QED Funding

QED: Awardees - Science Center

Introduction

Elements of the Program

How to Apply

Awardees

Market Representation

 

Spring 2009 Application Cycle

Spring 2009 projects will be completed from October/November 2009 – October/November 2010.

Nanostructured bactericidal sol‐gel thin films on percutaneous orthopaedic external fixator pins
Principal Investigator: Paul Ducheyne, Ph.D. (University of Pennsylvania)

About 2,000,000 fracture fixation devices, including internal and external fixation devices, are implanted annually in the United States. They incur a postoperative infection rate of 5% overall and there is no good treatment available when infection occurs. In the specific cases when external fixation is used to stabilize the bone fragments, the treatment itself  can promote infection; in fact, the incidence of deep infection using this procedure is much higher than the average, namely 16.2% overall, with 4.2% developing chronic osteomyelitis. A totally unacceptable rate of infection, up to 32.2%, has been reported for the external fixation of fractures of the femur. Clearly, fixation of compound fractures, for which external fixation is preferred, is a clinical challenge and better treatments are urgently needed to prevent bacterial ingress at the percutaneous passage of the pins.

Herein we pursue a fundamental solution for the dire clinical issue of infection with external fixation. The approach is based on reliably and continuously delivering bactericidals to the tissue sites using the novel, breakthrough technology of micron‐thin sol‐gel films on fracture fixation pins. The program is based on an excellent foundation in basic science, a strong patent position, and a team of investigators with a track record of collaboration and a documented ability to advance concepts to the clinic. Sol gel films were used before in animal studies for another, distinct, application with different therapeutics and effective controlled release from the films was achieved in vivo.

The market is significant (in the USA more than $ 100 M), and the opportunity is substantial, as there is no standard of care. Health care savings in excess of $ 1 billion could be achieved. The objective of this QED program is the elimination of a key investment risk factor, namely “does it work in vivo?”, as a result of which next levels of capital become available.

The program covers essential steps to advance to the clinic. We propose to demonstrate (i) that bactericidal sol‐gel films releasing therapeutic effective quantities can be deposited and (ii) that these antibacterial sol‐gel films can prevent external fixator pin infection in vivo using an established animal model. With proof‐of‐concept data becoming available midstream into the program, the product development program would be advanced to the next level in collaboration with a major corporate partner from the health care industry.

Near Infrared Wound Monitor
Principal Investigator: Elisabeth Papazoglou, Ph.D. (Drexel University)

Wound Clinics who see patients with challenging wounds need faster evaluation of the healing process to save costs, improve patient outcomes and to be able to transfer some of the wound care to less specialized environments. Yearly incidence of skin ulcers (pressure, venous and diabetic) in the U.S. is estimated to be 6 million patients, and the annual costs for management of these wounds are greater than $20 billion. The current paradigm is measurement of wound size, by tracing or by digital imaging. This superficial evaluation delays proper treatment and results in continuation of non‐efficacious products/methods which ultimately lead to amputations. The proposed device uses NIR technology to
measure the level of oxygenated and deoxygenated hemoglobin at the wound site and compares it to a control/nonwound site. The time course of the oxygenated hemoglobin was found to be a strong indicator of wound healing (data obtained in animals and humans during the last 18 months). Two provisional patent applications relate to the methods of evaluating the condition of the wound and will be combined and filed as one utility application. The third provisional patent application, related to the device, will be converted to a PCT application. We estimate that shortening by 50% the observation time based on wound size, the cost of care for chronic wounds would be reduced by 30‐60%. Third‐party payers are reimbursing chronic wound care. The work will focus on performing additional clinical tests to expand the number of patients from the existing 15 patients to the statistically significant 50 patients or more. During the study weekly NIR measurements and wound size measurements of chronic wound patients will be compared until healing occurs (or for a maximum of 30 weeks). The NIR healing index will be compared to wound contraction as a predictor of wound healing. The commercial “proof‐of‐concept” in this project, needed to attract investors and companies, is having a statistically significant clinical data set proving that the technology works. The Wallace H. Coulter Foundation has invested $200,000 in the research effort during 2006 and 2007 through a competitive proposal process and the business plan of this project just won the 2008‐2009 Wharton Business Plan Competition. Therefore the funding by QED will significantly move this project along the commercialization pathway producing very tangible and pivotal clinical data to support additional follow on funding.

Portable, Low-Cost, Radiation-Free Breast Cancer Detection for Dense Breasts
Principal Investigator: Wan Shih, Ph.D. (Drexel University)

The piezoelectric finger (PEF) device is intended for use in breast cancer screening and diagnosis in populations where mammography is not widely available or as an adjunct to mammography for women with dense breast tissue where the procedure has decreased utility. Breast cancer affects 1 in 8 women in the U.S. and is a growing health care concern in developing countries such as in India as women become more westernized in diet and child bearing practices. Mammography is the established standard for breast cancer screening in the U.S. and Europe although there are limitations to its utility: 1) it does not perform well in areas of the breast comprised of dense breast tissue; 2) it is an Xray procedure and is not recommended for younger women who may be at risk for breast cancer; 3) its proper use requires a specially trained radiology technician and a radiologist is needed for interpretation. In developing countries, the cost of the mammography unit and cost per test limits its adoption. Its use is further limited by the higher incidence of dense breasts in Asian women.

We will develop a non‐invasive, radiation‐free device for breast cancer detection based on measurements of tissue elasticity. Breast tumor tissue is stiffer than the surrounding normal breast tissue and this difference in elasticity can be measured by the PEF device along two axes – top down compression and lateral shear. While each of these measurements alone can yield useful information on breast tissue elasticity, integrating these two readings provides an especially sensitive reading of abnormal breast mass. The sensors can also identify masses that are typically too small for detection by other screening devices.

Using funding provided by Drexel’s Wallace H. Coulter Foundation Translational Research Partnership Award, the elasticity and shear sensors have been designed and the operation of the device has been demonstrated on excised breast tissue samples. QED project funding will be used to build a working prototype and to obtain proof‐of‐concept clinical data. The working prototype will form the basis for production of a low‐cost unit that can be introduced into developing countries; Clinical data from early use of the PEF device will provide the body of evidence to support a U.S. entry. Further design development to increase the number of sensors in the arrays and a robotic arm for automated reading will position this device for use in the U.S. as an adjunct to mammography.

 

Fall 2009 Application Cycle

Fall 2009 projects will be completed from May 2010 – May 2011.

>Vasucular Magnetic Intervention
Principal Investigator:Robert Levy, Ph.D. (Children’s Hospital of Philadelphia)

Vascular Magnetic Intervention (VMI) is our novel approach to treat peripheral arterial disease (PAD). PAD affects more than 8 million Americans, and at present the only therapies for PAD are either surgical intervention or stenting. Outcomes for both of these therapies are suboptimal with more than 40% of grafted or stented patients experiencing re-obstruction of treated arteries by two to three years post procedure. Furthermore, while drug-eluting stents have been beneficial for coronary disease, these devices have been not shown in long term controlled studies to be of significant benefit for maintaining patency of treated blood vessels with PAD. Thus, effective therapy for PAD represents a major unmet need.

Our proposed approach, VMI, is a combination therapy involving stenting and magnetically targeting deployed steel stents with biodegradable, polymeric
paclitaxel-loaded magnetic nanoparticles (pMNP) for local delivery of paclitaxel to stented peripheral arteries using the uniform field magnetization effect, a novel mechanism published by our group in PNAS in 2008. Furthermore, a feasibility study demonstrating prevention of instent restenosis with magnetic targeting of pMNP to stented rat carotids is pending publication in PNAS. Our working hypothesis is that drug-eluting stents have failed in PAD because of inadequate dosing. VMI offers the possibility of providing a variable initial dose to a PAD patient depending on the extent of disease. In addition, since no effective medical therapy is available for PAD, it is expected that over time repeat VMI procedures, for either redosing or using other agents, will be indicated to maintain efficacy after the initial initial stenting-MNP targeting procedure.

Thus, in view of the likely need for both primary and repeated VMI treatments for PAD, the market potential for VMI is great. A proof-of-concept study is planned involving a rabbit femoral artery stenting model previously used by others for FDA IDE/IND preclinical studies, investigating both arterial/biodistribution of VMI targeted paclitaxel and an anti-restenosis efficacy study using a dose ranging protocol with pMNP targeting to stents compared with stenting with bare metal stents without paclitaxel. The results of these experiments are expected to show efficacy with VMI even at the lowest doses used. The paclitaxel doses to be used will be both orders of magnitude below established systemic toxic dosages and many fold lower than the doses loaded onto current drug-eluting stents.

In vivo validation of a novel, next-generation therapeutic gene silencing platform
Principal Investigator:Samuel Gunderson, Ph.D. (Rutgers University)

The goal of this project is to establish the feasibility of using U1 Adaptors, a newly invented gene silencing technology, to silence genes in an in vivo animal model system leading to a positive therapeutic outcome. Success in this application is key to the long-term goal of using this technology to treat patients with various types of diseases, with cancer and high cholesterol being the first two targets, both of which represent multi-billion dollar markets. Currently, two types of oligonucleotide-based gene silencing methods are being developed for therapeutic use. Traditional approaches use an antisense oligonucleotide (ASO) designed to base pair with its complementary target mRNA leading to either degradation or impaired function of the mRNA.
Current excitement has focused on RNAi that uses a distinct mechanism where siRNA oligonucleotides trigger an endogenous pre-existing gene suppression pathway. In spite of the general success of siRNA in cell culture, its translation into a commercial therapeutic has proven difficult, primarily because of the inability to deliver silencing activity to specific organs or cell types. Indeed, neither ASOs nor siRNAs have yet to produce a commercial therapeutic.

U1 Adaptors work via a different mechanism, involving blocking polyA tail addition to the 3' end of gene-specific mRNA, and have several advantages over these other methods, with the primary one being a highly flexible chemistry that permits a broad variety of nucleotide modifications to promote stability and cell-specific delivery in vivo. Two in vivo investigations are planned for this project. The first is to use U1 Adaptors to silence the human BCL2 gene, a key player in tumor progression, in a "xenograft mouse" system involving growing a human tumor in mice. The second is to use U1 Adaptors to silence the mouse PCSK9 gene, a key regulator of plasma LDL cholesterol levels. For both studies, the U1 Adaptors will be assessed for their efficacy in either suppressing tumor growth (BCL2 study) or in lowering cholesterol (PCSK9 study) and their potency in silencing the targeted gene in the target tissue.

Minimally Invasive Off Pump Mitral Valve Replacement
Principal Investigator:Joseph Gorman, M.D. (University of Pennsylvania)

Heart valve replacement therapy is in the early stages of a paradigm shift. Improvements in imaging, catheters and stents have combined to make transcatheter replacement of the aortic and pulmonic valves realities. These successes have piqued interest in minimally invasive off pump mitral replacement. Currently, there is a large patient population suffering from ischemic mitral regurgitation. Many of these patients would benefit from valve replacement but are too sick to tolerate the morbidity of standard mitral valve surgery. A minimally invasive off-pump technique would address this significant clinical need and has the potential to increase mitral valve replacement procedures 10 fold (350,000 cases per year).

A successful minimally invasive off-pump mitral valve replacement requires: 1) a sutureless atraumatic anchoring mechanism 2) a sealing mechanism to prevent perivalvular leakage 3) foldability. We have developed both a novel folding anchoring and sealing mechanism. The anchoring technology embodies a stent based foldable bi-flange mechanism to secure the valve on both the atrial and ventricular sides of the annulus. Perivalular leak has been a difficult problem for all minimally invasive off pump valve replacements including the aortic valve replacements which are in use clinically. The complex geometry of the mitral valve compounds this problem. Our sealing technology uses a cuff filled with a super absorbent material which expands to fill the space between the stent and valve annulus.

Using relatively crude prototypes we have shown our design to be robust in large animal models. The current protocol is designed to develop a more foldable and controllable device that can be placed reproducibly in a large animal model.

 

For more information, contact us: qed@sciencecenter.org