Grants Awarded

Principal Investigator:
Dr. Toni Cathomen
Medical Center – University of Freiburg
Breisgau, Germany

Date of Award:
December 2024

Amount of Award:
$50,000

Layperson Summary:

Familial hemophagocytic lymphohistiocytosis (FHL) is a severe inherited disorder in which the immune system becomes hyperactive. FHL type 3 (FHL3) is caused by mutations in a gene called UNC13D and accounts for 30-40% of all FHL cases. These
mutations disrupt the function of a protein named Munc13-4, which is important for the proper functioning of certain immune cells. This dysfunction leads to an overly active immune system, resulting in severe inflammation, organ failure, and often death. The only curative treatment is bone marrow transplantation, which can be difficult, among others due to the challenge of finding a suitable donor. As an alternative, gene therapy and genome editing have shown promise in preliminary studies. We and others have successfully used CRISPR-Cas technology to correct a specific mutation in a mouse FHL3 model and protect them from developing the disease. However, this
method only addressed a single mutation. This project aims to develop a genome editing technique that can correct multiple mutations in the affected UNC13D gene. The plan is to use a method called prime editing to replace an entire section (exon 14) of the UNC13D gene, which contains many mutations that cause FHL3. This approach could be adapted in the future to correct other genetic errors, potentially benefiting individuals with various immune system disorders. In summary, this project addresses a core disease of the Histiocyte Society and introduces a new genetic treatment option that could lead to significant advances in clinical care for affected patients.