Abstract
Sphingolipidoses are inherited genetic diseases characterized by the accumulation of glycosphingolipids. Sphingolipidoses (SP), which usually involve the loss of sphingolipid hydrolase function, are of lysosomal origin, and represent an important group of rare diseases among lysosomal storage disorders. Initial treatments consisted of enzyme replacement therapy, but, in recent decades, various therapeutic approaches have been developed. However, these commonly used treatments for SP fail to be fully effective and do not penetrate the blood–brain barrier. New approaches, such as genome editing, have great potential for both the treatment and study of sphingolipidoses. Here, we review the most recent advances in the treatment and modelling of SP through the application of CRISPR-Cas9 genome editing. CRISPR-Cas9 is currently the most widely used method for genome editing. This technique is versatile; it can be used for altering the regulation of genes involved in sphingolipid degradation and synthesis pathways, interrogating gene function, generating knock out models, or knocking in mutations. CRISPR-Cas9 genome editing is being used as an approach to disease treatment, but more frequently it is utilized to create models of disease. New CRISPR-Cas9-based tools of gene editing with diminished off-targeting effects are evolving and seem to be more promising for the correction of individual mutations. Emerging Prime results and CRISPR-Cas9 difficulties are also discussed.
Highlights
The present study was based on high-quality, peer-reviewed publications available at NCBI Pubmed until October 2019
In acid sphingomyelinase-deficient Niemann–Pick diseases (NPD) (ASM-deficient NPD), underlying defects are due to SMPD1 gene mutations, whereas in NP type C (NPC), which is currently described as a cholesterol trafficking defect, is due to NPC1 or NPC2 gene mutations [28,29]
Since CRISPR-Cas9 was discovered, many advances have been made in gene editing for disease treatment that were previously impossible
Summary
The present study was based on high-quality, peer-reviewed publications available at NCBI Pubmed until October 2019. Different types of defects may underlie LSDs, including, but not limited to, defects in lysosomal hydrolases, lysosomal membrane proteins, activator proteins, or transport proteins. They all present a common feature, which is the storage of macromolecules in the lysosomes. Depending on the type of storage materials, LSDs are classically divided in subgroups that reflect the analogous affected lysosomal pathway. Such is the case, for example, of the sphingolipidoses, mucopolysaccharidoses, Int. J. The LSDs are rare, research in the field has been abundant; LSDs have been the stage for the development of new therapies and have provided knowledge that extends beyond LSDs
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