Combination HSCT and intravenous AAV-mediated gene therapy in a canine model proves pivotal for translation of Krabbe disease therapy.

Hematopoietic stem cell transplantation (HSCT) is the only approved treatment for presymptomatic infantile globoid cell leukodystrophy (GLD [Krabbe disease]). However, correction of disease is not complete, and outcomes remain poor. Herein we evaluated HSCT, intravenous (IV) adeno-associated virus rh10 vector (AAVrh10) gene therapy, and combination HSCT + IV AAVrh10 in the canine model of GLD. While HSCT alone resulted in no increase in survival as compared with untreated GLD dogs (∼16 weeks of age), combination HSCT + IV AAVrh10 at a dose of 4E13 genome copies (gc)/kg resulted in delayed disease progression and increased survival beyond 1 year of age. A 5-fold increase in AAVrh10 dose to 2E14 gc/kg, in combination with HSCT, normalized neurological dysfunction up to 2 years of age. IV AAVrh10 alone resulted in an average survival to 41.2 weeks of age. In the peripheral nervous system, IV AAVrh10 alone or in addition to HSCT normalized nerve conduction velocity, improved ultrastructure, and normalized GALC enzyme activity and psychosine concentration. In the central nervous system, only combination therapy at the highest dose was able to restore galactosylceramidase activity and psychosine concentrations to within the normal range. These data have now guided clinical translation of systemic AAV gene therapy as an addition to HSCT (NCT04693598, NCT05739643).

Copyright © 2023 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Declaration of interests A.M.B. is a beneficiary of a licensing agreement with Axovant Gene Therapies (royalties) and has received income from Neurogene (consulting and honorarium). A.M.B and C.H.V are inventors on a patent application (Gray SJ, Lykken E, Vite CH, Bradbury AM. Optimized GALC Genes and Expression Cassettes and Their Use. PCT/US2019/067727). N.H. was a paid consultant for UPMC. M.E. is Chief Medical Officer at Forge Biologics. M.E. and P.S. are inventors on a patent application (Treatment of Krabbe disease with umbilical cord blood transplantation (UCBT) and increased galactocerebrosidase (GALC) expression. PCT/US2018/014370) and beneficiaries of a licensing agreement with Forge Biologics.