Passage Bio, Inc. announced publication of the robust pre-clinical studies that supported clinical study initiation for PBKR03 gene therapy for infantile Krabbe disease. In the paper reporting these preclinical results, Juliette Hordeaux, D.V.M., Ph.D., D.E.C.V.P., and colleagues from University of Pennsylvania's Gene Therapy Program (GTP), report marked improvements in both disease progression and key biomarkers in large and small animal models of Krabbe disease following a single administration of PBKR03, with no observed dose-limiting toxicities. Krabbe disease is a rare pediatric lysosomal storage disorder caused by mutations in the GALC gene, which encodes galactosylceramidase, an enzyme that breaks down galactosylceramide and psychosine.

Without adequate levels of galactosylceramidase, psychosine accumulates, causing widespread death of myelin-producing cells and progressive damage to neurons in both the brain and peripheral tissues of affected children. This is characterized in children by loss of acquired milestones, staring episodes, apnea, peripheral neuropathy, severe weakness, unresponsiveness to stimuli, seizures, blindness, and deafness. Life expectancy for infantile Krabbe disease, the most severe form, is two years.

For the preclinical studies, the researchers selected animal models in which a spontaneous mutation in the GALC gene recapitulates certain characteristics of human disease in the animal's central and peripheral nervous systems, such as low or no GALC enzyme activity, toxic accumulation of psychosine, and rapid neurological deterioration. Their experiment in mice which was designed to approximate developmental age and disease stage of the intended population with infantile Krabbe disease showed that administration of PBKR03 into the cerebrospinal fluid (CSF) led to dose-dependent improvements in histopathological, biochemical, and clinical disease signs. Further, in a canine model of Krabbe disease, intra-cisterna magna (ICM) delivery of the AAV gene therapy resulted in elevated GALC enzyme activity in brain, spinal cord and CSF, reduced psychosine accumulation, and preserved central and peripheral nerve myelination compared to the control group.

This led to marked improvements in nerve conduction function, ambulation, and survival. In Passage Bio's clinical trial GALax-C, patients are also administered PBKR03 via ICM. PBKR03 utilizes a next-generation proprietary AAV capsid to deliver, through ICM administration, a functional GALC gene into the CSF.

The GALax-C Phase I/II study utilizing PBKR03 is currently enrolling the first cohort of patients with infantile Krabbe disease with mutations in the gene that codes for galactosylceramidase. The gene therapy has the potential to treat both the central nervous system and peripheral nerve manifestations observed in patients with Krabbe disease. The U.S. Food and Drug Administration (FDA) has granted PBKR03 Fast Track, Orphan Drug, and Rare Pediatric Disease designations.

PBKR03 has also received an Orphan designation from the European Commission.