ABOUT THE GRANT

Globoid cell leukodystrophy (Krabbe disease) is a devastating, early-onset disease with rapid progression and often death by 2 years
of age due to the lack of an enzyme, galactocerebrosidase (GALC). As the harmful substance, psychosine, accumulates it leads to death
of critical myelinating cells in the central and peripheral nervous systems that are needed for nerve conduction. Even at birth babies with Krabbe
disease have lost cells that are crucial to normal development, and irreversible damage has occurred. However, since myelination of the nervous
system does not begin until the second trimester, a golden opportunity exists to treat the disease prenatally, prior to the onset of irreversible
disease. Our long-term goal is to treat Krabbe disease before the onset of disease.

Herein we will utilize the valuable canine model of Krabbe disease that closely resembles the disease in humans and allows testing of potential
therapies. In Aim 1 we will evaluate the disease in canine Krabbe fetuses. We know that psychosine is increased in the brain of Krabbe affected
dogs at birth and conjecture that, as in humans, this occurs during the prenatal period. We will determine the fetal time frame in which this occurs
to help guide our treatment window. In Aim 2 we will evaluate the biodistribution of fetal AAV gene therapy after intracranial delivery in healthy
dogs using a reporter protein. This will inform where the virus is distributed and if the gene expression is stable. Lastly, in Aim 3 we will evaluate
the effects in canine Krabbe disease after prenatal AAV9-CAG-cGALC gene replacement therapy. We have already evaluated this same gene therapy
postnatally in Krabbe affected dogs at 2 and 6 weeks of age. This study will allow us to directly compare the efficacy of pre- and post-natal
gene therapy in a valuable large animal model of Krabbe disease.

An Interview with Allison Bradbury, MS, PhD

Allison M. Bradbury, MS, PhD is a tenure track assistant professor in the Department of Pediatrics at The Ohio State University and Principal Investigator in the Center for Gene Therapy at Nationwide Children’s Hospital. She leads a R01-funded translational laboratory with the goal of improving the understanding of disease mechanisms resulting in rare pediatric neurologic disorders to develop safe and efficacious targeted gene therapy approaches.

Dr. Bradbury received her PhD in Biomedical Sciences from Auburn University (2009-2014) where her doctoral research was focused on the development of AAV gene therapy in a feline model of GM2 gangliosidosis. This therapy is now in human clinical trials. Successively, her postdoctoral research fellowship was completed at the University of Pennsylvania and supported by a NRSA F32 Fellowship and NIH K99/R00 Pathway to Independence grant. During her postdoctoral fellowship she conducted a comprehensive natural history study in the canine model of globoid cell leukodystrophy (Krabbe disease) and demonstrated therapeutic efficacy in this model for the first time by utilizing AAV gene therapy to target both central and peripheral nervous system disease, with successful translation to the clinic. In her independent laboratory, Dr. Bradbury continues to optimize and translate next generation gene therapies for Krabbe disease.