Gene Therapy for Lysosomal Storage Diseases: Progress, Challenges and Future Prospects

Sergey      S. Seregin; Andrea      Amalfitano

doi:10.2174/138161211797247578

Abstract

Lysosomal Storage Diseases (LSDs) comprise a group of over fifty inherited metabolic disorders, with their hallmark feature being deficient catabolism and accumulation (storage) of macromolecules in the lysosomes due to genetic deficiency of specific lysosomal enzymes. The combined incidence of LSDs is estimated to be ∼1 in 7,000 births. LSD symptoms can vary significantly, primarily due to the nature of the gene defect (null or missense mutations) as well as which cells are affected. Cumulatively, LSDs place a significant burden on patients and their families, causing much in the way of morbidity and mortality. Currently, there is no cure for any LSD. This review will describe currently available treatment options for LSD patients, and then focus upon gene therapy prospects for various LSDs. Worldwide, researchers have accumulated significant data in humans affected by LSDs, as well as several small and large animal models. As a result, various viral and non-viral gene transfer platforms have been developed and specifically optimized to treat LSDs. In this review we will describe advances suggesting that the LSDs may be some of the most amenable diseases to treat by gene therapy based approaches. However, to overcome the several remaining limitations encountered by these approaches, a deep understanding of the biology of the LSDs is required, as well as the host innate and adaptive immune responses to the act of gene transfer.

Keywords: Lysosomal storage disease, gene therapy, enzyme replacement therapy, innate immune responses, adaptive immune responses, Golgi apparatus, oncogenesis, glucocerebrosidase, glycogen, nanoparticles