Protocol

Gene Delivery and Therapy for Neurological Disorders

Volume 98 of the series Neuromethods pp 265-295

Date:

AAV Gene Therapy Strategies for Lysosomal Storage Disorders with Central Nervous System Involvement

  • Diane GolebiowskiAffiliated withDepartments of Neurology, University of Massachusetts Medical SchoolGene Therapy Center, University of Massachusetts Medical School
  • , Allison M. BradburyAffiliated withScott-Ritchey Research Center, College of Veterinary Medicine, Auburn University
  • , Churl-Su KwonAffiliated withDepartment of Neurosurgery, Massachusetts General Hospital
  • , Imramsjah M. J. van der BomAffiliated withDepartment of Radiology, University of Massachusetts Medical SchoolNew England Center for Stroke Research, University of Massachusetts Medical School
  • , Lorelei StoicaAffiliated withDepartments of Neurology, University of Massachusetts Medical SchoolGene Therapy Center, University of Massachusetts Medical School
  • , Aime K. JohnsonAffiliated withDepartment of Clinical Sciences, College of Veterinary Medicine, Auburn University
  • , Diane U. WilsonAffiliated withScott-Ritchey Research Center, College of Veterinary Medicine, Auburn University
  • , Heather L. Gray-EdwardsAffiliated withScott-Ritchey Research Center, College of Veterinary Medicine, Auburn University
  • , Judith A. HudsonAffiliated withDepartment of Clinical Sciences, College of Veterinary Medicine, Auburn University
    • , Jacob A. JohnsonAffiliated withDepartment of Clinical Sciences, College of Veterinary Medicine, Auburn University
    • , Ashley N. RandleAffiliated withScott-Ritchey Research Center, College of Veterinary Medicine, Auburn University
    • , Brian K. WhitlockAffiliated withDepartment of Large Animal Clinical Sciences, University of Tennessee College of Veterinary Medicine
    • , James L. SartinAffiliated withDepartment of Anatomy, Physiology & Pharmacology, College of Veterinary Medicine, Auburn University
    • , Anna Luisa KühnAffiliated withDepartment of Radiology, University of Massachusetts Medical SchoolNew England Center for Stroke Research, University of Massachusetts Medical School
    • , Matthew GounisAffiliated withDepartment of Radiology, University of Massachusetts Medical SchoolNew England Center for Stroke Research, University of Massachusetts Medical School
    • , Wael AsaadAffiliated withDepartment of Neurosurgery and Brown Institute for Brain Science, Brown University Alpert Medical School and Rhode Island Hospital
    • , Douglas R. MartinAffiliated withScott-Ritchey Research Center, College of Veterinary Medicine, Auburn UniversityDepartment of Anatomy, Physiology & Pharmacology, College of Veterinary Medicine, Auburn University
    • , Miguel Sena-EstevesAffiliated withDepartments of Neurology, University of Massachusetts Medical SchoolGene Therapy Center, University of Massachusetts Medical School Email author 

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Abstract

Gene therapy is one of the most promising approaches for the treatment of lysosomal storage disorders (LSDs). This is especially true for the 75 % of LSDs that have central nervous system (CNS) involvement, where enzyme replacement therapy (ERT), the standard of care for LSDs, is ineffective in treating the neurological features of these diseases. Recombinant adeno-associated virus (AAV) vectors have emerged as the most efficient and promising gene transfer vehicles for the CNS and in particular for LSDs. Direct infusion of AAV vectors into interconnected structures in the brain has achieved widespread distribution of vector and therapeutic levels of lysosomal enzymes throughout the CNS. Early stages of clinical trials are currently underway for treating neurological disorders with AAV vectors, with much anticipation for moving these treatments forward to aid patients and families affected by these terrible diseases. In this chapter, we will detail the protocols used for stereotaxic AAV infusion into the brain of mice, cats, sheep, and nonhuman primates.

Key words

Gene therapy Lysosomal storage disorders Stereotaxic brain injections Mouse Cat Sheep Nonhuman primate