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

Publication Type	Academic Article
Authors	Bradbury A, Bagel J, Swain G, Miyadera K, Pesayco J, Assenmacher C, Brisson B, Hendricks I, Wang X, Herbst Z, Pyne N, Odonnell P, Shelton G, Gelb M, Hackett N, Szabolcs P, Vite C, Escolar M
Journal	Mol Ther
Volume	32
Issue	1
Pagination	44-58
Date Published	11/11/2023
ISSN	1525-0024
Keywords	Leukodystrophy, Globoid Cell, Hematopoietic Stem Cell Transplantation
Abstract	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).
DOI	10.1016/j.ymthe.2023.11.014
PubMed ID	37952085
PubMed Central ID	PMC10787152