Therapeutic Use of Rapamycin (or derivatives) Through Akt-driven Cardiomyocyte Survival

The well known drug rapamycin is a fungal macrolide that inhibits mammalian target of rapamycin (mTOR) (See Figure), an important molecule for both growth and survival signaling. Rapamycin is currently used to inhibit inflammation during surgery, however its utility in other therapeutic areas is limited due to its toxicity. Studies have shown both beneficial and harmful effects of administering rapamycin in the heart. The present invention, developed by inventors at the Medical University of South Carolina (MUSC), relates to the use of rapamycin to treat pressure overload hypertrophy, a symptom of a cardiomyopathy. Hypertrophy of cardiac tissue initially compensates for the increased pressure, however it ultimately results in heart failure. The present invention determines specific effective dosages and time intervals of rapamycin administration that result in a beneficial effect and eliminate most or all negative effects. Using a relatively small dose of rapamycin, inventors at MUSC have augmented survival signaling via increased Akt activation and increased clearance of deleterious proteins via the ubiquitin proteasome system (in vivo and in vitro data is attached). The goal is to switch the growth response of hypertrophy to be purely physiological and therefore eliminate or reduce the risk of heart failure. This invention seeks to define the parameters of rapamycin administration as a therapy to reduce the development of heart failure. There are also other rapamycin derivatives and analogs with no known therapeutic effect. These derivatives and analogs may also be useful as part of the present invention. Since rapamycin is not currently used to treat heart conditions, the present invention is a novel and non obvious use for rapamycin and its derivatives.

Serotonin Agonist for the Treatment of Mitochondrial Dysfunction

Mitochondrial Dysfunction Is Both A Cause And Target Of Reactive Oxygen Species (Ros) During Ischemia/Reperfusion (I/R), Drug And Toxicant Injury.  Following Injury Renal Proximal Tubular Cells (Rptc) Recover Mitochondrial Function By Increasing The Expression Of The Master Regulator Of Mitochondrial Biogenesis, Pgc-1 Alpha.

Serotonin Agonists Increase Mitochondrial Biogenesis And Accelerate The Recovery Of Mitochondrial Function.  A Type 2 Serotonin Receptor Against Increased Pgc-1 Alpha Levels, The Expression Of Both Nuclear (Atp Synthase Beta) And Mitochondrial (Nd6) Encoded Mitochondrial Proteins, Mitotracker Red Staining Intensity, Cellular Respiration And Atp Levels Through A Serotonin Receptor Function Following Oxidant-Induced Injury In Rptc.  This Is The First Report To Demonstrate Serotonin Receptor Mediated Mitochondrial Biogenesis And That Serotonin-Agonists Are Effective In The Treatment Of Mitochondrial And Cell Injury.

New Treatment Option for Glioblastoma Multiforme

Provided is a novel method of treating recurrent glioblastoma multiforme (GBM).

GBM, a.k.a. as grade IV astrocytoma, is the most common and most aggressive of the primary brain tumors. GBM usually spread quickly to other parts of the brain. For this reason, this disease is difficult to treat. Surgical intervention is essential in the initial treatment of GBM. Chemotherapy is the most common treatment option for recurrent malignant gliomas. GBMs account for 12-15% of intracranial tumors and 50-60% of primary brain tumors. Few patients with GBM survive longer than 3 years and only a handful survive 5 years. In 2005, 12,940 cases of GBM were expected to be diagnosed in the U.S.

Dr. Bruce Frankel, at the Medical University of South Carolina, has developed a novel therapy for GBM using intrathecal delivery of Ara-C (a.k.a. cytarabine or cytosine arabinoside). Pilot studies in patients have shown that treatment with this compound can result in significant responses, warranting further study of this treatment in a Phase I/II clinical trial.  

Recently, Orphan Drug Status was obtained for using Ara-C to treat gliomas. Orphan drug status provides certain benefits, such as, among others, a 50 percent tax credit for expenditures on clinical trials and seven years of marketing exclusivity after the approval of the drug.

Methods and Formulations for the Treatment of ER+ Breast and Ovarian Cancer Tumors

Disclosed is a novel therapeutic strategy to sensitize Estrogen Receptor positive (ER+) breast and ovarian tumors to chemotherapy.

It is known that anti-estrogens are active in preventing the development or progression of estrogen receptor positive (ER+) breast cancer.  It is also known that breast cancer patients can develop chemosensitivity to subsequent chemotherapy with  paclitaxel. Thus far, it is not clearly understood what underlies the paclitaxel chemosensitivity.

Dr. Weimin Fan at the Medical University of South Carolina has discovered that Estrogen Receptor (ER) expression significantly reduces sensitivity to paclitaxel-induced apoptosis in breast cancer cells. In addition, Dr. Fan showed that inhibition of ER expression with an anti-estrogen significantly enhanced the sensitivity of breast cancer cells to paclitaxel-induced apoptosis.

This finding might lead to promising new treatment options for patients with ER+ breast and ovarian cancer.

Treatment of Nitric Oxide and Cytokine Mediated Disorders

Provided are methods of suppressing, inhibiting or preventing autoimmune or inflammatory diseases.

Nitric oxide (NO) is synthesized by different isoforms of Nitric Oxide Synthatase (NOS). One isoform is called inducible NOS (iNOS), which responds to a wide variety of internal stimuli, including endotoxins and proinflammatory mediators. Once stimulated, iNOS produces copious amounts of NO, which, if left uncontrolled, can lead to a host of inflammatory diseases.

The issued claims provide for various pharmacological strategies for modulation of iNOS expression and NO production. The claims provide for methods of treating NO or cytokine (TNF-alpha, IL-1beta, IL-2, IL-6, IL-8 and/or IFN-gamma) mediated disorders with one or more classes of compounds, including:

• Inhibitor of mevalonate synthesis (e.g. HMG-CoA reductases ("statins"), AICAR)
• Inhibitor of the farnesylation of Ras (e.g. FTI)
• Antioxidant (e.g. N-acetyl cysteine (NAC), Pyrolidine dithiocarbamate (PDTC))
• Enhancer of intracellular cAMP (e.g. forskolin, rolipram, papverine, theopylline)
• Enhancer of protein kinase A (PKA) (e.g. forskolin, cAMP)
• Inhibitor of NF-κβ activation (AICAR, statins)

Drug Delivery Vehicle to the Sinonasal Cavity

Researchers at the Medical University of South Carolina have developed a delivery vehicle to be used for nearly all sinonasal conditions, including acute/chronic rhinosinusitis, allergic rhinitis, non-allergic rhinitis, viral rhinitis, epistaxis, post-nasal drip, nasal conjestion, granulomatous/rheumatologic disorders, etc.  This vehicle could be used to deliver drugs such as steroids, antibiotics, peptide based therapeutics, mucolytics or other medications to simply to deliver saline or other hydrating/moisturizing agents. 

The advantage of this vehicle delivery system is that it remains in contact with the mucosa of the sinonasal cavity for hours without impairing mucociliary transport, as opposed to other forms of topical medication (drops, irrigations, sprays, etc) that contact the mucosa and then are rapidly swallowed down the throat.  Other delivery vehicles such as gels are too viscous and impair mucociliary clearance, leading to stasis of secretions and infections.  This delivery vehicle overcomes both of these problems

HDL Holoparticle Receptor

The present invention provides an isolated mammalian receptor termed cubilin (and associated proteins) which specifically binds high density lipoprotein (HDL) holoparticle and mediates endocytosis leading to lysosomal degradation of HDL. In addition, the present invention provides a method of screening a substance for the ability to modulate the HDL holoparticle binding and/or internalization activity of the receptor of this invention. The technology would be used for the design of compounds, drugs, or therapeutic agents that regulate the activity or expression of the HDL endocytosis receptor.

Prevention fo Post-Rape Psychopathology

The prevention of post-rape psychopathology videotape features four modules, the first of which is intended to reduce anxiety surrounding emergency and forensic exam room procedures and increase medical clinic follow-up attendance. This module is entitled Forensic Exam Anxiety Reduction Module. The latter three modules contain preventive information and exercises designed to address the risk areas of psychopathology outlined above. As mentioned, attention and concentration abilities of rape victims are expected to be negatively affected by the trauma. Therefore, this preventive intervention imparts information in an extremely clear, concise, and relatively straightforward manner. Additionally, because rape victims are frequently in extreme distress during emergency room procedures, the videotape intervention features non-threatening, racially and gender sensitive actors to reduce anxiety and engage victims.

The intervention has been specifically formulated to ameliorate, rather than exacerbate anxiety of rape victims during forensic exam procedures. As such, the videotape intervention complements crisis counseling currently provided by volunteers. As mentioned, the first module of the tape informs women of what is going to happen during the exam. That is, they are prepared for and given some sense of control and insight over procedures. This is achieved by introducing victims to individuals similar to those with whom they will interact during the exam, followed by general descriptions of forthcoming procedures. Next, actual depictions of the procedures occur, accompanied by rationales for each action, and description of victim options regarding each procedure. Finally, a follow up clinic is described and advantages of attendance are outlined.

Following the introductory section of the tape in which hospital staff and procedures are featured, information designed to allay concerns regarding novel and frightening symptomatology (e.g., panic) that rape victims often experience will be offered, combined with strategies that increase victims' expectations that they are capable of coping with emotional and physical distress that they might experience in the ensuing days. Next, PTSD/Panic, Depression, and Substance Abuse prevention modules are provided. Specific treatment modalities include modeling by culturally relevant actors, role-play and rehearsal, education, and self-assignment of therapeutic homework. Specific treatment techniques featured in the video include imaginal and in vivo exposure instructions and examples, cognitive restructuring and discussion of common cognitive distortions following rape, activity scheduling, urge identification, prevention and control, and cognitive coping skills training.

Inhibition of Fibrosis by Curcumin

We find that a natural compound may be a specific inhibitor of fibrosis. Although non-toxic to normal cells, the compound inhibits collagen expression by dermal fibroblasts derived from patients with the fibrotic disease scleroderma. This is a critical observation, because the essential definition of a fibrotic condition is one in which collagen is being overproduced. The compound also causes scleroderma fibroblasts to detach from culture dishes and to undergo programmed cell death (apoptosis). These observations specifically suggest that this compound may be a useful treatment for scleroderma and raise the possibility that it may also be a potential treatment for a range of fibrotic diseases including cirrhosis of the liver, atherosclerosis, connective tissue diseases, and pulmonary fibrosis.

Formulations of DEET with reduced skin absorption

DEET is the active ingredient in many commercial mosquito repellant formulations. DEET has been shown to be responsible for side effects, adverse reactions, and a few deaths in humans after use of DEET containing mosquito repellants. DEET also has been implicated as one of hte agents responsible for Gulf War Syndrome. Absorption of DEET through skin occurs very rapidly.

We have prepared formulations of DEET from which absorption of DEET through skin is reduced significantly or completely inhibited. Therefore, these DEET formulations can be safely used as mosquito repellants without the potential for any DEET related side effects or adverse reactions. These formulations use excipients which are commonly used in pharmaceutical preparations which by themselves are inert and known to be safe for human use. This approach can be used to design formulations of other occupational and environmental agents whose absorption through skin has to be prevented or minimized for prevention of toxicity.

Method of Treating Neoplastic Cells with Prostaglandin and Radiation Treatment or Prostaglandin and Platinum-Based Anti-Tumor Agents

The invention is directed to a method of increasing ionizing radiation's cytotoxic effects on a neoplasm in a subject by increasing the neoplasm's sensitivity to ionizing radiation, comprising administering a therapeutically effective amount of prostaglandin to the subject, and subjecting the neoplasm to a therapeutically effective amount of ionizing radiation, thereby increasing the cytotoxic effects of the ionizing radiation on the neoplasm. The invention is further directed to a method of reducing the therapeutically effective amount of ionizing radiation required to treat a neoplasm in a subject, compared to treating with ionizing radiation alone, comprising administering a therapeutically effective amount of prostaglandin to the subject, thereby reducing the therapeutically effective amount of ionizing radiation required to treat the neoplasm in the subject, compared to treating with ionizing radiation alone, and subjecting the neoplasm in the subject to the reduced therapeutically effective amount of ionizing radiation. The invention is also directed to a method of treating a neoplasm in a subject, comprising administering a therapeutically effective amount of prostaglandin and administering a therapeutically effective amount of cisplatin to the subject, wherein the therapeutically effective amount of the platinum-based anti-tumor agent is less than 60mg/meterÿ.

Cell Repair and Regeneration By Suramin and Related Polysulfonated Naphthylureas

The invention provides for a method to using suramin, a polysulfonated naphthylurea, to treat renal ischemic injury. The inventor's research showed that suramin stimulates outgrowth, scattering, and proliferation of primary cultures of renal proximal tubule cells (RPTC). These suramin effects were mediated by Src-dependent activation of the PI3K/Akt pathway. While results indicate that suramin-stimulated RPTC proliferation and scattering are not mediated by the production of autocrine growth factors, the exact mechanism of action remains unknown. The inventors are currently investigating whether it is possible that sarumin inhibits binding of TGF-beta to its receptor, thus resulting in the enhancement of RPTC proliferation and scattering. Proliferation and migration of renal epithelial cells are two crucial processes needed for structural regeneration of nephron following injury. Therefore, suramin has a therapeutic potential in promoting renal recovery after injury.

Method for prevention and treatment of inflammatory disease and disease conditions with inhibitors of glucosyl - and galctosyltransferase inhibitors for the synthesis of lactosylceramide and compound that increase intracellular cAMP

Traumatic injury to the adult central nervous system results in a rapid inflammatory response. Researchers at the Medical University of South Carolina have developed a tool that attenuates and treats the inflammatory disease process in various disease conditions. This tool can be used to treat and/or prevent inflammatory and cytokine mediated responses such as neuroinflammatory responses associated with injury to the central nervous system. This invention has promising application for spinal cord regeneration.

Patent protection has been initiated for this invention. Further information can be obtained through the MUSC Foundation for Research Development following the execution of a confidentiality agreement.

Antibody fragment targeted complement inhibitors and their therapeutic application

Complement plays an important role in the pathology of many autoimmune, ischemia and inflammatory diseases, and is also responsible for many disease states associated with bioincompatibility. Inappropriate complement activation can lead to cell lysis of target structures and tissue destruction. An antibody has been created at the Medical University of South Carolina that increases the efficacy and safety of complement inhibitors by having them target a specific site of complement activation and therefore the specific disease. This allows for a decrease in the dosing of complement inhibitors while still maintaining an effective serum concentration.

Patent protection has been initiated, and further information can be obtained through the MUSC Foundation for Research Development following the execution of a confidentiality agreement.

Use of surfactant and surfactant-associated proteins in the nose and sinuses

The clinical use of products in the lower airways for infectious, inflammatory, allergic and toxin-induced diseases is common. However, these same results have been shown in the upper respiratory tract after the topical application of a product developed at the Medical University of South Carolina.

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