2019 Ivy Biomedical Innovation Funded projects

Executive Summaries

Development of an inhibitor of myeloperoxidase (MPO) for the treatment of delayed cerebral injury after aneurysmal subarachnoid hemorrhage
Jose Javier Provencio, Danny Theodore, Aminata Coulibaly

This is an important application because it will allow us to investigate a potential treatment for the syndrome of delayed neurological injury (DCI) after the rupture of a cerebral aneurysm. This treatment has the potential to be a solution to a critical unmet need in the field of Neurocritical Care. Despite over 40 years of research, only one FDA approved treatment (nimodipine) for DCI is available. Even after approval of nimodipine, DCI remains the most important undertreated preventable consequence of aneurysmal subarachnoid hemorrhage and leads to a large number of severely disabled or dead patients. We believe inhibition of the neutrophil enzyme myeloperoxidase has the potential to prevent DCI in SAH patients. Given the 100,000 to 200,000 patients worldwide who experience DCI, a treatment could have significant impact in patient welfare, global health costs and potential marketability.
Work over the last 8 years in my laboratory has identified neutrophils and particularly the neutrophil enzyme, myeloperoxidase or MPO, as a critical link in the development of DCI after SAH. More importantly, we have shown that a genetic mutant mouse that does not make MPO does not develop DCI. More important to this application, we have shown that adding back MPO to the deficient mouse returns the symptoms of DCI. This gives us great hope that chemical inhibition of MPO is a feasible target for drug development.
In order to translate this finding from the bench to the bedside, we have identified a number of questions that need to be answered in our model and in patients with SAH. In addition, we have identified the need to validate tools for drug screening in patients with SAH to expedite small molecule screening in the future. We have developed an excellent team of scientists and clinician investigators who have experience in both animal models of SAH and human trials in patients with SAH. We believe that this group can quickly develop the data needed to move into the phase of drug discovery.

Improving End Stage Renal Disease outcomes through a predictive calcimimetic dosing algorithm
Brendan Bowman, Donald Brown, Benjamin Lobo

In patients with End Stage Renal Disease (ESRD), the most severe form of kidney disease, increased levels of parathyroid hormone (PTH) lead to abnormalities in bone health and blood vessel flexibility. The end result of these processes is significantly weakened bones leading to a massive increase in fracture risks as well as deposition of calcium and phosphorous into blood vessels – so called “vascular calcification”.
Etelcalcetide is a new injectable calcimimetic, approved by the FDA in 2017, to treat elevated PTH levels (secondary hyperparathyroidism) in ESRD patients. This new drug has a number of desirable traits that make it a marked improvement over earlier medications. As an injectable given at dialysis, treatment compliance is assured. In addition, Etelcalcitide’s long half-life is a vast improvement in the duration of action on the parathyroid gland. However, etelcalcetide is significantly more expensive than current therapeutic options.
While Etelcalcitide is currently reimbursed separately by insurance / Medicare Part D, it will soon be part of the ESRD “bundled” payment system – a capitated payment plan instituted to address the rising costs of care in ESRD, and will shift to a cost center for dialysis programs. As such, dialysis providers must optimize dosing of etelcalcetide so that the minimum amount of drug can be used to achieve desired clinical outcomes (which is advantageous from both a cost and a drug side-effect perspective). There is currently no predictive dosing algorithm or decision support tool to guide clinicians in the dosing of Etelcalcitide to manage secondary hyperparathyroidism.
Current protocols are based on clinical trials and clinician experience which is hampered by small sample sizes. These strategies are acceptable at the population level but do not provide a high level of precision. We propose the development of a predictive calcimimetic dosing algorithm and associated decision support tool that will enable physicians to make precise dosing plans tailored to achieve the desired clinical outcomes (suppressed PTH, reduced fracture risk, reduced serum phosphorous levels) in individual patients while efficiently utilizing the drug. The efficacy of the algorithm will be observed as a quality improvement study conducted at UVA dialysis centers, one of the largest academic dialysis programs in the nation and wholly owned and operated by UVA Health System. Follow-on funding will look to support a multi-center prospective clinical trial, the gold standard to evaluate the efficacy of the predictive dosing algorithm and decision support tool.

Cady Ventilator Vest
Patricia Cady, Jonathon Swanson, Rachel Nauman, Timothy Hicks, Lisa Letzkus, Elizabeth Miller-Monika Thielen

Neonatal intensive care units (NICUs) across America continue to experience the same rate of unplanned extubations (UEs) over the past 30 years 1. The incidence of UEs lead to life-altering sequalae for our most vulnerable patient population. By leveraging the collaboration between the UVA Health System, the School of Nursing, and the College of Arts & Science, we are currently developing a product to effectively reduce the rate of UEs across America. With a growing trend amongst insurance carriers, including Medicare and Medicaid, to withhold payments based on patient outcomes, there is a strong indication for the need to reduce the rates of UEs. The market currently lacks any device which will adequately secure an infant from the ability to self-extubate themselves, remove nasogastric or oral tubes, and remove bubble CPAP prongs.
In creating this developmentally appropriate vest, the infant’s hands will remain contained, while allowing free movement and proper alignment of their arms. The swaddle element of the vest provides a soothing effect, mimicking the womb, which will calm agitated infants, also decreasing the possibility for self-extubation and removal of other facial tubes. Simplified Velcro attachments will afford the bedside RN the ability to easily perform hourly assessments of any IV sites on the arms, while the shortened nature of the vest will allow continuous visualization of any umbilical lines.

Leveraging Advancements in the Design of Novel Chemokine-Derived Antimicrobial Peptides towards Combating Multidrug-Resistant Bacteria
Molly Hughes, Matthew Crawford, Lawrence Lum, Rachel Letteri

Antibiotic-resistant bacteria are among the most serious threats to global health, causing life threatening illnesses and, increasingly, infections for which available antibiotics are simply ineffective. In 2016, the Review on Antimicrobial Resistance published a report underscoring the urgent unmet need for addressing the alarming increase in antibiotic-resistant “superbugs” worldwide. Indeed, if left unchecked, by the year 2050 it is anticipated that infections caused by multidrug-resistant (MDR) human pathogens will result in ~10 million deaths globally every year and reduce the world’s gross domestic product by trillions of dollars annually. The mounting human and economic burden of MDR organisms is further compounded by a decades-old decline in the origination of new antibiotics. Countering the dangers posed by antibiotic resistance will require a multifaceted approach that includes the development of innovative therapeutic strategies for treating bacterial infections.

Toward developing novel therapeutic avenues to which antibiotic-resistant pathogens are vulnerable, we have previously identified bactericidal peptides derived from the N- and C-terminal regions of the human chemokine CXCL10. With support from the Ivy Foundation, we have recently elucidated key determinants important for peptide-mediated bactericidal activity and have begun to successfully translate this understanding into the development of non-obvious peptide variants/formulations that provide patentability. Indeed, together with the UVA Licensing & Ventures Group, we have submitted a provisional patent application for peptide-based therapeutic technologies and commenced an academic-industry collaboration to promote lead optimization. In the current Ivy Biomedical Innovation Fund application, we propose to leverage our recent findings to design and assess unique, cutting-edge peptide formulations (e.g. conjugate and polymeric peptides) that efficiently kill MDR bacteria. In addition to directly killing microorganisms, and consistent with preliminary data presented herein, peptides derived from the N-terminus of CXCL10 also exert tunable levels of receptor-dependent effects on host immune cells.
Thus, we also propose to tailor promising peptide formulations to elicit therapeutically advantageous levels of host-targeted bioregulatory activity. The research described in this award application will be accomplished by a well-balanced, multidisciplinary group of investigators with demonstrated productivity and expertise in the areas of antimicrobial resistance, chemokine biology, immunology, and peptide chemistry. Successful completion of the proposed investigations will yield lead candidate peptides for preclinical examination in murine models of bacterial infection and, ultimately, establish an original paradigm whereby next generation antimicrobial therapeutics not only kill microorganisms, but also enlist host processes to combat bacterial infections caused by MDR human pathogens.

Targeting AVIL in Glioblastoma
Hui Li, Michael Hilinski, Benjamin Purow

Gliobastoma (GBM) is the most common primary brain tumor and among the deadliest of human cancers. Despite advances in surgery, radiation and chemotherapy, survival of patients affected by GBM remains dismal (~15 months after diagnosis). We recently identified a novel oncogene, AVIL in GBM’s. AVIL gene is overexpressed in all the GBM’s we tested, but is hardly detectable in non-cancer astrocytes. Silencing AVIL resulted in complete eradication in GBM cell cultures, but had little effect on the astrocyte control cells. In animal models, silencing AVIL diminished in vivo growth as tumor xenografts. Conversely, overexpressing AVIL in cell culture systems promoted tumorigenesis. In patient cohorts, higher expression levels of AVIL in cases of GBM and other gliomas correlated with worse prognosis. High throughput small molecule screening has yielded several lead compounds, all of which phenocopy the effect of AVIL. Thanks to the Ivy support from last year, we have found that GBM stem cells/initiating cells express even higher levels of AVIL and are more susceptible to the inhibitors. We also synthesized over 60 derivatives of the lead compound 1. Some of them have EC50 in the nanomolar range. In this proposal, we aim to further confirm that these compounds are on target, and test their efficacy in animal models. We will also develop more accurate biophysical assay to measure direct activity of the compounds.