title: Synergistic effects of central nervous system-directed gene therapy and bone marrow transplantation in the murine model of infantile neuronal ceroid lipofuscinosis.
abstract: OBJECTIVE
  Infantile neuronal ceroid lipofuscinosis (INCL) is an inherited childhood neurodegenerative disorder caused by the loss of palmitoyl protein thioesterase-1 (PPT1) activity. Affected children suffer from blindness, epilepsy, motor dysfunction, cognitive decline, and premature death. The Ppt1(-/-) mouse shares the histological and clinical features of INCL. Previous single-therapy approaches using small molecule drugs, gene therapy, or neuronal stem cells resulted in partial histological correction, with minimal improvements in motor function or lifespan. Here, we combined central nervous system (CNS)-directed adeno-associated virus (AAV)2/5-mediated gene therapy with bone marrow transplantation (BMT) in the INCL mouse.
  
  
  METHODS
  At birth, Ppt1(-/-) and wild-type mice were given either intracranial injections of AAV2/5-PPT1 or bone marrow transplantation, separately as well as in combination. To assess function, we measured rotorod performance monthly as well as lifespan. At terminal time points, we evaluated the therapeutic effects on several INCL-specific parameters, such as cortical thickness, autofluorescent accumulation, and glial activation. Finally, we determined levels of PPT1 enzyme activity and bone marrow engraftment in treated mice.
  
  
  RESULTS
  AAV2/5-mediated gene therapy alone resulted in significant histological correction, improved motor function, and increased lifespan. Interestingly, the addition of BMT further increased the lifespan of treated mice and led to dramatic, sustained improvements in motor function. These data are truly striking, given that BMT alone is ineffective, yet it synergizes with CNS-directed gene therapy to dramatically increase efficacy and lifespan.
  
  
  CONCLUSIONS
  AAV2/5-mediated gene therapy in combination with BMT provides an unprecedented increase in lifespan as well as dramatic improvement on functional and histological parameters.
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, 660 S. Euclid Ave., St Louis, MO 63110, USA.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Macauley
authors.forename: Marie S
authors.initials: MS
authors.lastname: Roberts
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Wong
authors.forename: Francesca
authors.initials: F
authors.lastname: McSloy
authors.forename: Adarsh S
authors.initials: AS
authors.lastname: Reddy
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Cooper
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sands
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D016026:Bone Marrow Transplantation / Q000379:methods*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity; D009472:Neuronal Ceroid-Lipofuscinoses / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D045442:Rotarod Performance Test; D013869:Thiolester Hydrolases / Q000096:biosynthesis* / Q000172:deficiency / Q000627:therapeutic use
chemical_list: D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase