Krabbe disease successfully treated via monotherapy of intrathecal gene therapy
Allison M. Bradbury, … , Steven J. Gray, Charles H. Vite
Allison M. Bradbury, … , Steven J. Gray, Charles H. Vite
Published August 10, 2020
Citation Information: J Clin Invest. 2020;130(9):4906-4920. https://doi.org/10.1172/JCI133953.
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Krabbe disease successfully treated via monotherapy of intrathecal gene therapy

Abstract

Globoid cell leukodystrophy (GLD; Krabbe disease) is a progressive, incurable neurodegenerative disease caused by deficient activity of the hydrolytic enzyme galactosylceramidase (GALC). The ensuing cytotoxic accumulation of psychosine results in diffuse central and peripheral nervous system (CNS, PNS) demyelination. Presymptomatic hematopoietic stem cell transplantation (HSCT) is the only treatment for infantile-onset GLD; however, clinical outcomes of HSCT recipients often remain poor, and procedure-related morbidity is high. There are no effective therapies for symptomatic patients. Herein, we demonstrate in the naturally occurring canine model of GLD that presymptomatic monotherapy with intrathecal AAV9 encoding canine GALC administered into the cisterna magna increased GALC enzyme activity, normalized psychosine concentration, improved myelination, and attenuated inflammation in both the CNS and PNS. Moreover, AAV-mediated therapy successfully prevented clinical neurological dysfunction, allowing treated dogs to live beyond 2.5 years of age, more than 7 times longer than untreated dogs. Furthermore, we found that a 5-fold lower dose resulted in an attenuated form of disease, indicating that sufficient dosing is critical. Finally, postsymptomatic therapy with high-dose AAV9 also significantly extended lifespan, signifying a treatment option for patients for whom HSCT is not applicable. If translatable to patients, these findings would improve the outcomes of patients treated either pre- or postsymptomatically.

Authors

Allison M. Bradbury, Jessica H. Bagel, Duc Nguyen, Erik A. Lykken, Jill Pesayco Salvador, Xuntian Jiang, Gary P. Swain, Charles A. Assenmacher, Ian J. Hendricks, Keiko Miyadera, Rebecka S. Hess, Arielle Ostrager, Patricia ODonnell, Mark S. Sands, Daniel S. Ory, G. Diane Shelton, Ernesto R. Bongarzone, Steven J. Gray, Charles H. Vite

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Figure 1

Experimental design, vector construct, and survival.

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Experimental design, vector construct, and survival. (A) GLD dogs were t...
(A) GLD dogs were treated with AAV9 delivered to the cisterna magna in a 1-mL volume. Ten GLD dogs were treated at 2 weeks of age with 1 × 1014 vg (2Wk-High); 4 GLD dogs were treated at 2 weeks of age with 2 × 1013 vg (2Wk-Low); 4 GLD dogs were treated at 6 weeks of age with 1 × 1014 vg (6Wk-High); 4 GLD dogs were treated at 6 weeks of age with 2 × 1013 vg (6Wk-Low). All dogs received an immunosuppression protocol consisting of 20 mg/kg intravenous methylprednisolone 1 hour before AAV infusion followed by 4 months of daily oral prednisone (0.5 mg/kg) with a 2-week taper. Four GLD dogs received immunosuppression protocol alone (IS-only). Four 2Wk-High dogs were euthanized at a predetermined endpoint of 16 weeks, while the remaining 22 dogs were followed long-term. (B) The AAV9 construct consisted of inverted terminal repeats (ITR), a CAGGS promoter, a codon-optimized canine GALC transgene, and a polyadenylation signal. (C) Percentage survival of untreated GLD (black), IS-only (gray), 2Wk-High (red), 2Wk-Low (blue), 6Wk-High (green), and 6Wk-Low (purple). A drop in the line indicates a death due to disease progression, and a black tick mark indicates dogs still alive (n = 1 in the 6Wk-High cohort, n = 6 in the 2Wk-High cohort). NCV, nerve conduction velocity testing; BAER, brainstem auditory evoked response testing.