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Targeting GALC in Krabbe disease
PHILADELPHIA—Passage Bio Inc. recently presented preclinical data for its Krabbe disease program at the American Society of Gene and Cell Therapy (ASGCT) 23rd Annual Meeting. The data were presented by Dr. Juliette Hordeaux, senior director of translational research at the University of Pennsylvania’s Gene Therapy Program (GTP).
“The underlying cause of Krabbe disease is mutations in the GALC gene that encodes for the galactosylceramidase (GALC) enzyme,” Dr. Gary Romano, chief medical officer of Passage Bio, tells DDN. “This enzyme breaks down certain fats, including galactosylceramide and psychosine. The myelin-producing cells in the central nervous system (CNS) and peripheral nervous system (PNS) are particularly sensitive to the accumulation of psychosine, resulting in the widespread death of these cell populations. Without myelin, nerves in the brain and other parts of the body cannot transmit signals properly, leading to the signs and symptoms of Krabbe disease.”
Krabbe disease is a rare and often life-threatening lysosomal storage disease. The early infantile form of the disease is the most severe, typically manifesting before six months of age and accounting for 60 to 70 percent of diagnoses.
“Symptoms of infantile Krabbe disease usually develop from ages two to five months,” Romano notes. “Manifestations include irritability, developmental delay or regression, limb spasticity, axial hypotonia, absent reflexes, optic atrophy and deafness. These children demonstrate rapid developmental regression, with most dying before reaching two years of age.”
Late infantile patients, defined by onset between 7 to 12 months of age, present similar symptoms and a median survival of approximately five years from onset of symptoms. There are currently no disease-modifying therapies for Krabbe disease.
“The data presented ... showcase the promising potential of pairing CSF [cerebrospinal fluid] administration with high potency vectors to achieve robust, scalable effects utilizing cross-correction on central and peripheral nerve function,” said Dr. James Wilson, director of the GTP and chief scientific advisor of Passage Bio. “The marked improvements on critical markers of disease—such as myelination and neuroinflammation, as well as, and perhaps more importantly, phenotypic improvements in function and ultimately prolonged survival—suggest that ICM [intra-cisterna magna-delivered] gene therapy may be incredibly efficacious for rare CNS indications such as Krabbe disease.”
Low GALC activity results in accumulation of psychosine, which is toxic to the myelin producing oligodendrocytes of the CNS and Schwann cells in the periphery—resulting in damage to both the central and peripheral nervous systems.
“The goal of our gene therapy for Krabbe disease, PBKR03, is to deliver a functional copy of the GALC gene using a next-generation, proprietary AAVhu68 capsid and return GALC enzyme activity to levels that are consistent with normal development,” Romano explains. “In preclinical models (murine and canine), we observed meaningful transduction of CNS and PNS, with consequent improvement in neural function.”
Passage Bio believes that PBKR03 has the potential to treat both central and peripheral nerve manifestations observed in Krabbe disease patients.
“In the Twitcher mouse model of Krabbe, cerebrospinal fluid delivery of AAV encoding GALC showed substantial increases in GALC enzyme activity, improved myelination of peripheral nerves, improved neuromotor function and increased survival,” states Romano. “Similarly, in the naturally occurring Krabbe dog model, a single ICM injection of AAV encoding GALC showed normalization of GALC activity, reduction of CSF psychosine levels, normalization of peripheral nerve conduction velocity, improvement in brain myelination, reduction in brain inflammation and phenotypic correction, and increased survival. Treatments in the mouse and dog models were shown to be well-tolerated with no observed toxicities.”
“The dog model offers the opportunity to use the ICM route of administration, which we expect to provide a biodistribution of PBKR03 that is more representative of the biodistribution we have observed in non-human primates and will observe in human infants. As mentioned by Dr. Hordeaux in her 2020 ASGCT presentation, this may account for the more robust treatment effects observed in motor function in the dogs due to better transduction of motor neurons and sensory ganglia,” he points out.
Romano says that Passage Bio is excited about this preclinical data, finding it quite encouraging.
“These findings suggest that PBKR03 may be able to normalize GALC activity and restore myelination and nerve function in the brain and key peripheral tissues that would have otherwise resulted in neurodegeneration and eventual death,” he adds. “We are presently completing our IND enabling studies, including a dose-ranging pharmacological study of the Twitcher mouse and a toxicology study of non-human primates.”
Passage Bio expects to submit an IND for PBKR03 in the second half of 2020, and to initiate a Phase 1/2 trial in the first half of 2021.
“For continuing research, we recently expanded our partnership with Dr. James Wilson’s Gene Therapy Program at the University of Pennsylvania. The team at the GTP has a large research and discovery program for investigating new gene therapy technologies and is constantly working to improve the state of the modality,” notes Romano. “When the right opportunity arises, Passage Bio intends to collaborate with the GTP and incorporate any significant capsid-related or technological advancements into its clinical programs.”
Reiterating Wilson’s emphasis on the data showing improvements with regard to critical disease markers in the animal models—prolonged survival for one but also improvements in terms of myelination, neuroinflammation and phenotypic improvements in function—Romano also thinks that ICM gene therapy may be a boon for patient with various rare CNS diseases, concluding: “We are pleased with the progress made so far, and are looking forward to advancing this program into the clinic and for the opportunity to serve these patients.”