Read about the projects funded by the Midwest Biomedical Accelerator Consortium (MBArC ) in 2022.
Removal of Arterial Emboli by Ultrasound-assisted Endovascular Laser Therapy (KU)
Stroke is among the leading causes of long-term disability and death, with up to 50% of survivors are chronically disabled. Worldwide ischemic stroke prevalence was 77 million in 2019. In the United States (US), the prevalence of stroke is about 3% in adults 20 years or older, which accounts for about 7 million strokes in the population. Of all strokes, 87% are ischemic. Annually, about 795,000 people experience a new or recurrent ischemic stroke in the US, and 140,000 people die from it. The direct and indirect cost of stroke in the US was $49.8 billion. The estimated direct medical cost of stroke was $30.8 billion. This includes hospital outpatient or office-based provider visits, hospital inpatient stays, emergency room visits, prescribed medicines, and home health care. Between 2015 and 2035, total direct medical stroke-related costs are projected to more than double, from $36.7 billion to $94.3 billion, with much of the projected increase in costs arising from those ≥80 years of age. Our goal is to develop an enabling technology that can treat acute ischemic stroke complicated by atherosclerosis during the time of emergency. Acute Ischemic stroke is a medical emergency and occurs when a vessel supplying blood to the brain is obstructed. In the last few years, the paradigm-shift endovascular therapy (EVT) (or mechanical thrombectomy) has been established as a standard for the treatment of acute ischemic stroke. The current available EVT are based on either stent retriever or aspiration tubes. While these devices work efficiently in removing blood clots, they cannot remove atherosclerotic plaques, which can occur in 8% to 25% of the patients who are eligible for EVT. We propose to develop a new therapy that can remove both clots and atherosclerotic plaques. While our primary targeted market is for acute ischemic stroke in the time of emergency, the proposed device can also be used to remove atherosclerotic plaques in carotid arteries, coronary arteries, and peripheral arteries to prevent potential artery occlusion. There are currently about 38 million people in the US with such conditions. This market is, however, dominated by stenting and other treatment options.
Dual Immune Therapy with Novel PD-L1 and CTLA-4 Inhibitory Peptides for Colorectal Cancer (K-State)
Colorectal cancer (CRC) is the second leading cause of cancer-related morbidity and mortality in the USA with 104,270 new cases and 52,980 deaths reported in 2021. Although the relative 5-year survival rate of patients with all stages of CRC has been improved (65%), the survival rate for CRC with distant metastasis is only 14%. Current strategies for CRC treatment have limited success. Therefore, novel treatment strategies for primary as well as metastatic CRC are urgently needed. Immune checkpoint inhibitor (ICI) therapy has emerged as a powerful new tool for cancer therapy; however, only CRCs associated with high microsatellite instability (MSI-hi) or DNA mismatch repair gene defects (dMMR, approximately 15% of all CRCs) are sensitive to this therapy and systemic side effects remain concerns. Therefore, development of effective and safe ICI therapies applicable to the remaining microsatellite stable (MSS) CRC would significantly benefit CRC patients.
Flexible Virus Sensor for Detecting Infectious Respiratory Diseases Including COVID-19 and Flu (MS&T)
The COVID-19 pandemic has infected more than 53M individuals and caused over 818k deaths in US. During flu and COVID-19 seasons, the distinction between SARS-CoV-2, influenza A, and influenza B is significant as they do not share the same treatment or public health implications (e.g., quarantine needs). These viruses are spread through respiratory aerosols and can cause similar symptoms, as well as concurrent respiratory infections, making the ability to differentiating these viruses in a single patient more critical. The state-of-art testing to differentiate COVID-19 from influenza viruses are multiplex testing, where intrusive nasal swab sampling is typically used. These tests are based on PCR analysis and genome sequencing, which can take hours. The intrusive sampling together with the time-consuming analysis and high cost make it impossible for these tests to be utilized for fast screening, which are desperately needed for public transients, hospitals, and military operations. To overcome these issues, we have developed an immunosensor that utilizes the high-surface sensitivity of 2D materials and high surface bonding between the surface terminating groups and viruses to achieve aerosol (breathing) based test for infectious respiratory diseases including COVID-19 and flue. The developed sensors can be mounted on any substrates serving as disposable breath analyzer type sensing devices. The sensing system takes about 30 seconds to obtain readings on the mobile devices that can communicate with the sensors through a Bluetooth data transmitter. The developed system can be utilized in both at-home testing or airport screening purposes. It should be noted that the proposed tests are as accurate as the RT-PCT tests, which are the current testing standard, but much faster (30 seconds in comparison with 45 mins of testing time for RT-PCR). The developed platform can also be utilized to test other viruses that responsible for various infectious respiratory diseases.
Targeted Radiopharmaceutical Diagnosis and Therapy of Prostate Cancer (MU)
Co-Investigators: Carolyn Anderson, Amolak Singh
According to the American Cancer Society, prostate cancer (PCa) will account for an estimated 268,490 new cases and 34,500 deaths in 2022, continuing to be the most commonly diagnosed cancer and second-leading cause of cancer deaths in men in the United States. There are ~489,000 PCa patients in the VA Healthcare System today, with 16,000 of these individuals having a metastatic disease. Surgery and various forms of radiation and systemic treatments have sought to eliminate primary tumors and prevent/slow metastatic progression. Unfortunately, nearly all metastatic PCas eventually reach a stage whereby they become refractory to androgen deprivation therapy and achieve metastatic potential, which accounts for the majority of the complications and mortalities associated with PCa. Furthermore, treatments themselves may cause side effects due to the inherent, imprecise nature of how they are delivered. Likewise, the current methods of clinical determination for patients with PCa are considered inadequate for early diagnosis. For example, diagnostic methods such as serum PSA and needle biopsy historically have limitations in their usefulness to accurately detect early-stage PCa, resulting in missed diagnoses as well as unnecessary treatments. Oftentimes, by the time a malignancy has been detected and a clinical diagnosis made, the disease has already become metastatic. Therefore, new and innovative strategies with increased sensitivity/selectivity are necessary for early detection, staging, and therapy of metastatic PCa. Gastrin Releasing Peptide Receptors (GRPR) and Prostate-Specific Membrane Antigen (PSMA) are validated biomarkers that are expressed in very high numbers on PCa cells, making them ideal candidates for molecular targeting with radiolabeled peptides or small molecules. The objective of this research application is validation and clinical translation of a new heterobivalent GRPR-/PSMA-targeting radioligand for Positron Emission Tomography (PET) imaging and potential therapy of GRPR- and PSMA-positive prostate tumors. We hypothesize that our new, heterobivalent, radiotracer will be useful for targeting GRPR and PSMA using only a single agent for detection, staging, and therapy of both primary and metastatic PCa. We propose that these novel radiotracers will be able to reach a larger cohort of male patients with PCa as compared to single receptor, cell targeting, GRPR or PSMA agents alone.
A Novel Drug to Promote Mucosal Healing and Combat Aspirin and NSAID Mucosal Damage (NEOMED)
Beyond over-the-counter NSAIDs or aspirin, NSAIDs comprise 7.7% of all prescriptions. 11% of all patients reported continuous NSAID use in the 2018 National Ambulatory Medical Care Survey. 65% of chronic NSAID users experience some GI ulceration, more commonly in the distal small bowel. Annual US medical costs of adverse GI events from NSAIDs exceed $4 billion. Although proton pump inhibitors were co-prescribed with NSAIDs to ameliorate proximal GI injury, they worsen the distal injury, perhaps by altering the microbiome,8 and should no longer be co-prescribed with NSAIDs unless patients are at particular risk for gastroduodenal injury. Patients require chronic NSAIDs for analgesia or cardiovascular risk reduction; there is an urgent need to prevent and treat their mucosal complications. No therapeutic promotes mucosal healing directly. IBD and peptic ulcer therapy only reduce injury by inflammation or acid, hoping the mucosa will heal. Although we focus on NSAID injury, a first-in-class drug promoting epithelial healing could be synergistic with treatment for peptic ulcer or IBD, and potentially applicable to other wounds such as diabetic foot ulcers or corneal ulcerations.
Developing a Bioabsorbable Platform to Enhance Dialysis Access (UNMC)
For more than 468,000 Americans, hemodialysis is a life-saving replacement for kidney function. However, the vascular access required for dialysis remains a major challenge. For decades clinical practice guidelines for hemodialysis have encouraged the use of an arteriovenous fistula (AVF) as the preferred method of vascular access. An AVF is a surgical connection between an artery and a vein that allows blood to flow from the artery directly into the vein. Because it functions without inserting synthetic material into the body, an AVF is much less prone to clotting and infection than an arteriovenous graft (AVG) or central venous catheter (CVC) and can last for much longer — up to five years. Unfortunately, connecting an artery and a vein in this way creates turbulent blood flow and vascular wall shear stress, which often leads to reactive intimal hyperplasia, stenosis, and blocked or clotted access. As a result, only about half of these fistulae actually become usable access sites. Patients are thus forced to rely on harmful catheters and grafts for dialysis and to undergo repeat surgeries attempting to establish a successful AVF. Our solution is the BioFlowTM, an arteriovenous fistula maturation platform. The BioFlow is a coil of bioabsorbable alloy deployed into a vein as it is sutured to an artery during AVF surgery, holding the vein open and at an angle conducive to natural hemodynamics. There is currently no medical device or medication that successfully facilitates AVF maturation, and we estimate that widespread adoption of the BioFlow in AVF surgery has the potential to improve AVF maturation success rates immensely — from around 50% to over 90%.
Preclinical Development of a Stimuli-triggered Gated Drug Delivery Nanoassembly to Target Metastatic Colorectal Cancer (USD)
Co-Investigator: Khosrow Rezvani
According to WHO, there were over 1.93 million new cases of colorectal cancer diagnosed in 2020 around the world, which led to 916,000 deaths in 2020. A five-year survival rate of 91% for localized colorectal cancer (stage I) can be attributed to the success of surgical resection, but this rate drops to approximately 10% for patients diagnosed with disseminated disease (stage IV) because of a lack of effective therapies. The dire need for efficient treatments translates to both hope and market potential. Now it is time to solve this problem because our work made available a selective mTORC2 inhibitor which leaves mTORC1 unchanged in normal and cancer cells. This new targeted therapeutic agent (veratridine, VTD) is selectively delivered to cancerous cells, selectively released at these cells while the rest of the organs such as the brain remain intact. VTD has previously been used as an antihypertensive supplement in humans. Therefore, developing VTD into an antimetastatic agent carried and released by a smart nanoparticle technology is a repurposing strategy that will allow for quicker progression through the drug development process while reducing project costs as compared to traditional de novo drug design. Our novel nanoassembly will selectively deliver a therapeutic dosage of VTD to cancer cells, release it on-demand and keep VTD out of the brain.
