Studying Stem Cell Gene Therapy for NOD2-associated Crohn's Disease

Summary

Approximately 20% to 40% of Crohn's disease (a common form of severe inflammatory bowel disease) patients are known to have mutations within one or both copies of a gene known as NOD2. Normal working copies of the NOD2 gene are needed by a specialised type of white blood cell (monocytes), to detect and alert the body to possible bacterial infections, including potential intestinal infections.

Several recent research studies suggest that mutated NOD2 genes are related to the severity of Crohn’s disease symptoms, and may also limit a patient’s ability to respond to other available therapies. Mutations within NOD2 may prevent monocytes from efficiently detecting bacterial infections that occur in the gut, which could instead drive Crohn’s disease progression.

Research conducted by Orchard Therapeutics Ltd, in our laboratory based within King’s College London, has shown that monocytes with NOD2 mutations cannot efficiently detect bacterial proteins. Importantly, we have also shown that we can correct this through the gene modification of monocytes, and Peripheral Blood Stem Cells (PBSC), which can go on to generate monocytes. This suggests that a stem cell gene therapy approach may be able to provide a new treatment for Crohn’s disease patients with 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, this research will enable us to generate more meaningful results for the potential application of stem cell gene therapy to directly benefit human health, and support the development of Orchard Therapeutics' OTL-104 stem cell gene therapy for NOD2-associated Crohn’s disease.