Krabbe disease (KD, or Globoid cell leukodystrophy) is a neurodegenerative disease caused by a deficiency of the lysosomal enzyme GALC. The early childhood form represents 85‐90% of cases and the onset of symptoms is between the 3rd and the 6th month after birth. During the advanced state, blindness and deafness show up; then a vegetative state arises which ends with death within the first 1‐2 years after birth. Unfortunately, for infants who have already developed symptoms of KD, there is no treatment that can change the course of the disease. Treatment, therefore, focuses on managing symptoms and providing supportive care.

Currently, the literature indicates that GALC‐deficiency correction might not be sufficient to cure the patients with KD, suggesting that not yet identified players could be implicated in KD pathogenesis. In this context, we identified some clear evidence pointing to the protein named GPR65 as a key factor in the pathogenesis of the disease.

Here, we propose a deep investigation of GPR65 and its evaluation as a druggable target in KD. In particular, we will evaluate GPR65 expression in patients with KD and test drugs to correct GPR65 deficiency in KD cell models. Moreover, we will explore the combination of a GPR65 mRNA‐based therapy with the GALC correction.

In case of a successful project outcome and in a forward‐looking vision, GPR65 mRNA‐based therapy might be used in combination with a main GALC‐deficiency correcting therapy, to help in achieving the complete KD phenotype rescue.