Title: DEPTH SENSOR IMPROVES EFFICACY OF CARDIAC ABLATION
Inventor: Peter Spector
Cardiac arrhythmia is often treated with selective ablation of heart tissue. This blocks the heart’s irregular electrical signals and restores normal rhythm.
In ablation, correct lesion depth is critical to a successful outcome. If too deep, the lesion can reach the lung, aorta, or esophagus and result in fatal complications. If too shallow, it may be inadequate to prevent arrhythmia.
The Need for Feedback
A significant challenge to cardiologists performing ablation has been the inability to accurately judge the ablative energy required. This cannot be determined in advance, and the only attempted solution, electrical signal monitoring, has proven of limited value.
Measuring Lesion Depth
The technology proposed here is a catheter-mounted lesion depth sensor for use during the ablation procedure.
Pairs of electrodes are mounted along the sensor, sharing a midpoint and spaced with increasing distance from the interior to the exterior. Signal amplitude values are measured and fed to a processor, where differential values are calculated to determine signal attenuation. This provides an accurate measure of lesion depth.
With this tool, the cardiologist can adjust the energy and duration as the ablation proceeds. The result is a lesion that prevents arrhythmia but causes no damage to other structures.
Next Steps
After computer modelling, prototypes will be developed for animal testing.
Competitive Advantages
- Anticipate high demand from cardiac electrophysiology facilities.
- Ensures lesion depth is adequate to control arrhythmia
- Reduces need for repeat procedures.
- Prevents damage to surrounding tissues.
- Incorporates easily into standard ablation procedure.
- Introduces no additional risk.
Patent / Licensing Status
Patent pending. Worldwide rights available.
Title: LABELING SYSTEM IMPROVES TRACKING OF SYRINGE CONTENTS
Inventor: Mark Fung
Labels used by medical facilities on plastic blood bags typically include information such as collection facility, blood group, expiration date, and inventory data.
When small quantities of blood products are transferred from the bags to syringes (such as for neonates), the space available for labeling is much smaller. This often results in a syringe that remains unlabeled, or has a small label that is insecurely attached or holds minimal information.
Similar problems arise when medicines and biologics are transfered to unlabeled or poorly labeled syringes. Inappropriate compounds and dosages may be administered and put patients at risk.
Low Cost, High Value System
An effective new way to enhance patient safety and reduce facility liability is a low-cost, modular syringe ID system. This consists of a serrated plastic ring that fits over and encircles plungers of various widths, a plastic connecting strip, and a label. Information can then be added to the label, including alphanumeric data, a barcode, or an RFID tag.
An alternative system replaces the plunger ring with a hole punched into the flange at the top of the syringe barrel. In this version, a wire or plastic loop connects the label to the syringe.
Ensuring Patient Safety
This ID system allows healthcare personnel to securely attach complete information about the syringe contents. It adds minimal cost to the facility’s supply budget while greatly enhancing patient care and workplace efficiency.
Commercialization
The product could be manufactured as a complete syringe system, with the label and connecting components pre-attached to the syringe. It could also be provided as an aftermarket kit that facilities would use to retrofit new and existing stocks of syringes.
Competitive Advantages
- Improves patient safety.
- Increases efficiency of patient care.
- Reduces waste of blood products and medicines.
- Promotes accountability through the healthcare chain.
- Adds minimal cost to a facility’s supply budget.
Patent / Licensing Status
Patent pending. Worldwide rights available.
Title: ANTIOXIDANT PREVENTS ORGAN DAMAGE FROM CONTRAST AGENTS
Inventor: Markus Meyer
Certain radiographic procedures, such as imaging of the vasculature, require large amounts of contrast agents that can inflict life-threatening damage on the kidneys.
Safe, Effective Protection
The readily available antioxidant compound N-Acetylcysteine (NAC) is known to protect many tissues and organs, including the kidneys. The renal protection offered by NAC is especially advantageous in patients having pre-existing risk factors, such as renal failure and diabetes, that increase the potential for contrast-induced damage.
A Single Injection
The current invention is based on the simultaneous administration of NAC and a contrast agent. This approach simplifies preoperative and peri-operative care, and it prevents the contrast agent from reaching the organs in the absence of the protective compound.
When tested in a standard pig model for myocardial infarction, simultaneous intracoronary administration of NAC and contrast agent reduced kidney damage by 50 percent and reduced the size of myocardial infarctions.
Commercialization
This invention could be commercialized in the form of kits that combine NAC and a contrast agent. We believe a large market share could be realized if the kit were priced below the combined cost of the individual compounds.
Next Steps
A larger study of pigs will be conducted to confirm our findings and prepare a human trial. An NIH grant application has been filed to fund this study.
Competitive Advantages
- Antioxidant already proven to reduce or prevent organ damage from contrast agents.
- Invention uses readily available compounds.
- Shown in pig studies to significantly reduce kidney and heart damage.
- Simplifies patient care.
Patent / Licensing Status
Patent pending. Worldwide rights available.
Title: TEST OFFERS EARLY DETECTION OF METASTATIC MELANOMAS AND OTHER CANCERS
Inventor: Marcus Bosenberg
A new blood and tissue test can detect metastatic cancer at an early and treatable stage.
Unprecedented Sensitivity
This noninvasive test, which analyzes specific genes for abnormalities in a chemical process called DNA methylation, detects over 95% of advanced melanomas. It is also up to 1,000-fold more sensitive than other testing methods, enabling it to detect very low levels of cancer.
Improves the Prognosis
The sensitivity of the test enables patients to start treatment at an early stage of their disease, thus improving the prognosis and potentially allowing them to receive lower and less toxic doses of chemotherapy.
A Versatile Test
The test could be used for the detection of cancers other than melanoma. These include cancer of the pancreas, ovary, lung, colon, and breast.
Quantitative Measurement
Rather than detect only the presence or absence of malignant cells, the test is quantitative. It yields measurement data for metastatic cancer cells that can be used in determining a patient’s treatment and monitoring individual response to therapy.
Commercialization
We anticipate a low cost to develop and produce a commercial application of this technology. Entry into the heathcare market should be rapid as the technology does not directly involve a therapeutic intervention.
If commercialized by a medical laboratory, the test could be ordered by healthcare providers. The only specimen required would be a simple blood or tissue sample.
Next Steps
Clinical studies will determine the sensitivity and specificity of the test in patient populations.
Competitive Advantages
- Diagnostic test finds over 95% of advanced melanomas.
- Extreme sensitivity allows early detection & treatment.
- Could also be used for cancers of pancreas, ovary, lung, colon & breast.
- Quantifies cancer cells.
- May be used to monitor effectiveness of chemotherapy.
- Low cost to commercialize.
Patent / Licensing Status
Patent pending. Worldwide rights available.
watch the video on early detection of melanomas
Title: EMBRYONIC STEM CELLS PROTECT AND TREAT HEART PATIENTS
Inventor: Diender Singla
Cell death (apoptosis) and tissue scarring (fibrosis) are major factors in the impairment of cardiac function associated with myocardial infarction. The resulting damage often leads to chronic heart failure and death.
This invention is based on our finding that cardiac apoptosis and fibrosis can be prevented through the use of embryonic stem cells. When implanted in heart tissue, these cells release cytoprotective factors through the mediation of a specific protein, TIMP-1.
Protecting Heart Cells
The chart below illustrates the protective effect of embryonic stem cells on heart cells exposed to hydrogen peroxide (H2O2), a substance that causes cell death through oxidative stress.
When exposed to H2O2 alone, the heart cells exhibit a death rate approximately three times higher than when they are exposed to the H2O2 but protected by the factors released from embryonic stem cells.
In addition, in vivo studies on mice have demonstrated decreased apoptosis and improved cardiac function following stem cell transplantation and release of the cytoprotective factors.
Safety
We expect the stem cells and their
released factors to be generally safe for clinical use. To date, they appear to cause no trauma or major side effects.
Monitoring Treatment
After stem cell implantation, patient progress can be monitored through the use of echocardiography.
Next Steps
In vivo studies will be conducted on large animals to determine the effects and potential mechanisms of action of the released factors.
Competitive Advantages
- Inhibits cell death and
tissue scarring in the heart.
- May be used to prevent and treat ischemic heart disease and myocardial infarction.
- Does not cause trauma in the heart and has no major side effects.
- Echocardiography can be used to monitor treatment progress.
Patent / Licensing Status
Patent pending. Worldwide rights available.
Title: PERINEAL MASSAGER EASES CHILDBIRTH ANXIETY
Inventor: Roger C. Young
Perineal massage in late-stage pregnancy can relieve anxiety and reduce the need for episiotomies and Caesarian deliveries. However, the technique is difficult, requires instruction, is impeded by the mother’s enlarged abdomen, and is often performed incorrectly even with instruction.
A Simple, Effective Solution
This device provides a simple, convenient, and effective way for patients to perform perineal self-massage. The patient grasps two handles connected to an angled retractor that she positions behind her back. Allowing the retractor’s tip to contact the perineum, she then applies massage by moving the handles.
Multiple Sizes & Adjustments
Envisioned as a molded plastic device, the massager could be manufactured in multiple sizes, and the grips and retractor made adjustable to accommodate individual needs and preferences.
Wide Distribution Potential
This simple device would require minimal patient training, and instructions could be provided as pictograms. Thus, it could easily be repackaged and sold in worldwide markets. In the U.S., if medical claims were avoided in marketing the device, regulatory approval would not be required prior distribution. Potential sales channels include pharmacies, maternity supply stores, obstetricians, primary care physicians, and midwives.
Next Steps
Prototypes will be developed and tested on human subjects.
Competitive Advantages
- Relieves anxiety inexpectant mothers.
- Based on a technique long-known to minimize trauma.
- Intuitive to use...instructions can be provided as simple graphics.
- Unique product.
- Multiple sizes possible.
- Potential worldwide market with numerous distribution channels.
Patent / Licensing Status
Patent pending. Worldwide rights available.
Title: DRUG COMBINATION ACTS SYNERGISTICALLY ON CANCER CELLS
Inventor: Benjamin Littenberg
Cancer chemotherapies are often toxic, ineffective, or both. The limitations of these compounds are especially evident in treatment-resistant cancers such as breast and lung tumors.
A New Approach
Now a novel combination therapy has been shown to dramatically increase the kill rate in cancer cell cultures compared to either drug alone.
The combination includes:
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A ribonuclease such as ranpirnase, an investigational drug now in Phase III clinical trials for use in thoracic cancer.
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A thiazolidinedione such as rosiglitazone, an FDA-approved medication currently prescribed for the long-term treatment of diabetes. This compound has also shown a potential antitumorogenic effect.
Effect on Cancer Cells
These charts illustrate the synergistic effect on breast and lung cancer cells:
Lower Toxicity
In clinical trials, both components have been used with little or no toxicity. Thus, the combination is likely to be very well tolerated in clinical practice. Also, the synergistic action allows lower doses of the two drugs, resulting in a less toxic effect on normal cells.
Versatile Treatment
The combined therapy is potentially effective in a wide range of cancerous and precancerous conditions, including breast, ovarian, prostate, and lung cancer.
Personalized Medicine
This invention includes a method for assessing the therapeutic potential in a given patient. Cancer cells can be biopsied and exposed to the treatment to determine whether viability is reduced.
Next Steps
Small-scale animal testing begins in 2008.
Competitive Advantages
- Shown to reduce viability of cancer cell cultures.
- Potentially useful against a wide range of cancer types.
- Individual components well tolerated in clinical trials
- Cell testing predicts individual response to treatment.
Patent / Licensing Status
Patent pending. Worldwide rights available.
Title: TREATMENT OF MELANOMA
Inventors: Marcus Bosenberg, et al.
Summary of Invention: Two small molecules with tumor suppressive activity in malignant melanoma have been identified. Malignant melanoma is difficult to treat with standard procedures, as it often does not respond to chemotherapy and/or radiation therapy and long-term survival remains dismal for this group of patients. New work in the lab of Dr. Marcus Bosenberg has found that expression of these molecules in metastatic melanoma cell lines is low to absent compared to benign primary melanocytes and in vivo expression results in greater than four-fold reduction of tumor size in mouse xenograft studies. These molecules are small secreted proteins (in the 7KD range) that could be delivered directly via intravenous delivery, as well as via gene therapy. These molecules may have similar therapeutic effect in additional types of cancers beyond advanced melanoma.
Advantages: Current therapies for advanced melanoma are systemic and are not effective. These molecules provide the potential for significant survival benefit for advance melanoma and other cancer patients.
Patent Status: Patent pending
Licensing Status: Worldwide rights available
Title: MOLECULAR ACCESSIBILITY ASSAY
Inventors: Jeffrey Blaisdell and Susan Wallace
Summary of Invention: DNA binding proteins play critical roles in all living organisms, notably in pathways known to be affected in certain diseases, such as cancer. An initial step in the characterization of these proteins is purification by affinity chromatography. This typically involves over-expression of the protein and often leads to a fraction of molecules being in a mis-folded (non-active) state. Considering that many studies require an exact quantification of “active” protein molecules, some measurement of activity is needed. This technology provides a novel assay for rapidly determining the binding state of stable protein-DNA interactions based on the molecular accessibility of a fluorescent reporter molecule. Using this assay, the fraction of active protein molecules can be determined rapidly, accurately, and utilizing a high-throughput microplate-based system.
Advantages: Total time to determine the active fraction of a protein preparation is reduced from the standard 1-2 days of a traditional gel-based method, to less than 1 hour for the accessibility-based method. In addition, neither radioactive nor fluorescent labels are required for target DNA sequences. The molecular accessibility assay can be generalized for use with many types of DNA binding proteins using target specific reporter molecules or florophore-tethered nucleic acids and can be modified for various protein/DNA complex experiments including reaction rate analysis, characterization of enzyme active site residues, or binding-site identification to name a few.
Patent Status: Patent pending
Licensing Status: Worldwide rights available
Title: MAINTAINING SELF-RENEWING, PLURIPOTENT EMBRYONIC STEM CELLS
Inventors: Dinender K. Singla
Summary of Invention: Embryonic stem (ES) cells are derived from the inner cell mass (ICM) of the pre-implantation embryo and are capable of self-renewal (proliferation without differentiation) and pluripotency (the capability to differentiate into all three of the embryonic germ layers). With these capabilities, ES cells hold the promise to serve as a source of cells in transplantation medicine, provided that growth of these cells is done in a way that reduces opportunity for contamination by infectious agents from feeder cells or other animal sourced contamination. This invention identifies wnt3a as another factor involved in keeping ES cells capable of self-renewal and pluripotency and provides methods for use of media conditioned by wnt3a expressing cells or media containing wnt3a as one of multiple supporting factors as alternatives for feeder cell and LIF maintained ES cells.
Advantages:Identification of the role of wnt3a in ES cell self-renewal and pluripotency offers another option in the arsenal of feeder free culture methods for growth of and future therapeutic use of ES cells.
Patent Status: Patent pending
Licensing Status: Worldwide rights available
Title: MONOCLONAL ANTIBODIES FOR MCJ DETECTION
Inventors: Mercedes Rincon, et al.
Summary of Invention: Loss of expression of the methylation controlled J (MCJ) protein in ovarian cancer has been found to be an indication of poor drug response in patients, and now has been associated by Dr. Rincon and her group with drug response in breast cancer. The Rincon group has developed three monoclonal antibodies against the N-terminus of human MCJ and is currently using the antibodies to confirm the role of MCJ in the response of breast cancer to specific chemotherapy treatment. The anti-MCJ antibodies are currently available for both research and as a potential diagnostic for ovarian, breast and other cancers.
Advantages: No monoclonal anti-MCJ antibodies exist in the current market today and current diagnosis of ovarian, breast, and other cancers does not include a test for drug response. Use of such a diagnostic tool will help doctors determine the best specific treatment, providing better response and recovery for their patients.
Patent Status: Patent pending
Licensing Status: Worldwide rights available
Title: DETECTION OF GLUTATHIONYLATED PROTEINS
Inventors: Yvonne Janssen-Heininger, et al.
Summary of Invention: This invention represents a new method (process) to detect oxidated proteins, in particular glutathionylated proteins. In addition to detection, spatial location and concentration of these oxidated proteins can be achieved. Oxidative stress conditions can be detected both in vitro and in vivo.
Prior to this invention, the only method available to detect S-nitrosylation diagnostically was the use of an antibody directed against S-nitrosocysteine which has questionable specificity, as the NO-cysteine bond (known as S-nitrosylation or S-nitrosation is highly labile). Thus using our method, the ability now exists to visualize S-nitrosylated proteins in intact cells or tissues which is not possible with currently accepted methods. This offers the advantage to visualize the altered NO function which is believed to be important in many diseases.
Advantages: Hospitals and research centers can use this invention to determine functional Glutahionylated proteins in cells or tissues from patients or animals. This may serve as a diagnostic tool in diseases, and can also evaluate the effectiveness of NO-delivery strategies.
Patent Status: Patent application published: 20080014595
Licensing Status: Worldwide rights available
watch the video on detection of glutathionlyated and nitrosylated proteins
download glutathionlyated proteins article (Biochimica et Biophysica Acta, 2006)
(OTT invention description)
Title: DETECTION OF NITROSYLATED PROTEINS
Inventors: Yvonne Janssen-Heininger, et al.
Summary of Invention: This invention represents a new method (process) to detect NO-conjugated cysteines in proteins (S-nitrosylation) in intact cells or tissues. We have taken the approach published by Jaffrey et. al., in Nature Cell. Biol. In 2001 which first described a biotin switch method to detect S-nitrosylated proteins in homogenized cells and tissues for proteomics approaches. We have modified this approach by using other chemical reagents, and adapted it in order to be able to visualize the conjugation of NO to proteins in intact cells or fresh frozen tissues. This new method provides a direct approach to directly visualize NO conjugation to proteins that can be used in diagnostic settings.
Prior to this invention, the only method available to detect S-nitrosylation diagnostically was the use of an antibody directed against S-nitrosocysteine which has questionable specificity, as the NO-cysteine bond (known as S-nitrosylation or S-nitrosation is highly labile). Thus using our method, the ability now exists to visualize S-nitrosylated proteins in intact cells or tissues which is not possible with currently accepted methods. This offers the advantage to visualize the altered NO function which is believed to be important in many diseases.
Advantages: Hospitals and research centers can use this invention to determine functional NO in cells or tissues from patients or animals. This may serve as a diagnostic tool in diseases, and can also evaluate the effectiveness of NO-delivery strategies.
Patent Status: Patent application published: 20050238734
Licensing Status: Worldwide rights available
watch the video on detection of glutathionlyated and nitrosylated proteins
download nistrosylated proteins article (Nitric Oxide Biology and Chemistry, 2004)
(OTT invention description)
Title: HIGHLY SENSITIVE IMMUNOASSAYS AND ANTIBODIES FOR DETECTION OF BLOOD FACTOR VIII
Inventors: Behnaz Parhami-Seren, Kenneth Mann
Summary of Invention: The invention provides highly sensitive immunoassays and antibodies capable of accurate detection of FVIII concentration in the plasma of normal human subjects and those with hemophilia. This assay detects FVIII concentrations significantly below 1% normal physiological concentration which is important for management of
hemophilia and in FVIII replacement therapy. Levels of detection exhibited by particular embodiments greatly exceed those of previously described assays. This assay works between 1-4000 pM (0.001-4 nM, 3 orders of magnitude range). The enhanced sensitivity of the assays is contributed in part by using a combination of two antibodies that can bind human FVIII protein in plasma with high affinity and selectivity following treatment with an agent that causes the FVIII to dissociate from FVIII-binding molecules to which it is bound, such as Von Willebrand factor (vWF).
Advantages: Sensitivity of the assay is contributed in part by the very high binding affinity of a preferred capture antibody, and by ability of the anti-FVIII antibodies used in the assay to bind to FVIII protein under conditions in which the protein is dissociated from FVIII-binding molecules such as von Willebrand factor after treatment with a reducing agent. Using this method, the concentration of FVIII protein detectable in the sample is between about 0.001 nM and 1000 nM. This assay is not only useful for quantifying FVIII in healthy individuals and hemophilia patients, it can also be used to quantify FVIII in FVIII concentrates. FVIII assay is useful to quantify FVIII in patients with anti-coagulant antibodies (anti-phospholipid antibodies such as Lupus where APTT cannot be used).
Patent Status: Patent pending
Licensing status: Worldwide rights available
Title: MANIPULATION OF NITRIC OXIDE SYNTHASE TO PROMOTE WEIGHT LOSS OR WEIGHT GAIN
Inventors: Richard Galbraith, MD, Ph.D.
Summary of Invention: Obesity is an overwhelming health problem, with numerous strategies that have had marginal results in reducing the overall problem being overweight, which affects 60% of the US population. The inhibition of nitric oxide synthase (NOS) activity in the hypothalamus promotes weight loss. Targeting of NOS activity to the hypothalamus circumvents the side effects of systematic NOS modulation. The foundation of the invention is based on the understanding that the administration of cobalt protoporphyrin IX (CoPP) into the brain results in prolonged weight loss (in rodents). It is anticipated that the compound would be administered intracranially to the hypothalamus. Existing stereotactic imaging and delivery devices would make this a lower risk treatment than current gastric bypass surgery for weight loss, which currently has an 11% morbidity rate requiring surgical intervention for correction. This same targeting could be altered to induce the opposite affect, namely weight gain for those suffering anorexia. This form of administration would obviate the temptation for a patient to decrease caloric intake inappropriately.
Advantages: Targeting of hypothalamic NOS activity circumvents the side effects of systemic NOS inhibition. By targeting administration of CoPP to the hypothalamus, the dose of CoPP required is substantially less than the dose needed when administered systemically in order to effectively promote weight loss or weight gain.
Patent Status: Patent pending
Licensing Status: Worldwide rights available
Title: DETECTION OF TUMOR CELLS
Inventors: David Krag, MD
Summary of Invention: This invention verifies the type of cell identified in a test which determines the presence of micrometastasis in blood or bone marrow. Two cytokeratin antibodies are used which are derived from different species or are from different isotypes of the same species. These two antibodies have slightly different antigen targets within the cell. Some may overlap, some may not. A third set of antibodies is utilized to identify hematopoetic cells and to eliminate cross reactive cells. Each antigen/antibody reaction is detected separately with either different fluorescent emissions or colors. Previous methods have utilized only one cytokeratin for detection and identification. Or other methods have utilized one cytokeratin and plus one “non cytokeratin” antibody. This method could be utilized as part of a staining/detection kit for the presence of micrometastasis by a commercial vendor.
Advantages: This invention allows for further verification of cytokeratin positive stained cells. Studies have shown that some types of hematopoetic cells will stain with one cytokeratin antibody thereby giving an inaccurate result to the presence of micrometastasis. By utilizing other antibodies detected by other means (colors, chromogens), a falsely stained cell will be identified and only true micrometastasis will be detected.
Patent Status: Patent pending
Licensing status: Worldwide rights available
Title: METHODS FOR DETERMINING NOTCH SIGNALING AND USES THEREOF
Inventors: Cedric S. Wesley
Summary of Invention: Notch signaling regulates the differentiation of almost all tissue in all animals from worms to humans and is critical for normal development. Loss or abnormal Notch signaling is linked to numerous cancers, birth defects and neurological diseases, including dementia, stroke and Alzheimer's, but until now identification of the level of Notch signaling in vivo has been notoriously difficult. This invention provides methods for the detection of Notch signaling in vivo based on a new discovery that the level of certain truncated Notch polypeptides and the ratio of the amount of such Notch truncated polypeptides to the amount of full-length Notch molecules is an accurate indicator of the level of Notch signaling. As a result, simple reagents and kits can provide researchers and clinicians a direct method of measuring Notch levels in vivo for basic research, diagnostics and screening for therapeutics.
Advantages: To date there is no reliable, predictive, and generally applicable assay or method to determine the level of Notch signaling in vivo in the course of normal tissue differentiation, normal organ development and abnormal or disease development. This invention will enable determination of Notch signaling in all of these situations.
Patent Status: Patent pending
Licensing status: Worldwide rights available
FOCUS FEEDBACK SYSTEM FOR MICROSCOPY
Inventors: David Warshaw, Guy Kennedy
Summary of Invention: There has been a recent surge in the use of totally internally reflected (TIR) microscopy for high spatial resolution imaging of objects at a glass-liquid interface. Most often TIR microscopy is used in fluorescence imaging and thus referred to as TIR fluorescence microscopy (TIRFM). For “through the objective” TIRFM to work properly, a focused laser beam enters the back of the objective close to the outer edge of its diameter. The light leaves the objective into the sample at the required critical angle for TIR. The light is then TIR at the glass – liquid interface where it creates an evanescent field propagating into the liquid from the glass surface. This invention takes advantage of the returning TIR light, which is adjusted such that the reflected beam returns back into the objective lens when the image plane is coincident with the evanescent field. When the objective is slightly out of focus, the returning light impinges on a different area of the objective lens, causing the light refracted by the lens to exit the objective at a different angle. Also, if the objective is greatly out of focus, or the coupling oil between the objective and glass has an air bubble, no light will return through the objective. Using this phenomenon, our invention provides an accurate means of establishing the critical distance between the high NA objective and the specimen plane where TIR is desired, and confirms the quality of TIR. This invention uses the return TIR beam as a signal source which can have multiple applications including focus control and TIR quality indication in a TIRFM system.
Advantages: At present there are no automated methods for determining whether or not total internal reflectance (TIR) has been obtained in a sample slide on a microscope stage. This invention provides a rapid and extremely accurate method for confirming the existence of TIR. In addition, the same signal used to confirm TIR can be used to drive a feedback-based auto focusing system. This would provide significant advantages over any existing focusing system by being rapid, extremely sensitive, and accurate.
Patent Status: Patent issued: 7,075,046
Licensing status: Worldwide rights available
PRODUCTION OF RECOMBINANT PROTEINS IN
ACANTHAMOEBA CASTELLANII BY STABLE TRANSFECTION
Inventor: Erik Bateman
Summary of Invention: A system for the stable expression of recombinant proteins in the organism Acanthamoeba castellanii has been successfully developed. It is the use of this organism for protein production, rather than specific plasmids, for which patent protection is sought. Acanthamoeba has previously never been used successfully for this purpose.
Several plasmids designed to express proteins in Acanthamoeba were made. These contain the gene for neomycin phosphotransferase (Abbr.: neor), an enzyme which confers resistance to the drug neomycin G418. Expression of neo r is driven by an Acanthamoeba promoter previously isolated in the inventor’s lab. Other promoters, such as commercially available viral promoters do not work in Acanthamoeba. DNA is introduced into Acanthamoeba using Superfect (Qiagen). After several days of culture in the presence of neomycin G418, expression of neor is evidenced by cell growth. Expression of neor was confirmed by Western blotting.
While this simple experiment demonstrates the proof of concept, in order for the system to be useful, a second promoter was introduced into a different part of the basic neo plasmid (above), and used to express green fluorescent protein (GFP). Transfected cells were again grown in the presence of neomycin G418, and after several days, cell growth became apparent. Microscopic analysis showed that GFP is expressed in all cells, and this was confirmed by Western analysis as described above.
A fusion protein containing GFP and Acanthamoeba TBP (TATA binding protein) has also been stably expressed in Acanthamoeba (not shown).
Advantages: The Acanthamoeba expression system is presented as an alternative to existing systems such as E.coli, yeast, Pichia or insect cells. Each of these has advantages and disadvantages, but some proteins are not well expressed in existing systems, and alternatives such as Acanthamoeba are potentially useful. An inducible promoter (CSP21) is available for expression of toxic proteins, and is being tested at time of application.
An additional feature unique to Acanthamoeba is that it lacks a cell wall and is therefore very easy to lyse; the first step in producing a recombinant protein. Acanthamoeba are simple to grow in shake cultures on a large or small scale using inexpensive media. Acanthamoeba can also be cultured to high density in fermentors. Stable cell lines can be induced to form non-growing encapsulated cysts, which can be stored at room temperature for months to years. These cysts are fully viable and retain the genes encoding neor and GFP. No other system offers this convenient way to store valuable cell lines.
Patent Status: Patent issued: 7,175,998
Licensing status: Worldwide rights available
watch the video on Acanthamoeba
Title: DISPOSABLE FIBER OPTIC TIR LAUNCHING SYSTEM
Inventors: Guy Kennedy, David Warshaw
Summary of Invention: Totally internal reflected fluorescence microscopy (TIRFM) has a fast growing user group in the scientific community anxious to use its high spatial resolution imaging of objects and reduction of background fluorescence.
This invention provides for a microscope slide based TIRFM platform. Using a fiber optic light guide to launch laser light into a microscope slide, the light totally internally reflects and produces an evanescent energy gradient suitable for TIRFM. The slide based TIRFM platform can be used on nearly any microscope with very little or no special modifications needed. In addition, the simple design provides for simple, rapid product development, refinement and manufacturing scale-up with low overhead.
Advantages: The ability to grow the current user group for TIRFM is limited by the high costs of the high numerical aperture objective lenses and highly processed set of associated optics currently needed to do TIRFM. This simple, inexpensive, disposable microscope slide approach provides a low cost alternative, as well as the possibility of a disposable component for current TIRFM flow chambers eliminating difficult and time consuming cleaning processes.
Patent Status: Patent application published: 20060280404
Licensing status: Worldwide rights available
watch the video on TIRF microscopy
Title: USE OF INHIBITORS OF PACAP RECEPTOR ACTIVITY FOR TREATMENT OF OVERACTIVE BLADDER AND PELVIC FLOOR PAIN SYNDROME
Inventors: Margaret Vizzard, Peter Zvara
Summary of Invention: Pituitary adenylate cyclase-activating polypeptide (PACAP) is a polypeptide hormone
that stimulates andenylate cyclase in pituitary cells. It has now been discovered that inhibitors of PACAP
receptor activity can be used for treating pelvic floor pain syndrome and overactive bladder. These
receptors are membrane-bound proteins existing in various tissues. Since significant differences in functions
of PACAP receptors are not observed among animal species, PACAP receptors can be used regardless of their
origin. Disorders such as urinary bladder inflammation and chronic cystitis increase PACAP immunoreactivity
in micturition pathways. Inhibiting PACAP may be useful in the treatment of these diseases as
well as overactive bladder and pelvic floor pain syndrome.
Advantages: The inventors have demonstrated the treatment for overactive bladder and pelvic floor
pain syndrome in an animal model. There are currently no therapeutic interventions that are available
for these indications. Therefore, the development of these compounds could provide an important breakthrough for this population. UVM is looking for commercial partners to further the animal testing in
order to bring the inhibitors to Phase I clinical trials.
Patent Status: Patent application published: 20050129687
Licensing status: Worldwide rights available
Title: ANTI-FUNGAL AGENTS AND ASSAY
Inventors: Douglas I. Johnson, Ph.D., Kurt A. Toenjes, Ph.D.
Summary of Invention: The pathogenicity of many opportunistic fungal pathogens depends on their ability to switch between budded and hyphal growth patterns. The inventors have identified a number of small molecules that may be used to treat fungal infections, including Candida albicans and Aspergillus flavus, by inhibiting the budded-to-hyphal phenotypic transitions required for pathogenicity. The inhibitors and related structural derivatives have been identified, characterized, and a high-throughput small molecule assay has been developed to screen additional candidates. Identification of the cellular targets for these inhibitory small molecules using biochemical and cell biological approaches is currently underway. Controlling opportunistic fungal infections in immuno-compromised individuals is critical for their long term survival and a factor in over 90% of AIDS patients alone.
Advantages: The inventors have developed a robust and reproducible assay that is amenable to high-throughput screens of inhibitory and stimulatory small molecules. The inventors have used the assay to identify and characterize novel small molecules that can inhibit the budded-to-hyphal morphological transition that is essential for fungal virulence, and therefore, are potential therapeutic molecules against fungal infections and biofilms.
Patent Status: Patents issued: 20060194769 & 20060154991
Licensing status: Worldwide rights available
Title: EMERGENCE OF A R-TYPE CA2+ CHANNEL CONTRIBUTES TO CEREBRAL ARTERY CONSTRICTION FOLLOWING SUBARACHNOID HEMORRHAGE
Inventors: George Wellman, Masanori Ishiguro
Summary of Invention: Cerebral aneurysm rupture and subarachnoid hemorrhage (SAH) inflict disability and death among thousands of individuals each year. The consequences of SAH following cerebral aneurysm rupture are devastating, with mortality rates as high as 50% and the majority of survivors left with moderate to severe disability. Cerebral vasospasm, characterized as a delayed and sustained arterial constriction, is a major contributor to these high morbidity and mortality rates. Large diameter arteries have been implicated in contributing to decreased blood flow resulting in SAH. However, small diameter arteries, below the resolution limits of standard angiography, may also be affected by subarachnoid blood. The invention is based in part on the discovery that such small diameter arteries have R-type voltage dependent calcium channels that are involved in regulating calcium flow and play an important role in decreased cerebral blood flow observed following SAH. It has been discovered that SAH leads to enhanced Ca2+ entry in myocytes of small diameter cerebral arteries through the emergence of R-type voltage-dependent Ca2+ channels (VDCCs) encoded by the gene Cav2.3.
Advantages: The inventors believe that the administration of an R-type voltage-dependent calcium channel inhibitor will allow the management of the cerebral blood flow during a time when it would normally decrease blood flow in small diameter arteries. The emergence of Cav2.3 in cerebral arteries 2.3 in cerebral arteries following subarachnoid hemorrhage is unique and the fi rst to be described in the expression of this ion channel in vascular smooth muscle. A unique peptide has been identified that may selectively antagonize Cav2.3 and therefore reverse subarachnoid hemorrhage-induced vasospasm.
Patent Status: Patent application published: 20060229269
Licensing status: Worldwide rights available
watch the video on reversing vasospasm
Title: HYBRID DESIGN KNEE JOINT PROSTHESIS
Inventors: Bruce Beynnon, Stephen Incavo
Summary of Invention: This invention is directed to a knee joint prosthesis having femoral, patellar, and tibial components having surfaces for receiving bone cement which promote bone ingrowth. The femoral component is concave in shape wherein the posterior end forms two condyles along an axis of the femoral component, and the bone facing surface contains surfaces for receiving fixation material adjacent to the anterior and posterior ends, and a central surface for promoting one ingrowth. There is a corresponding tibial design as well as a patellar component with a peripheral surface designed to receive fixation material. These designs utilize a unique “hybrid” design that allows a combination of both cement and natural bone ingrowth for fixation.
Advantages: Hybrid knee replacement prosthetic components have been developed in an attempt to overcome the loosening problems of either bone cemented or bone ingrowth methods of replacement. Current hybrid designs have limited surface area for cement. There are several aspects of the design of this invention that overcome this limitation, while allowing a large undersurface area for bone ingrowth for long term stability. Mechanical data and drawings are available under a confidentiality agreement.
Patent Status: Patent application published: 20070100461
Licensing status: Worldwide rights available
Title: METHODS AND COMPOSITIONS FOR TREATING TOXOPLASMA
Inventors: Mariana Matrajt
Summary of Invention: Opportunistic infections of the intracellular protozoan parasite Toxoplasma gondii (T. gondii) can cause life threatening disease in immuno-compromised individuals, including cancer chemotherapy patients, transplant recipients, and individuals with AIDS or other immunosuppressive disorders. Virtually any nucleated animal cell can be infected, but the cellular immune response typically controls such infections rapidly leaving a latent infection consisting of bradyzoite cysts that can re-emerge periodically. Critical to the activation of bradyzoite cysts to an active infection is the transfer to an active tachyzoite stage. Professor Matrait has identified a regulator of this conversion pathway from bradyzoite to tachyzoite in the form of a heat shock protein of T. gondii. As expected, inhibitors of this protein stop the inter-conversion process, but more critically, inhibitors destroy even the potential for reactivation of the latent cysts by eliminating the bradyzoite cysts altogether.
Advantages: Currently there exists no effective treatment for chronic toxoplasmosis due to a lack of drugs capable of eliminating the bradyzoite cysts. This invention identifies potential inhibitor therapeutics and provides for a screen for the identification of other inhibitors.
Patent Status: Patent application published: 20060269618
Licensing status: Worldwide rights available
Title: Noninvasive Pulmonary Airway Resistance Measurement System
Inventor: Jason Bates, Charles Irvin, Lennart Lundblad, John Thompson-Figueroa
Summary of Invention: The assessment of lung mechanical function in small animals, particularly mice, is essential for many investigations into the pathophysiology of pulmonary disease. The forced oscillation technique applied in anesthetized tracheostomized animals provides the most accurate and specific assessment of lung function but is highly invasive. Unrestrained plethysmography in conscious animals provides a parameter called PenH, but this quantity is actually a reflection of the control of breathing and not lung mechanics. Thus, there is currently no completely noninvasive method available for determining lung function in small animals, despite the continued erroneous use of PenH in this regard. However, our research has shown that unrestrained plethysmography would provide a valid means for following changes in lung mechanical function if it could be coupled to independent measurements of changes in lung volume. The invention combines unrestrained plethysmography with the measurement of changes in lung volume using orthogonal video images of the thorax, titled unrestrained video-assisted plethysmography (UVAP).
Applications/Advantages: This device will provide researchers with the ability to follow changes in airway resistance in mice, in response to both acute and chronic interventions, without harming or even interfering with the animal in any way. This will greatly increase the throughput possible when screening large numbers of animals, and will allow non-destructive testing of valuable animal models of lung disease.
Patent Status: Patent application published: 20060030770
Licensing status: Worldwide rights available
Title: Crystal Structure of Factor Vai and Method of Identifying Blood Factor Va Modulators
Inventor: Stephen Everse, et al.
Description: The structure (the coordinates) of bovine factor Vai reveals for the first time the domain organization and more importantly the atomic positions of atoms forming the structure. Factor Vai is a physiological relevant inactivation product of factor Va produced by activated protein C. Purified bovine factor Vai in 20 mM HEPES, 150 mM NaCl, 2 mM CaCl2 (pH 7.4) was crystallized at ~6.5 mg/mL by the vapor diffusion sitting-drop method at 12°C against 200 mM MgCl2, 16% PEG 3350 (pH 5.0). After 5-21 days, diffraction quality crystals appeared. Three isomorphous heavy atom derivative crystals were identified from native crystals soaked in mother liquor containing either 10 mM tetrakismercuroxymethane (TAMM), 10 mM ethylmercury (EtHg) or 2.5 mM lead acetate (PbAc).
Advantages: Prior to this structure models of factor Va were built on homologous proteins. Though they were fairly accurate in determining the fold of the individual domains they did not correctly identify the domain organization and therefore the more subtle interactions that take place. Nor were the models able to correctly identify the location of a bound copper atom.
Possible commercial applications: Factor Va serves as the cofactor in the prothrombinase complex that results in a 300,000 fold increase in the rate of thrombin generation compared to factor Xa alone. In its role, factor Va interacts with both factor Xa and prothrombin. Structural based design of therapeutics continues to be a productive commercial avenue for the design of new drugs. The best known example of this are the inhibitors designed for the HIV protease which are still some of the most effective drugs to date. In addition, with the high degree of identity shared between factor Va and factor VIIIa (hemophilic factor) it would be appropriate to also use this structure to build models of factor VIIIa and use that to design potential therapeutics.
Patent Status: Patent pending
Licensing status: Worldwide rights available
Title: Toxoplasma Gondii Apical Membrane Antigen-1
Inventor: Gary E. Ward, Brian Ward
Description: Toxoplasmosis is among the most common parasitic diseases of man. One child out of every 1000-4000 born in the USA acquires Toxoplasma infection in utero, with rates as high as 1 in 100 in other parts of the world. Approximately 45% of women who acquire an acute infection during pregnancy and are not treated will give birth to a congenitally infected child. This invention relates to the protein termed TgAMA-1 and is part of the extensively studied apical membrane antigen-1 (AMA-1) family of proteins. Dr. Ward has sequenced TgAMA-1, characterized it and produced recombinant protein for use in vaccine methods and formulations. The vaccines are useful for vaccinating the animal reservoir species for Toxoplasma (pigs, sheep, cats) as well as humans.
Toxoplasma gondii belongs to a phylum of parasitic protozoa (the phylum Apicomplexa) that includes Plasmodium, the causative agent of malaria, Cryptosporidium, a water-borne pathogen of worldwide medical importance, and several significant veterinary pathogens including Theileria, Sarcocystis, and Eimeria. All of these parasites are obligate intracellular parasites, and the pathogenesis of the diseases they cause are directly due to repeated cycles of host cell invasion, growth, and host cell lysis. Agents that interfere with the ability of these parasites to invade cells of their hosts could therefore be of medical and veterinary importance.
Using high-throughput screening of large collections of structurally diverse small molecules, we have identified 115 compounds that affect the ability of Toxoplama gondii to infect mammalian cells. 92 of these are invasion inhibitors, and 23 and invasion enhancers. Both inhibitors and enhancers have value as research reagents, for studies aimed at elucidating the mechanisms of host cell invasion. Both classes also have potential value as lead compounds for the development of novel anti-Toxoplasma chemotherapeutics. Preliminary results show that at least some of the compounds also inhibit the invasion of malaria parasites into red blood cells, suggesting that these compounds or derivatives of these compounds may also be useful in the treatment of malaria and the diseases caused by other Apicomplexan parasites.
Advantages: Current therapies and preventative treatments suffers from short shelf life, the induced immunity declines significantly in the first two years post-inoculation, and has shown to establish infection in some cases, causing infection of the plecenta and damage to the fetus.
Patent Status: Patent issued: 6,902,926
Licensing status: Worldwide rights available
Title: Identification Of Anti-Protozoal Agents
Inventors: Gary E. Ward, Kimberly Carey, Timothy Mitchison (Harvard Medical School), and Nicholas Westwood (Harvard Medical School)
Description: The present invention provides methods of identifying compounds capable of inhibiting protozoal infection. It will be appreciated that there is an urgent need for new chemotherapeutic agents to combat protozoal parasites that are sufficiently effective, do not have harmful side effects, and are not difficult or expensive to administer. The anti-protozoal compounds should be active against a broad spectrum of protozoa, while remaining non-toxic to human and other mammalian cells. Using a novel screening method, the inventors have developed a library of inhibitors of parasites that prevent invasion into a cell. The assay system can measure the ability of a parasite to invade a cell, as well as the ability of that parasite to increase or decrease its invasion activity. Pharmaceutical compositions can therefore be designed to treat microbial infections.
Advantages: Current therapies and preventative treatments suffers from short shelf life, the induced immunity declines significantly in the first two years post-inoculation. The treatments often have severe adverse side affects, require hospitalization, and are not always effective. The inhibitors discovered are believed to be active against a broad spectrum of protozoa, while remaining non-toxic to human and mammalian cells.
Patent Status: Patent issued: 7,067,315
Licensing status: Worldwide rights available, Licensing/ Sharing agreement in place with Harvard Medical School
Title: Knee Joint Prosthesis With a Femoral Component Which Links the Tibiofermoral Axis With the Patellofemoral Axis of Rotation
Inventor: Bruce Beynnon, Stephen Incavo, Kathyrn Coughlin
Summary: This invention is directed to a knee joint prosthesis that is configured to orient the coronal and rotational position of the tibia and the position of the patella relative to the femoral epicondylar (FE) axis of the femur after surgery. The design was based on testing cadaver specimens in a fixture designed to stimulate squatting. Electromagnetic sensors were positioned to measure the kinematics of the tibia, femur, and patella. After testing, the joint capsule was opened, and the articular surfaces of the femoral condyles were examined. The regions of the tibiofemoral contact were digitized, and the data points of each condyle were fit to a sphere. Using these techniques, an optimal FE axis can be developed.
Advantages: Two important factors need to be considered in total knee arthroplasty: a) the screw home mechanism does not necessarily occur after total knee arthroplasty because the geometry of most commercially available implants do not replicate that of the normal knee, and b) the screw home mechanism tends to move the patella laterally by externally rotating the tibial tubercle relative to the femur as the knee is extended. In applying the findings of this invention, one could ensure an implant that provides a rotational position that would more closely resemble what the normal knee experiences through a majority of the range of motions.
Patent Status: Patent application published: 20050102032
Licensing status: Worldwide rights available
Title: METHODS AND COMPOSITIONS FOR OPTICAL DETECTION OF SINGLE-STRANDED POLYNUCLEOTIDES
Inventors: Scott Morrical, Ph.D., Na Qian, Ph.D.
Description: A conjugated, fluorescent molecule has been conjugated that bind to single strand polynucleotides in a way that is unique to current commercially available fluorescent stains. The fluorescence properties of Gp32F protein make it useful as a coupling system for monitoring DNA and RNA reactions that involve conversions between single- and double-stranded states. The Gp32F probes have proven to be highly sensitive, with assays conducted at or below the nanomolar threshold. The Gp32F protein binds to single-stranded polynucleotides including single-stranded gaps, tails, flaps, loops, or bubbles within double-stranded DNA or RNA molecules, allowing detection and localization by fluorescence microscopy. Biomedical research applications of this detection system include analyses of nucleic acid intermediates: DNA replication, DNA repair pathways including mismatch of repair, double-strand break repair, and nucleotide excision repair, homologous recombination, transcription, translation, and RNA processing.
Advantages: This invention is a highly sensitive research tool for the fluorescent detection of DNA and RNA reactions previously unattainable with current commercially available methods. Single and double stranded polynucleotides are typically both stained, and therefore undifferentiated. This invention overcomes this limitation.
Patent Status: Patent application published: 20070178455
Licensing status: Worldwide rights available
Title: MONITORING INTRACRANIAL PRESSURE DYNAMICS USING WHOLE-BODY PHYSIOLOGY
Inventor: William Lakin, Paul Penar, Scott Stevens, Bruce Tranmer
Description: The whole body mathematical model for intracranial pressure dynamics can be used to study the development of pathological conditions and can thus be used to test the efficacy of various clinical treatment modalities, including the potential effect of a new drug. This device could alert Intensive Care Unit personnel when there is a danger of deterioration in a patientís condition. This model considers the intracranial pressures as they relate to the whole body physiology and the environment. As a result, the model has a wide variety of applications.
Advantages: All prior intracranial pressure models have been forced to consider the region inside the skull as a closed system. With this approach, 16 separate parts are used to achieve adequate spatial resolution. Variable compliances and resistances must be used within the intracranial space to realistically for cerebrovascular autoregulation, cerebrospinal fluid (CSF) production, and the volume adjustments produced by changing pressure differences. With extracranial physiology now an integral part of the model, flows involving filtration between the capillaries and tissues, lymphatic flows, and the regulation of arterial pressure and cardiac activity by the sympathetic nervous system is included.
Patent Status:Patent issued: 7,182,602
Licensing status: Worldwide rights available
watch the video on intracranial pressure dynamics
Title: A NUMERICAL MODEL DESCRIBING BLOOD COAGULATION AND ITS REGULATION
"Clotspeed II™"
Inventor: Kenneth Mann, Mathew Hockin, Keven Cawthern, Stephen Everse, Thomas Smith
Description: The invention is a mathematical algorithm which provides a synthesis for all the relevant procoagulant reactions in the blood clotting process and the influence of the stoichiometric anticoagulants on the process. This model involves more than 25 molecular species interacting in more than 30 chemical steps. It permits moment to moment analysis of the concentrations of all active species in the reaction system. It is robust, i.e. less than 20 seconds computational time, and accurately reflects the empirical physical data obtained when constructs of the same reactions are developed. Advantages: It is possibly the only model which will accurately predict how blood clotting reactions will progress in complex biologically relevant media. It’s predictive capability can identify appropriate targets for pharmacologic intervention in thrombosis.
Patent Status: Patent application published: 20060166176
Licensing Status: Worldwide rights available
watch video on Clotspeed II
Title: DNA DELIVERY SYSTEM: RIP60 NUCLEIC ACID COMPOSITION AND USES
Inventor: Nicholas Heintz
Description of the Technology: Using a one hybrid screen in yeast, we cloned a protein called RIP60 that binds to the dhfr origin of replication. The protein is 62 kd in length and contains three clusters of zinc fmgers (ZFs) that we call hands Z1, Z2, and Z3. The central Z2 cluster contains ZFs 6-8; it is located adjacent to a proline-rich region that we believe is involved in protein multimerization. Using ligation enhancement assays and atomic force microscopy (AFM), we showed that Z2 will support DNA looping between two RIP60 binding site, an activity that we had demonstrated previously for the fall length protein.
We then went on and used AFM to examine binding of Z2 to linear, supercoiled, and relaxed circular DNA. Z2 has relaxed binding specificity as compared to the full length protein, and it bound all these substrates avidly. We then looked at the ability of Z2 to bind to large bacterial artificial chromosomes (BACs). Z2 binds at multiple dispersed sites, and then condenses the BAC DNA into a structure with a protein core and multiple DNA loops (the structure looks like a flower with 6-8 petals). Using cationic lipids, we can then condense the loops onto the protein core, resulting in a spherical particle we think of as an inside-out virus. Remarkably, cells ingest these molecules with very high efficiency. It is trivial for us to introduce a 150 kb BAC into cells in culture at 25% efficiency. There is no need for specific sequences in the DNA, and it can be in a linear, relaxed, or supercoiled state.
The presence of the 26 kd OST purification tag on Z2 does not inhibit DNA condensation or uptake, suggesting that we can engineer fusion proteins with amino terminal cell recognition domains (e.g. toxins, growth factors, etc) that would allow targeting to specific cell types. Moreover, the true value of this technique is that you can put an entire gene into cells, including boundary elements, promoter and enhancers, exons and introns, and 3’ flanking sequences. Introduction of the entire locus obviates all regulatory considerations - all of the regulatory signals within and without the gene are present in their native form. Coupled with the work of Hunt Willard, which shows large episomes are stable in the absence of selection when they contain centromeric repetitive DNA, we expect that we could use this method for gene therapy. No viruses, no integration, no heterologous promoters or other regulatory elements - just the native gene in an episomal state.
Advantage of the Technology:
We therefore think the Z2 core provides a highly flexible platform for the delivery of large DNA molecules into cells. In addition, work by many labs shows that the DNA itself can be decorated with peptides or other conjugates, again for cell targeting, increasing stability, etc. The method is simple beyond belief - mix soluble protein with DNA, incubate 15 min at room temperature, and then feed to cells. The protein is not toxic and the cells are 100% viable.
Proprietary Position: Patents issued: 6,780,986; 6,903,077
Title: BREAST CANCER TARGET ErbB2
Inventors: Lyn Oligino, David Krag
Description: ErbB2 (also known as HER2 or neu) is a member of the ErbB family of growth factor receptors, which includes ErbB1 (also known as epidermal growth factor receptor). ErbB2 is a membrane protein containing a cysteine-rich extracellular domain (ECD), a transmembrane domain, and an intracellular tyrosine kinase domain. ErbB2 is overexpressed on the surface of breast cancer cells in approximately 30% of newly diagnosed patients and is associated with a poor prognosis. Importantly, metastatic tumor cells in the bone marrow of 60-70% of breast cancer patients overexpress ErbB2 on their surface (Pantel et al., J Natl Cancer Inst 85:1419, Braun et al., Cancer Research, 61:1890). Therefore, ErbB2 is an extremely promising breast cancer target molecule.
The inventors have identified a peptide that binds strongly and specifically to the important breast cancer target discussed above- the extracellular domain of ErbB2. Peptide-phage displaying this peptide give an excellent ErbB2-specific signal by ELISA and immunofluorescence assay (data available).
Hypotheses for the present preclinical studies: 1) The effectiveness of doxorubicin in killing breast cancer cells overexpressing ErbB2, in vitro, in animal models, and in clinical studies, will be significantly improved by covalent attachment of a small peptide that binds specifically to ErbB2. 2) ErbB2-binding peptides may also be used to deliver other therapeutic agent to cells overexpressing ErbB2, such as chemotherapeutic agents other than doxorubicin, immunomodulatory agents, or nucleic acid molecules (gene therapy vectors or anti-sense molecules) 3) ErbB2-binding peptides, in an unconjugated form, may effectively inhibit the function of ErbB2 and, therefore, the proliferation of cells overexpressing ErbB2. Inhibition of proliferation may ameliorate disease caused by the overexpression of ErbB2 directly and/or may lead to induction of apoptosis of cells overexpressing ErbB2.
Advantages: Only one other small molecule ligand to ErbB2 has been described (Park et al.). The peptide described by Park and coworkers has no homology to the peptide described in this invention disclosure. The only other ligands to ErbB2 that have been described are antibodies- molecules that are approximately 100 times larger than the present invention. It is commonly believed that smaller molecules have greater potential to be developed into effective therapeutics.
In fact, although ErbB2 has high homology to established growth factor receptors, no natural ligand to ErbB2 has yet been identified, despite an intensive search for over ten years. Of great interest, a homology search with our peptide in protein databases has suggested some similarity between the peptide of this invention and bone morphogenetic protein- a molecule involved in mitosis and differentiation. Therefore, this invention may also lead to identification of the natural ligand to the important signaling molecule ErbB2.
As discussed above, nearly all treatments for breast cancer and other cancers are severely toxic and lack efficacy. Successful development of this peptide into a cancer therapeutic would address the critical problem of a lack of specific and effective cancer therapeutics. Although this invention specifically addresses the therapy of diseases caused by, or associated with, cells overexpressing ErbB2, our approach can be used as a model for developing therapeutics directed towards other target molecules in cancer and other diseases.
Patent Status: Patent issued: 7,098,302
Licensing status: Worldwide rights available
Title: BREAST CANCER TARGET GRB7
Inventor: David Krag, Lyn Oligino, Stephanie Pero
Description: The invention identifies seven novel non-phosphorylated peptides, called Grb-7 Binding Peptides (G7BP), G7BP-1, G7BP-2, G7BP-3, G7BP-4, G7BP-5, G7BP-6, G7BP-7, which all bind to the Src-Homology Domain 2 (SH2) of Grb7. Grb7 is an adapter molecule that binds to the intracellular domain of ErbB2 through its SH2 domain. Grb7 is frequently found associated with ErbB2 in breast and esophageal cancer cells. In addition, it maps closely to erbB2 on chromosome 17q and is often co-amplified with erbB2 in breast cancer cells. ErbB2 overexpression is found on the tumor cells of 30% of breast cancer patients, where the increase in expression correlates with poor patient prognosis. The combined overexpression of Grb7 and ErbB2 gene products is likely to up-regulate a signaling pathway which plays an important role in the pathogenesis of breast and other cancers (Janes et al., 1997; Tanaka et. al., 1997).
These Grb7 binding peptides will be useful as a starting point for the identification of high affinity peptides that will be able to inhibit the function of Grb7 and its downstream signaling events in vivo. Inhibitors of two signaling pathways may be developed into effective breast cancer therapeutics. These Grb7 binding peptides are small cyclic molecules, containing 20 amino acids, approximately 2 kilodaltons in size. These peptides have been shown to bind specifically to Grb7 and not to Grb2, a similar SH2 domain protein.
Advantages: These peptides serve as a model for drug development with significant advantages, including their relatively small size and the fact that they are non-phosphorylated. Their small size may optimize the ability of the peptides to penetrate target tissue and tumors. Additionally, inhibition of SH2 domain function of Grb7 has been previously attempted using peptides that contain a phosphotyrosine residue (Janes et. al., 1997). However, a non-phosphorylated peptide is a more stable structure in vivo, especially within the cytoplasm, and is not susceptible to the problem of endogenous phosphotases removing a phosphate moiety critical for activity. These Grb7 binding peptides should also offer improved cell penetration as they do not contain a charged residue on the tyrosine.
Patent Status: Patent issued: 7,229,960
Licensing status: Worldwide rights available
Title: IN VIVO METHODS FOR IDENTIFYING TARGET SPECIFIC BINDING MOLECULES
Inventor:David Krag, Lyn Oligino
Description: Phage-displayed random peptide library used to screen unique targets in human cancer patients, collecting tumor tissue, recovering the bound phage, and customize a ligand for that individual. The peptide ligand would be synthesized free of bacterial or biological contaminants. The binding molecules identified by the methods of the invention can be coupled to cytotoxic agents and used to mediate the specific destruction of tumor or other diseased cells. Small ligands will likely have pharmacokinetics and tumor penetration superior to that of antibodies or antibody fragments, are less immunogenic, and will allow development of more effective targeted therapeutics. These smaller molecules are easier to synthesize, and are less likely to interfere with the effects of conjugated cytotoxic drugs.
Advantages: This system will be specific to the patient. Current methods lack specificity for tumor cells, too toxic to the patient, and become resistant over long periods of treatment.
Patent Status: US Patent applied for 7/29/98
Licensing status: Worldwide rights available
Titles: COMPOSITIONS AND METHODS FOR DETECTING A FACTOR V MUTATION, FACTOR VA FRAGMENTS, FACTOR VLEIDEN CARRIERS
Inventor: Kenneth Mann, et al.
Description: Dr. Mann has a family of patents and patent applications around Normal blood coagulat
