Krabbe Disease Successfully Treated With Gene Therapy in Preclinical Animal Model

Krabbe Disease Successfully Treated With Gene Therapy in Preclinical Animal Model 1024 575 Lauren Dembeck

Gene therapy shows promise for clinical benefit in demyelinating, neurodegenerative disease.

Krabbe disease is an aggressive, incurable pediatric neurodegenerative disease caused by mutations in the galactosylceramidase (GALC) gene. Deficiency of the GALC protein activity leads to cytotoxic accumulation of a cellular metabolite called psychosine, which compromises normal turnover of myelin in the central and peripheral nervous system (CNS, PNS). The ensuing damage leads to progressive disease, including paralysis, loss of sensory functions and death, in the developing infant. The incidence of Krabbe disease is estimated at 1 in 100,000 live births.

The standard of care for presymptomatic babies is hematopoietic stem cell transplantation (HSCT); however, the morbidity and mortality of HSCT is high due to the strong ablative chemotherapy just after birth, and notably, this treatment is not curative. Furthermore, affected babies must be diagnosed and receive HSCT prior to symptom onset, typically a mere 4 weeks of age. No standard of care has been established for post-symptomatic treatment of the disease.

A recent study published in The Journal of Clinical Investigation reports the successful treatment of Krabbe disease in a preclinical animal model using gene therapy.

The study evaluated the efficacy of an intrathecal gene therapy delivering GALC in a naturally occurring animal model of Krabbe disease. Alongside controls, groups of animals were administered the gene therapy presymptomatically or postsymptomatically, and within each disease state, the animals were given a low or high dose.

“In our preclinical model, this study has shown unprecedented results. It has been very exciting that a single intrathecal injection of a gene therapy, which we feel is relatively noninvasive, effectively targeted not only the central nervous system but also the peripheral nervous system,” says first author of the study Allison Bradbury, MS, PhD, a newly recruited principal investigator in the Center for Gene Therapy at the Abigail Wexner Research Institute at Nationwide Children’s Hospital. The study summarizes work performed while Dr. Bradbury was a postdoctoral research fellow at the University of Pennsylvania.

Over the study period, the team collected cerebrospinal fluid and blood, and every eight weeks, they obtained readouts for clinically relevant tests, including nerve conduction velocity and brainstem auditory evoked response. Imaging was also performed at study endpoints or annually.

The gene therapy restored GALC enzyme activity and normalized psychosine concentration in the brain, spinal cord and peripheral nerves in treated animals in a dose-dependent manner. The animals that received the presymptomatic, high dose gene therapy showed the greatest outcome. In this group, the treatment improved myelination in the CNS and PNS and significantly extended lifespan of the animals to more than 7-times that of untreated animals. Importantly, high dose intrathecal delivery of the gene therapy at a symptomatic age, when the standard of care HSCT no longer has clinical benefit, also delayed disease progression and significantly increased survival.

“This study clearly showed that both the timing and the dose are critical. If we under-dose affected animals, we essentially just make an attenuated form of Krabbe disease. It was not curative,” says Dr. Bradbury, who is an assistant professor in the Department of Pediatrics at The Ohio State University. “However, when delivered early and at a high dose, a single, intrathecal injection of gene therapy had remarkable benefit in this model of Krabbe disease.”

Dr. Bradbury’s team is now evaluating the long-term immune response and persistence of the therapeutic enzyme in the surviving animals and evaluating different routes of administration in other ongoing studies.

“This work in animal models will help translate gene therapies to clinical use in the most successful way possible,” says Dr. Bradbury.



Bradbury AM, Bagel JH, Nguyen D, Lykken EA, Pesayco Salvador J, Jiang X, Swain GP, Assenmacher CA, Hendricks IJ, Miyadera K, Hess RS, Ostrager A, O’Donnell P, Sands MS, Ory DS, Shelton GD, Bongarzone ER, Gray SJ, Vite CH. Krabbe disease successfully treated via monotherapy of intrathecal gene therapyJournal Clinical Investigation. 2020 Sep 1;130(9):4906-4920.

About the author

Lauren Dembeck, PhD, is a freelance science and medical writer based in New York City. She completed her BS in biology and BA in foreign languages at West Virginia University. Dr. Dembeck studied the genetic basis of natural variation in complex traits for her doctorate in genetics at North Carolina State University. She then conducted postdoctoral research on the formation and regulation of neuronal circuits at the Okinawa Institute of Science and Technology in Japan.