Synergistic effects of central nervous system‐directed gene therapy and bone marrow transplantation in the murine model of infantile neuronal ceroid lipofuscinosis
- 1 February 2012
- journal article
- research article
- Published by Wiley in Annals of Neurology
- Vol. 71 (6), 797-804
- https://doi.org/10.1002/ana.23545
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. Interpretation: 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. ANN NEUROL 2012;This publication has 31 references indexed in Scilit:
- Bone Marrow Transplantation Augments the Effect of Brain- and Spinal Cord-Directed Adeno-Associated Virus 2/5 Gene Therapy by Altering Inflammation in the Murine Model of Globoid-Cell LeukodystrophyJournal of Neuroscience, 2011
- Long-term Safety and Efficacy Following Systemic Administration of a Self-complementary AAV Vector Encoding Human FIX Pseudotyped With Serotype 5 and 8 Capsid ProteinsMolecular Therapy, 2011
- Assessing the potential for AAV vector genotoxicity in a murine modelBlood, 2011
- Disruption of adaptive energy metabolism and elevated ribosomal p-S6K1 levels contribute to INCL pathogenesis: partial rescue by resveratrolHuman Molecular Genetics, 2010
- Therapeutic Efficacy of Bone Marrow Transplant, Intracranial AAV-mediated Gene Therapy, or Both in the Mouse Model of MPS IIIBMolecular Therapy, 2010
- Palmitoyl:protein thioesterase (PPT1) inhibitors can act as pharmacological chaperones in infantile Batten diseaseBiochemical and Biophysical Research Communications, 2010
- Cerebellar pathology and motor deficits in the palmitoyl protein thioesterase 1-deficient mouseExperimental Neurology, 2009
- Successive neuron loss in the thalamus and cortex in a mouse model of infantile neuronal ceroid lipofuscinosisNeurobiology of Disease, 2007
- Central Nervous System-directed AAV2/5-Mediated Gene Therapy Synergizes with Bone Marrow Transplantation in the Murine Model of Globoid-cell LeukodystrophyMolecular Therapy, 2007
- Recombinant adeno-associated virus purification using novel methods improves infectious titer and yieldGene Therapy, 1999