We propose a TPPG Cycle II that builds on the success of Cycle I in showing pre-clinical efficacy of Elafin as a treatment to reverse pulmonary arterial hypertension (PAH), ventilator induced lung injury of the newborn, and lung transplant rejection. Each of these conditions could be the subject of Cycle II. However, we chose to focus on PAH since the FDA granted orphan drug status to Elafin as a treatment for PAH, as an urgent unmet medical need. Current therapies do not reverse or arrest the progressive obliteration of the lung blood vessels in PAH that results in clinical deterioration and the need for lung transplantation. During Cycle I, we obtained help through the NIH-SMARTT program, to fund non-GLP pharmacokinetic and toxicology studies that showed a favorable profile for daily subcutaneous administration of Elafin in rats. Under the guidance of NIH-SMARTT consultants, we worked with our industrial partner, Proteo, to prepare a preIND briefing document for our upcoming joint meeting with the FDA. A contractual agreement between Proteo and Stanford is underway to pursue an IND for investigator-initiated clinical trials with Elafin at Stanford in Cycle II. The goal of Project 1 is, therefore, to better understand why and in whom Elafin is most likely to show clinical efficacy. We will investigate the role of Elafin in neutrophil function and interaction with pulmonary arterial endothelial cells (PA EC). EC derived from induced pluripotent stem cells will be investigated as surrogates for native PA EC to understand the basis for responsivity to Elafin, and we will define the interactome of Elafin to identify novel functions and potential pitfalls of this therapy. In collaboration with Projects 2 and 3 and the Advanced Proteomic Phenotyping Core, we will use CyTOF to extend the `PAH signature' we have found in circulating cells (PBMCs) and to investigate the extent to which this abnormal signature is modified by Elafin both in vitro and in subjects being treated with Elafin. We will use MIBI and apply ABseq to determine the biology of immune cells and neutrophils that are recruited to the lung perivascular niche. Project 2 aims to address the potential synergy of Elafin and Treg immunotherapy by attacking both the abnormal innate and adaptive immune responses in PAH. The subverted function of Tregs in the context of known risk factors for PAH (female gender, BMPR2 mutation) is investigated in novel experimental rat models of pulmonary hypertension. Strategic approaches are tested to amplify and improve Treg function as a combinatorial treatment with Elafin or as a stand-alone PAH therapy. The objectives of Project 3 are to carry out a Phase I clinical trial utilizing pharmacokinetic and toxicity endpoints in the facilities of the new Stanford Clinical Research and Translation Unit (CRTU). An extended 180 day GLP toxicity and pharmacokinetic study in the rat will precede a small multi-center Phase II clinical trial in patients, that will incorporate toxicity, pharmacokinetic and efficacy endpoints. Our TPPG translates decades of basic mechanistic studies that converge on elastase inhibition, and Elafin as a promising PAH therapy and also positions us to evaluate Treg immunotherapy for PAH.
We propose clinical trials that will enable daily subcutaneous human recombinant Elafin as a treatment for patients with pulmonary arterial hypertension, because this agent both inhibits elevated elastase activity and inflammation in these patients and activates a critical pathway that protects against this disease, the BMPR2 receptor pathway. We investigate the functions of Elafin in pre- clinical studies in human cells including those derived from patient-specific pluripotent cell-derived endothelial cells, to find out who might best respond to this therapy, and we use novel mass spectrometry techniques to inform us about the pathobiology of the disease at the single cell level in circulating immune/inflammatory cells and in the tissues. As not all therapies are expected to be beneficial to all patients with pulmonary arterial hypertension, we extend our studies to novel experimental animals that explain female gender bias in this disease and the potential for regulatory T cell immunotherapy as an adjunct to Elafin or as a stand-alone treatment.
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