Gene transfer to the CNS is efficacious in immune-primed mice harboring physiologically relevant titers of anti-AAV antibodies.
Central nervous system (CNS)-directed gene therapy with recombinant adeno-associated virus (AAV) vectors has been used effectively to slow disease course in mouse models of several neurodegenerative diseases. However, these vectors were typically tested in mice without prior exposure to the virus, an immunological scenario unlikely to be duplicated in human patients. Here, we examined the impact of pre-existing immunity on AAV-mediated gene delivery to the CNS of normal and diseased mice. Antibody levels in brain tissue were determined to be 0.6% of the levels found in systemic circulation. As expected, transgene expression in brains of mice with relatively high serum antibody titers was reduced by 59-95%. However, transduction activity was unaffected in mice that harbored more clinically relevant antibody levels. Moreover, we also showed that markers of neuroinflammation (GFAP, Iba1, and CD3) and histopathology (hematoxylin and eosin (H&E)) were not enhanced in immune-primed mice (regardless of pre-existing antibody levels). Importantly, we also demonstrated in a mouse model of Niemann Pick Type A (NPA) disease that pre-existing immunity did not preclude either gene transfer to the CNS or alleviation of disease-associated neuropathology. These findings support the continued development of AAV-based therapies for the treatment of neurological disorders.
Genzyme, a Sanofi Company, Framingham, Massachusetts, USA.
Christopher M
CM
Treleaven
Genzyme, a Sanofi Company, Framingham, Massachusetts, USA.
Thomas J
TJ
Tamsett
Genzyme, a Sanofi Company, Framingham, Massachusetts, USA.
Jie
J
Bu
Genzyme, a Sanofi Company, Framingham, Massachusetts, USA.
Jonathan A
JA
Fidler
Genzyme, a Sanofi Company, Framingham, Massachusetts, USA.
S Pablo
SP
Sardi
Genzyme, a Sanofi Company, Framingham, Massachusetts, USA.
Gregory D
GD
Hurlbut
Genzyme, a Sanofi Company, Framingham, Massachusetts, USA.
Lisa A
LA
Woodworth
Genzyme, a Sanofi Company, Framingham, Massachusetts, USA.
Seng H
SH
Cheng
Genzyme, a Sanofi Company, Framingham, Massachusetts, USA.
Marco A
MA
Passini
Genzyme, a Sanofi Company, Framingham, Massachusetts, USA.
Lamya S
LS
Shihabuddin
Genzyme, a Sanofi Company, Framingham, Massachusetts, USA. Electronic address: jim.dodge@genzyme.com.
James C
JC
Dodge
D000328:Adult; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology* / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000276:immunology* / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007114:Immunization; D051379:Mice; D052536:Niemann-Pick Disease, Type A / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D019076:Transgenes
D000914:Antibodies, Viral; D015415:Biomarkers