Efficacy and Safety of a Krabbe Disease Gene Therapy

Abstract

Krabbe disease is a lysosomal storage disease caused by mutations in the gene that encodes galactosylceramidase, in which galactosylsphingosine (psychosine) accumulation drives demyelination in the central and peripheral nervous systems, ultimately progressing to death in early childhood. Gene therapy, alone or in combination with transplant, has been developed for almost two decades in mouse models, with increasing therapeutic benefit paralleling the improvement of next-generation adeno-associated virus (AAV) vectors. This effort has recently shown remarkable efficacy in the canine model of the disease by two different groups that used either systemic or cerebrospinal fluid (CSF) administration of AAVrh10 or AAV9. Building on our experience developing CSF-delivered, AAV-based drug products for a variety of neurodegenerative disorders, we conducted efficacy, pharmacology, and safety studies of AAVhu68 delivered to the CSF in two relevant natural Krabbe animal models, and in nonhuman primates. In newborn Twitcher mice, the highest dose (1 × 10 11 genome copies [GC]) of AAVhu68.hGALC injected into the lateral ventricle led to a median survival of 130 days compared to 40.5 days in vehicle-treated mice. When this dose was administered intravenously, the median survival was 49 days. A single intracisterna magna injection of AAVhu68.cGALC at 3 × 10 13 GC into presymptomatic Krabbe dogs increased survival for up to 85 weeks compared to 12 weeks in controls. It prevented psychosine accumulation in the CSF, preserved peripheral nerve myelination, ambulation, and decreased brain neuroinflammation and demyelination, although some regions remained abnormal. In a Good Laboratory Practice-compliant toxicology study, we administered the clinical candidate into the cisterna magna of 18 juvenile rhesus macaques at 3 doses that displayed efficacy in mice. We observed no dose-limiting toxicity and sporadic minimal degeneration of dorsal root ganglia (DRG) neurons. Our studies demonstrate the efficacy, scalability, and safety of a single cisterna magna AAVhu68 administration to treat Krabbe disease. ID: NCT04771416.

Gene Therapy of Sphingolipid Metabolic Disorders

“…AAVhu68, also a neurotropic vector, is one a new variant of AAV9. Studies have confirmed the high efficiency of gene transfer using this vector in the brain and spinal cord following administration into the cerebrospinal fluid [ 25 , 68 , 114 , 115 , 116 ].…”

Gene therapy for lysosomal storage diseases: Current clinical trial prospects

“…NCT 04771416 is a study of PBKR03 delivered as a one-time dose administered into the cisterna magna of subjects with early infantile KD. Hordeaux et al (2022) reported the safety, scalability, and efficacy of a single cisterna magna PBKR03 administration to treat KD model mice and dogs (Table 1).…”

A neglected neurodegenerative disease: Adult-onset globoid cell leukodystrophy

“…This implies that multiple injections are not required in virus-mediated gene therapy, which is different from ERT. The efficacy of virus-mediated gene therapy correlates with the improvement of adenovirus vectors, and this therapy is one of the most 10.3389/fnins.2022.998275 promising therapies for treating GLD (Rafi, 2016;Nasir et al, 2021;Hordeaux et al, 2022).…”