Development of new gene editing delivery systems that cross the blood brain barrier for the treatment of Krabbe Disease and other lysosomal storage disorders

Infantile Krabbe Disease (KD) is a rare genetic disorder caused by mutations in the GALC gene causing lack of the enzyme β-galactocerebrosidase. This deficiency leads to the destruction of the nervous system's protective myelin sheath, causing severe inflammation, progressive nerve damage and early death. Currently, there's no cure for KD, making it crucial to find a safe and effective treatment that can correct the genetic issue and prevent nerve damage in affected infants.

To address this, we developed a gene editing method to fix GALC mutations in the nervous and blood systems using specific DNA-modifying proteins (base editors) packed into a harmless, empty virus shells known as Virus Like Particles (VLPs) and delivered in the blood stream. Early lab tests in KD animal models showed up to 95% correction of the faulty gene in specific nerve and blood cells, leading to restored GALC enzyme levels and function similar to healthy cells. However, while base editors reached blood cells well, they had trouble targeting the brain due to the Blood Brain Barrier (BBB), a network of blood vessels and tissue that keeps harmful substances from reaching the brain.

Our proposal aims to decorate VLPs with molecules binding the BBB, allowing them to cross the barrier and deliver the gene editors to the brain. We'll use a combination of lab cultures, artificial BBB systems, and live models to evaluate the potential of these targeted delivery methods to treat KD. This could also serve as a proof-of-concept for treating other severe neurodegenerative diseases.