Src Homology and Collagen (Shc) inhibition for the treatment of transplant-related pulmonary fibrosis. - PROJECT SUMMARY/ ABSTRACT Lung transplantation and hematopoietic cell transplantation (HCT) are life-saving treatments for a variety of diseases, but survival after transplant can be limited by a transforming growth factor (TGF)-β-mediated pulmonary fibrosis. Transplant-related pulmonary fibrosis (TPF) is a rare condition that affects the distal airways, known as bronchiolitis obliterans syndrome (BOS). In lung transplants, fibrosis can also affect the lung parenchyma and pleura, collectively known as chronic lung allograft dysfunction (CLAD), the major obstacle to long-term survival after lung transplant. Yet, there are no available treatments for TPF. We recently completed a phase I trial that examined pirfenidone, a TGF-β inhibitor, FDA-approved for idiopathic pulmonary fibrosis (IPF), for use in persons with BOS after HCT (NCT03315741). Treatment with pirfenidone was associated with an improvement in pulmonary function tests, as well as a decrease in liver and skin markers of chronic Graft-Versus- Host-Disease (GVHD), suggesting a role for antifibrotics in alloimmune-mediated fibrosis. The transition of pirfenidone to the generic drug market has prevented additional drug sponsorship necessary for a trial seeking FDA-approval for TPF. Hence, we are focused on developing new TPF drugs that target the TGF-β pathway. In this proposal, we outline the development of a small molecule, called Shc301, that inhibits Src Homology and Collagen (Shc) signaling involved in a non-canonical TGF-β pathway. In preliminary studies Shc301 treatment: (i) decreased markers of fibrosis in TGF-β stimulated human precision cut lung slices (hPCLS) obtained from patients with IPF and CLAD; (ii) in a mouse orthotopic tracheal transplant (OTT) model of TPF, treatment with Shc301 decreased fibrosis, when used in both a preventative (after transplant) and a treatment-based strategy (after 21 days of acute graft rejection), and (iii) Shc301 was more effective than pirfenidone in mitigating TPF in both models. In the OTT model, fibrosis in the Shc treated allotransplants was equivalent to that seen in the non- rejecting syngeneic transplants. This proposal will test the central hypothesis that Shc301 can mitigate fibrillar collagen accumulation and crosslinking in preclinical models of TPF. Specific Aim 1 will assess the efficacy of increasing doses of Shc301 in hPCLS derived from patients with CLAD and HCT-BOS at the time of lung transplantation. Specific Aim 2 will evaluate the in vivo efficacy, pharmacodynamics, and pharmacokinetics of Shc301 in the mouse OTT model. In both aims the primary outcome measure for efficacy will be collagen levels, as quantified by the hydroxyproline assay. Secondary correlative measures will include Second Harmonic Generation microscopy to quantify tissue stiffness (i.e., fibrillar collagen), and the expression of pro-collagen precursors ⍺-smooth muscle actin and collagen type I, alpha 1. Pharmacokinetic analysis will use liquid chromatography-mass spectrometry to measure plasma and lung tissue concentrations over time in the murine airway transplant recipients. Successful completion of the proposed studies would represent a first step toward a paradigm shift in TPF treatment, providing rigorous evidence supporting the further development of Shc301.
