title: Emerging therapies for neuropathic lysosomal storage disorders.
abstract: Approximately 1 in 5000-8000 children are born annually with a lysosomal storage disease (LSD), which affects their cells' ability to break down naturally occurring substrates. Accumulation, or "storage," of undegraded substrates leads to a wide variety of clinical symptoms, and early mortality. Currently, for LSDs with central nervous system (CNS) involvement, there is no available treatment. Four methods of treatment are being explored in clinical trials and preclinical settings: enzyme replacement therapy, ex vivo gene therapy, in vivo gene therapy, and nanoparticle-based therapy. In general, each therapeutic approach has been hindered by an inability to cross the blood-brain barrier (BBB) without invasive intracranial surgeries. Also, once the treatment has entered the brain, it is difficult to ensure therapeutic levels of enzyme distributed evenly throughout the entire parenchyma. Enzyme replacement therapy (ERT) is the current standard of care for lysosomal diseases without CNS involvement. However, with the recent advent of nanoparticle-based therapy, direct targeting of either gene therapy or ERT to the brain has become plausible. Ex vivo gene therapy, in vivo gene therapy, ERT and nanoparticle-based therapies are explained, while synthesizing and analyzing their potential as clinical treatments targeted to the CNS. While difficulties in treating the entire brain remain, preclinical studies demonstrate profound therapeutic benefit in animal models and generate hope for successful translation to humans.
authors.affiliation: Biomimetic & Biohybrid Materials, Biomedical Devices, and Drug Delivery Laboratories, Department of Chemical Engineering, Samuel Ginn College of Engineering, Auburn University, Auburn, AL 36849, USA; Scott Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA; US Department of Education GAANN Graduate Fellowship Program in Biological and Pharmaceutical Engineering, Auburn University, Auburn, AL 36849, USA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Kelly
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Bradbury
authors.affiliation: Scott Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA; Department of Anatomy, Physiology, and Pharmacology, Scott Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Martin
authors.affiliation: Biomimetic & Biohybrid Materials, Biomedical Devices, and Drug Delivery Laboratories, Department of Chemical Engineering, Samuel Ginn College of Engineering, Auburn University, Auburn, AL 36849, USA; US Department of Education GAANN Graduate Fellowship Program in Biological and Pharmaceutical Engineering, Auburn University, Auburn, AL 36849, USA; Biomimetic & Biohybrid Materials, Biomedical Devices, and Drug Delivery Laboratories, Department of Biomedical Engineering, Rowan University, Glassboro, NJ 08028, USA. Electronic address: byrnem@rowan.edu.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Byrne
mesh_terms: D056947:Enzyme Replacement Therapy / Q000639:trends*; D019317:Evidence-Based Medicine; D005544:Forecasting; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D016464:Lysosomal Storage Diseases / Q000150:complications / Q000235:genetics* / Q000628:therapy*; D053758:Nanoparticles / Q000627:therapeutic use*; D010523:Peripheral Nervous System Diseases / Q000150:complications / Q000235:genetics* / Q000628:therapy*; D016896:Treatment Outcome