Sphingolipid-neutralizing molecular therapy reduces psychosine cytotoxicity in Krabbe disease

The deficiency of β-galactosylceramidase causes a lysosomal leukodystrophy, known as Krabbe disease (KD), resulting in elevated psychosine (PSY) levels, which are highly cytotoxic to myelin-forming cells. 2-hydroxypropyl-α-CD (HPaCD), a cyclic-oligosaccharide containing a lipophilic central cavity and hydrophilic outer surfaces, significantly reduces PSY cytotoxicity in cultured KD patient cells. Further ¹H-NMR studies revealed stronger interactions between HPaCD and PSY. Regarding safety, HPaCD-treated mice showed no electrophysiological and histological ototoxicity signs. In the murine KD model, HPaCD improved neurobehavior and reduced PSY levels in the CNS and PNS. The reduction of astrogliosis, increased myelin basic protein, and improvements in PNS axonal-myelin morphometrics were also observed in HPaCD-treated mice. In summary, this is an innovative therapeutic approach that leverages HPaCD's dual properties of molecularly shielding and neutralizing PSY and facilitating its CNS and PNS clearance. Since several newborn screening programs currently include KD, HPaCD becomes highly important as an adjunctive/bridge therapy for improving outcomes in this devastating disorder.