Direct Intracranial Injection of AAVrh8 Encoding Monkey beta-N-Acetylhexosaminidase Causes Neurotoxicity in the Primate Brain
Authors
Golebiowski, Dianevan der Bom, Imramsjah M. J.
Kwon, Churl-Su
Miller, Andrew D.
Petrosky, Keiko
Bradbury, Allison M.
Maitland, Stacy A.
Kuhn, Anna L.
Bishop, Nina
Curran, Elizabeth
Silva, Nilsa
Guhasarkar, Dwijit
Westmoreland, Susan V.
Martin, Douglas R.
Gounis, Matthew J.
Asaad, Wael F.
Sena-Esteves, Miguel
UMass Chan Affiliations
Department of Animal MedicineNew England Center for Stroke Research
Department of Radiology
Horae Gene Therapy Center
Department of Neurology
Document Type
Journal ArticlePublication Date
2017-06-01Keywords
AAVTay-Sachs disease
adeno-associated virus
gene therapy
hexosaminidase
intracranial delivery
Genetics and Genomics
Radiology
Therapeutics
Metadata
Show full item recordAbstract
GM2 gangliosidoses, including Tay-Sachs disease and Sandhoff disease, are lysosomal storage disorders caused by deficiencies in beta-N-acetylhexosaminidase (Hex). Patients are afflicted primarily with progressive central nervous system (CNS) dysfunction. Studies in mice, cats, and sheep have indicated safety and widespread distribution of Hex in the CNS after intracranial vector infusion of AAVrh8 vectors encoding species-specific Hex alpha- or beta-subunits at a 1:1 ratio. Here, a safety study was conducted in cynomolgus macaques (cm), modeling previous animal studies, with bilateral infusion in the thalamus as well as in left lateral ventricle of AAVrh8 vectors encoding cm Hex alpha- and beta-subunits. Three doses (3.2 x 1012 vg [n = 3]; 3.2 x 1011 vg [n = 2]; or 1.1 x 1011 vg [n = 2]) were tested, with controls infused with vehicle (n = 1) or transgene empty AAVrh8 vector at the highest dose (n = 2). Most monkeys receiving AAVrh8-cmHexalpha/beta developed dyskinesias, ataxia, and loss of dexterity, with higher dose animals eventually becoming apathetic. Time to onset of symptoms was dose dependent, with the highest-dose cohort producing symptoms within a month of infusion. One monkey in the lowest-dose cohort was behaviorally asymptomatic but had magnetic resonance imaging abnormalities in the thalami. Histopathology was similar in all monkeys injected with AAVrh8-cmHexalpha/beta, showing severe white and gray matter necrosis along the injection track, reactive vasculature, and the presence of neurons with granular eosinophilic material. Lesions were minimal to absent in both control cohorts. Despite cellular loss, a dramatic increase in Hex activity was measured in the thalamus, and none of the animals presented with antibody titers against Hex. The high overexpression of Hex protein is likely to blame for this negative outcome, and this study demonstrates the variations in safety profiles of AAVrh8-Hexalpha/beta intracranial injection among different species, despite encoding for self-proteins.Source
Hum Gene Ther. 2017 Jun;28(6):510-522. doi: 10.1089/hum.2016.109. Epub 2017 Jan 26. Link to article on publisher's siteDOI
10.1089/hum.2016.109Permanent Link to this Item
http://hdl.handle.net/20.500.14038/48226PubMed ID
28132521Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1089/hum.2016.109