Adeno-associated virus-mediated SGPL1 gene therapy as a first-in-class treatment for idiopathic pulmonary fibrosis that acts by reducing sphingosine-1-phosphate and downstream profibrotic signaling

Summary Idiopathic pulmonary fibrosis (IPF) is a severe age-related lung disease that affects millions of people worldwide. It causes progressive lung dysfunction leading to death, usually within a few years of diagnosis. Two targeted drugs are available to treat IPF, but they merely slow lung function decline. The only cure for IPF

is lung transplantation. Thus, new treatments with potential to cure IPF are direly needed. A growing body of evidence implicates the bioactive sphingolipid sphingosine-1-phosphate (S1P) in the pathophysiology of IPF. S1P promotes inflammation and fibrosis by activating a family of G protein-coupled receptors (S1PRs), thus

stimulating signaling pathways that interact with TGFa multifunctional cytokine with a central role in fibrosis. Drugs targeting S1PRs are already on the market or in clinical trials for treating autoimmune diseases. Although targeting S1P appears to have a promising future in treatment of fibrotic diseases, chronic S1PR

antagonism and the immunosuppression it causes increase the risk of cancer and neurodegenerative disease, especially in older patients. Thus, alternative S1P-targeting approaches may be needed in the context of IPF. S1P lyase (SPL), encoded by SGPL1, catalyzes the final step of sphingolipid metabolism in which S1P is

irreversibly degraded. We find that endogenous lung SPL plays a protective role in pulmonary fibrosis. Further, we demonstrate that augmenting SPL activity by intravenous delivery of an adeno-associated virus 9 expressing human SGPL1 (AAV-SPL) to mice 10-14 days after bleomycin treatment attenuates lung TGF

signaling and pulmonary fibrosis. Our findings have led us to hypothesize that AAV-SPL represents a novel single-dose IPF treatment that acts by reducing lung S1P and downstream profibrogenic signaling. It does so without causing immunosuppression, thus providing an S1P targeting approach superior to S1PR antagonists.

In this proposal, we will confirm our hypothesis and advance AAV-SPL as a therapeutic agent for IPF. In the R61 phase of this award, we will rigorously validate the efficacy of AAV-SPL in IPF and confirm the cellular target for AAV-SPL. In Aim One, we will measure the impact of AAV-SPL on lung fibrosis: a) in a mouse IPF

model in which the Trf1 gene encoding a telomere-specific protein is disrupted specifically in lung alveolar type II cells, and b) in cytokine-stimulated and IPF precision cut lung slices. In Aim Two, we will create a lung epithelial cell-specific Sgpl1 knockout mouse and demonstrate that it develops pulmonary fibrosis. In the

project’s R33 phase, we will begin to characterize AAV-SPL’s pharmacological characteristics. In Aim Three, we will optimize AAV-SPL performance by comparing potency, bioavailability, and early safety profile after intravenous versus intratracheal delivery in murine models of IPF. The R33 phase will culminate in completion

of Aim Four, in which we will plan next steps in development of AAV-SPL by submitting an INTERACT meeting request to the Food and Drug Administration. By completing this project and with guidance from our accelerator partner, we will be positioned to establish AAV-SPL as a first-in-class gene therapy for IPF.