthesis of micro-molar inhibitors of β-catenin/Tcf inhibitors with outstanding selectivity, suitable for additional drug development.


BCAA/ARGININE SOLUTION

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Autophagy is a cellular process that activates under conditions of nutrient stress. Excessive and long-term induction of autophagy leads to the destruction of essential proteins and organelles. It is also related to congestive heart failure, myocardial infarction, and ischemia reperfusion.

The proposed precise formulation of an amino acid solution comprised of isoleucine, leucine, valine and arginine increases mTOR signaling and cell growth in patients with damaged tissues and heart disease. In addition, the osmolarity and pH of the solution allow it to be administered in large volumes without risk of significant osmotic shift.


ANTAGONIST OF TRPV1 RECEPTOR

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Transient Receptor Potential Vanillaoid-1 (TRPV1) mediates pain and inflammation. Stimuli, such as heat, protons, and chemical ligands, generate action potentials that release neurotransmitters and neuroactive peptides to stimulate nerves causing a painful, burning sensation. Studies indicate inhibiting TRPV1 could suppress pain, as well as treat chronic pain and inflammatory hyperalgesia.

The proposed invention is a series of peptides that act as TRPV1 channel antagonists. These peptides are delivered to the TRPV1 channel using a carrier that prevents off-site toxicity, but still allows the antagonist to bind to the TRPV1 channel. The peptides can be delivered topically or intravenously for use in pain treatment.


INHIBITION OF ANGIOGENESIS AND LYMPHANGIOGENESIS USING TARGETED MORPHOLINOS

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Vascular endothelial growth factor (VEGF) is a signal protein produced by cells that stimulates lymphangiogenesis and angiogenesis. When VEGF is overexpressed, it can contribute to various disease conditions, such as cancer and age-related macular degeneration.

The proposed technology modifies the polyadenylation mechanism, serving as a new drug for cancer and neovascularization disorders. It presents a new strategy for inhibition of angiogenesis and lymphangiogenesis through manipulation of VEGFR isoform expression. The VEGFR1 and VEGFR2 genes produce both membrane-bound and soluble isoforms, which have different effects on these processes. The membrane bound isoforms promote angiogenesis, while the soluble isoforms suppress lymphangiogenesis.


BROADLY PROTECTIVE INFLUENZA VACCINES

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Influenza A causes seasonal epidemics that affect millions of people every year and result in the death of between 250,000 and 500,000 annually. These seasonal epidemics and pandemics arise because of the constant evolution of the virus through both mutations and genetic reassortment. Current flu vaccines are type-specific, and while these vaccines may be effective against the target strain, they fail to prevent illness from variant strains. Universal vaccines target stable viral epitopes rather than the continuously changing seasonal varieties, but fail to provide meaningful protection.

A novel methodology has been developed to create a more functional universal influenza vaccine. The vaccine is designed to block immune response to hemagglutinin primary antigenic determinants and elicit antibodies to less dominant antigens or proteins on the virus. This allows the immune system to recognize viral threats from non-selective proteins that are typically present in many variants of the virus, providing broader protection. The vaccine also uses antibody binding to interrupt essential viral functions and prevent spread of the disease.


REVERSIBLE CROSS-LINKED POLYMERS FOR DRUG DELIVERY

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Controlled-release drug delivery systems often use hydrogels as drug carriers due to their adjustable swelling capacities. Hydrogel fabrication, however, typically requires cytotoxic materials or conditions that limit their use in biological systems. Additionally, synthetic hydrogels fail in high stress application because they are unable to self-heal.

The proposed invention enables creation of self-healing, reversible, cross-linked polymers. The hydrogels are fabricated by mixing two liquid-state pre-polymer under physiologic conditions to form a gel at body temperature. In acidic conditions, the hydrogel becomes a viscous, free-flowing gel, but can return to its original form when pH is adjusted. These cross-linked hydrogels also exhibit shear thinning and viscoelastic recovery properties. The novel hydrogel has potential applications in vaginal drug delivery, tissue engineering, lysosomal drug delivery, gastric drug delivery, cell culture, and food gelation.


STAPLED PEPTIDE THERAPEUTIC FOR NON-DRUGGABLE TARGETS

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Existing therapeutic platforms and drug arsenals utilize small molecules and large antibody proteins, addressing only 20 percent of the druggable market. The chemical space required for inhibition of protein-protein interactions is considered “undruggable” and remains underexplored. Undesirable properties of peptides such as instability, lack of cell/ tissue penetration, and immunogenicity of synthetics compound the problem and make it unsuitable for use in humans.

The new method is a proprietary facile and efficient synthetic platform method to generate high yield stapled peptides involving macrocyclization and a two-component thiol-ene based reaction.


5-HT2B SELECTIVE INHIBITORS

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Novel family of 5HT2B-selective antagonists for neuropathologies, such as Alzheimer’s disease, depression, ADHD, and migraines. Potential application in cardiology, gastroenterology, and bone marrow diseases.

Serotonin receptors are popular targets for many diseases, particularly neuropathologies. The existence of 14 subtypes, however, necessitates selective ligands. Current drugs tend to bind non-selectively to 5-HT2A and 5-HT2C as well as 5-HT2B, limiting their use. The proposed antagonists offer increased selectivity to 5-HT2B. These compounds exhibit nanomolar to micromolar selective interactions, which increases efficacy and reduces side effects of therapeutics. 5HT2B has additional potential applications in gastrointestinal, cardiac, and bone marrow related conditions.