Lucy Kornblith, Anthony Luke, Saul Villeda & Roland Bainton
“The Platelet Function, Transcriptome, and Proteome in Platelet-Rich Plasma for Intra-Articular Therapy in Knee Osteoarthritis: A Pilot Characterization of Platelet Biology for Advancing Regenerative Transfusion Medicine”
Osteoarthritis will reach epidemic proportions over the coming decades, and is already estimated to affect 63 million people in the United States alone in 2020. Platelet rich plasma (PRP) injections are a popular modern treatment alternative to steroids and hyaluronic acid injections for osteoarthritis in the knee and other joints, beneficial by reducing symptoms and progression. However, the precise mechanism of action is unknown. As such, we seek to identify biological mechanisms by which PRP acts in the degenerative condition of knee osteoarthritis. Various classification systems exist for describing the composition of PRP, but they fall short in adequately characterizing the biologically active cellular component of the therapy, namely the platelets. Clinical trials of PRP for intra-articular therapy for knee osteoarthritis present an opportunity to understand the regenerative biology of the platelets contained in the PRP, and to identify the platelet function, transcriptome, and proteome associated with better post-treatment clinical outcomes after PRP intra-articular therapy.
Dr. Philip Norris, Dr. Satish Pillai and Dr. Laurence Corash
“Does Pathogen Inactivation Change the Inflammatory Profile of Transfused Platelets?”
This award exemplifies a three way partnership between Vitalant Research Institute, University of California, San Francisco and Cerus.
Provocative data from a randomized clinical trial showed a >35% reduction in the need for mechanical ventilation in recipients of INTERCEPT treated platelets compared to standard platelet units. The mechanism of this reduction is not clear but could be due to decreased inflammation induced by INTERCEPT treated platelets. The current project will determine how treatment with UVA plus a psoralen compound affects mitochondrial DNA (mtDNA) in platelet units. Our hypothesis is that INTERCEPT treatment disrupts mtDNA and attenuates its known pro-inflammatory properties, and this will be quantified via next-generation sequencing of mtDNA and assays to determine the ability of treated mtDNA to activate immune cells.
Dr. Omar Khan, M.D. Ph.D., Brian Shy, Chris Dvorak & Julia Chu
“Development of a Novel “in-line” Manufacturing method for the Rapid, Cost-Effective, and “off-the-shelf” Production of Cellular Therapeutics”
Engineered cellular therapeutics have transformed our ability to treat patients with cancer, yet challenges remain to improve the accessibility, applicability, and safety of these therapies. The goal of our study is to leverage mRNA and lipid nano particle technologies to enable single-day manufacturing of complex cellular therapies for patients in an out-patient setting.
Dr. Michael Matthay and Dr. Carolyn Calfee
“To Test the Efficacy of Allogeneic Bone Marrow Derived MSCs in a Mouse Model of Hyper- and Hypo-Inflammatory ARDS”
These studies will recapitulate the findings in our studies in critically patients with ARDS who have a biologic profile of either hyper- or hypo-inflammatory phenotypes based on measurements of key cytokines in the plasma such as IL-6 and TNFR1. In several publications from clinical trials and observational studies these biologic measurements identify patients with the hyper-inflammatory phenotype who have a higher mortality and more morbidity (more time requiring mechanical ventilation) in compared to the patients with the hypo- phenotype. Clinical indices alone cannot identify these two groups. Additionally, in several of our secondary analyses there is a differential treatment benefit in the hyper-phenotype compared to the hypo-phenotype, with fluid therapy, the level of positive end-expiratory pressure or simvastatin (probable anti-inflammatory mechanisms).
Therefore, these pre-clinical studies provide a novel opportunity to test the effects of allogeneic mesenchymal stromal cells and extra-cellular vesicles compared to placebo controls by randomizing the hypo- and hyper-inflammatory mice at 18 hours to different treatment groups and measuring the degree of arterial hypoxemia (oxygen saturation), lung vascular and epithelial permeability to protein (in the air spaces of the lung), and the degree of pulmonary edema (gravimetric methods).
Dr. Emin Maltepe & Dr. Aijun Wang
"Stem Cell Based Extracellular Vesicles for Neuroprotection in Newborn Brain Injury"
Birth asphyxia, or hypoxic-ischemic encephalopathy (HIE), is a global driver of infant mortality and cerebral palsy. The only therapy for HIE—therapeutic hypothermia (aka, cooling)—is not effective globally where 95% of disease burden resides. Novel therapies are urgently needed. We propose to conduct preliminary biodistribution studies of our stem cell-derived extracellular vesicle (EV) product in a highly clinically relevant model of newborn hypoxic-ischemic brain injury. We previously demonstrated that this product was neuroprotective in vitro and in small animal models. Using our model designed for the global setting, we additionally propose to determine safety endpoints to help guide future pre-clinical development efforts. Our stem cell-derived product is highly translatable with a potential to improve outcomes globally for infants born in the setting of birth injury.