Emerging therapies for neuropathic lysosomal storage disorders

Jessica M. Kelly, Allison Bradbury, Douglas R. Martin, Mark E. Byrne

Research output: Contribution to journalReview articlepeer-review

22 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)166-180
Number of pages15
JournalProgress in Neurobiology
StatePublished - May 1 2017
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Neuroscience


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