Idiopathic pulmonary fibrosis (IPF) is a disease of aging, with a mean age of 66 years at the time of diagnosis. Despite this strong association, cellular/molecular mechanisms that account for the aging predilection to fibrotic disease have not been elucidated. Previous studies in our lab have demonstrated that myofibroblasts, key effector cells in fibrogenesis, demonstrate a diminished capacity to maintain redox homeostasis in aging; this was in part regulated by a deficient induction of the antioxidant response transcription factor, Nrf2. Human subjects with IPF exhibit decreased Nrf2 expression in myofibroblastic foci, supporting this cellular redox imbalance in a human fibrotic disease. Our preliminary data support this Nrf2 redox imbalance in a novel aging model of non-resolving fibrosis in mice. This represents, to our knowledge, the first aging model of fibrosis that recapitulates the non-resolving nature of human IPF. The Nrf2-activator, dimethyl fumarate (DMF), is an FDA- approved drug for the treatment of multiple sclerosis via the oral route of administration. We have developed a novel DMF microparticulate/nanoparticulate formulation using nanotechnology and FDA-approved excipients, which can be administered locally to the lungs as a Dry Powder Inhaler (DPI). We will utilize FDA-approved human inhaler devices, FDA-approved excipients, and an FDA-approved Nrf2 activator to deliver this novel Nrf2- activator formulation in vivo via an inhaled route. Experiments will be conducted under FDA/USP conditions using required in vitro tests specified by the FDA/USP, including in vitro 2D cell culture (i.e. liquid-covered culture and air-interface culture mimicking the air-liquid lung interface), in vitro 3D cell culture (i.e. air-interface culture), and in vivo pharmacokinetics/pharmacodynamics studies. These studies will evaluate mechanisms influencing cell viability as a function of drug dose, particle-cellular membrane interactions, particle cellular uptake, membrane permeability, drug cellular transport, and activation of cellular Nrf2. Finally, we will evaluate the efficacy of this novel Nrf2-activator formulation and delivery method in an aged mouse model of established fibrosis. The proposed studies in this application were designed to: (1) Determine the efficacy of DMF, an FDA- approved drug (multiple sclerosis), for a new indication (pulmonary fibrosis); (2) Test the efficacy of a novel DMF formulation, as a DPI; (3) Investigate oral versus inhaled (local) administration of an antioxidant strategy for IPF; and (4) evaluate safety and efficacy profiles of therapeutics that could lead directly to clinical trials for IPF.
Idiopathic pulmonary fibrosis (IPF) is a disease of aging, with a mean age of 66 years at the time of diagnosis. Human subjects with IPF exhibit decreased Nrf2 expression in myofibroblastic foci, supporting this cellular redox imbalance in a human fibrotic disease. Our preliminary data support this Nrf2 redox imbalance in a novel aging model of non-resolving fibrosis in mice. This represents, to our knowledge, the first aging model of fibrosis that recapitulates the non-resolving nature of human IPF. In addition, we have designed and developed the first novel DMF microparticulate/nanoparticulate formulations using nanotechnology and FDA-approved excipients, which can be administered locally to the lungs as a Dry Powder Inhaler (DPI). We will utilize FDA- approved human inhaler devices, FDA-approved excipients, and an FDA-approved Nrf2 activator to deliver this novel Nrf2-activator formulation in vivo via an inhaled route. This approach can provide a first-in-class therapeutic platform for the treatment of IPF in a targeted manner.
| Hecker, Louise (2018) Mechanisms and consequences of oxidative stress in lung disease: therapeutic implications for an aging populace. Am J Physiol Lung Cell Mol Physiol 314:L642-L653 |
