Stratified Therapeutic Assessment Platform for Short Telomere related Lung Fibrosis using Patient-Derived iPSC

Introduction

Idiopathic pulmonary fibrosis (IPF) is a lethal scarring lung disease often leading to death within 3 years of diagnosis. New antifibrotic medications slow disease progression, but they are poorly tolerated by patients.

Background

Telomeres, protective structures or caps at the ends of chromosomes, governed by the enzyme telomerase, are shortened in type 2 alveolar epithelial cells (AT2s) in sporadic IPF, but particularly so in inherited mutations of telomere-related genes causing severe disease with early onset.

Early clinical studies indicate that danazol modulates telomere length and prevents the progression of pulmonary fibrosis, but it is poorly tolerated by patients, causing liver toxicity. Gene therapies, including mRNAs that target telomerase, have potential, but human preclinical models do not exist to test their efficacy.

Thus, a new human preclinical model is required to better understand pathogenesis and find new treatments.

Preliminary Work

In preliminary work, I demonstrate that AT2 cells generated from patient-iPSC (iAT2) can replicate elements of pulmonary fibrosis pathogenesis.

Telomere Length

Telomere length in these cells undergoes heterogeneous shortening over time, analogous to the shortening which occurs in vivo. Based on this data and previously published mouse studies, I hypothesize that:

1. Telomere shortening in AT2 cells causes senescence, DNA damage, and inflammation in both sporadic and inherited forms of IPF.
2. Specific gene-stratified mRNA-nanomedicines delivered to the lung can modulate telomere length in a precise manner, avoiding toxicity.

Research Objectives

I will compare iAT2 and hepatic cells generated from patients recruited to a clinical trial of danazol to their own clinical outcomes from the study. This will allow me to perform the first ‘clinical trial in a dish’ in pulmonary fibrosis:

a) To better understand the role of telomere shortening in IPF.
b) To identify and test gene-stratified mRNA-nanomedicines and delivery chemistries leading to improved patient survival.