Genome Editing and Gaucher Disease Treatment

Abstract: In the present review, data published on Gaucher Disease (GD) signcommon treatments was comprehensively examined, focusing on CRISPR/Cas9 as the most promising tool for treatment and understanding correlations between pathophysiological disease complications and related neurodegeneration and neuroinflammation. GD is an inherited autosomal recessive, lysosomal monogenic disease. Changes in the GBA gene sequence encoding acid ?-glucocerebrosidase lead to classical and sequential defects, such as lysosomal accumulation of glycosphingolipids, glucosylceramide and glucosylsphingosine, in reticuloendothelial descendants and macrophages. Glucosylceramide deposits in macrophages eventually result in the functional impairment of various tissues, including bone marrow, spleen, and liver, causing additional complications. A neurological hallmark of GD is GBA1 mutation, considered a key factor in Parkinson?s disease development. Hence, GD patients are grouped into three categories according to their defect level and affected organ(s): non-neuropathic (type I), acute neuropathic (type II) and chronic neuropathic (type III). Enzyme replacement therapy and substrate reduction are effective treatments for type I GD. However, they are expensive and lifelong, necessitating development of novel therapeutic techniques that successfully treat all types of GD in a cost-effective, robust manner. In particular, in vivo, ex vivo and in vitro gene therapy research has shown the CRISPR/Cas9 system to be an efficient gene editing tool widely considered to be a new key player in the treatment of genetically inherited diseases. CRISPR/Cas9 technology was used to produce two isogenic GD Model cell lines with induced GBA1 mutations (THP-1 from monocytes and U87 from glioblastoma) relevant to affected cells in GD patients. Additional research and development of advanced CRISPR/Cas9 systems able to deal with complex situations seen in some GD cases is needed where attention to controlling extra downstream sequences beyond target genes, multi-allelic defects and/or target genomic sequences sharing a high rate of similarity with other vital functional sequences is considered.