Evaluating the Application of Haematopoietic Stem-Cell Gene Therapy as a Novel Therapeutic for Crohn’s Disease patients with Loss-of Function NOD2 Polymorphisms

Summary

Approximately 20% to 40% of Crohn's Disease patients are known to have mutations within the NOD2 gene. Normal working copies of the NOD2 gene are needed by specialised white blood cells (e.g. monocytes), to detect and alert the body to bacterial infections, including gastrointestinal infections.

Several research studies now suggest that some NOD2 mutations are related to the severity of Crohn’s Disease patients may experience, and that this may also limit a patient’s ability to respond to available therapies that help alleviate symptoms of Crohn’s Disease. Our current knowledge suggests that mutations which cause NOD2 to dysfunction, may prevent monocytes from efficiently detecting bacterial infections that occur in the gut, and that this can instead drive Crohn’s disease progression.

Our research has confirmed that monocytes which have these NOD2 mutations cannot efficiently detect bacterial proteins. Importantly, we have shown that by introducing a working copy of the NOD2 gene using gene therapy, we can correct monocyte dysfunction, and that we can also achieve this by gene modification of blood stem cells, which go on to generate monocytes. These data therefore suggest that stem cell gene therapy may provide a new treatment for Crohn’s Disease patients with some NOD2 mutations.

To understand the potential of this new therapy, we will study the ability of blood monocytes from healthy donors and Crohn’s Disease patients to detect and respond to bacterial proteins, and test whether gene modification can correct NOD2-defective monocytes and stem cells. Combined with on-going studies in our laboratory to understand the role of NOD2 in different white blood cell types, and its relationship with Crohn’s Disease colitis, this research will enable us to generate translationally relevant data to support development of Orchard Therapeutics' OTL-104 stem cell gene therapy for NOD2-associated Crohn’s Disease (www.orchard-tx.com).