Adeno-associated virus 2-mediated gene therapy decreases autofluorescent storage material and increases brain mass in a murine model of infantile neuronal ceroid lipofuscinosis

Neurobiology of Disease

Beth Levy¹  Carole Vogler²  Mark S Sands²  Ellen Bible³  Jonathan Cooper³  Megan Griffey⁴  Praveena Gupta⁴ 

[1] Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA;Department of Pathology, St. Louis University School of Medicine, St. Louis, MO 63104, USA;Pediatric Storage Disorders Laboratory and Department of Neuroscience, Institute of Psychiatry, De Crespigny Park, King's College London, London SE5 8AF, UK;Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA;

关键词: Infantile neuronal ceroid lipofuscinosis;    Lysosomal storage disease;    Batten disease;    Gene therapy;    Neurodegenerative disease;    Adeno-associated virus;   

DOI  :  

来源: DOAJ

【 摘 要 】

Infantile neuronal ceroid lipofuscinosis (INCL) is the earliest onset form of a class of inherited neurodegenerative disease called Batten disease. INCL is caused by a deficiency in the lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1). Autofluorescent storage material accumulates in virtually all tissues in INCL patients, including the brain, and leads to widespread neuronal loss and cortical atrophy. To determine the efficacy of viral-mediated gene therapy, we injected a recombinant adeno-associated virus 2 vector encoding human PPT1 (rAAV–PPT1) intracranially (I.C.) into a murine model of INCL. INCL mice given four I.C. injections of rAAV–PPT1 as newborns exhibited PPT1 activity near the injection sites and decreased secondary elevations of another lysosomal enzyme. In addition, storage material was decreased in cortical, hippocampal, and cerebellar neurons, and brain weights and cortical thicknesses were increased. These data demonstrate that an adeno-associated virus 2 (AAV2)-mediated gene therapy approach may provide some therapeutic benefit for INCL.

【 授权许可】

Unknown