TSXV:BTI.H - Post by User
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prophetoffactzon Mar 01, 2023 12:32pm
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RE:Sangamo
RE:SangamoChiesi is a top 50 global pharma company that has targeted Lysosomal Storage as a strategic focus. It is a very patient company directed at the long term.
. 2022 Apr 19;25:370-381. doi: 10.1016/j.omtm.2022.04.010. eCollection 2022 Jun 9. Liver-directed gene therapy corrects neurologic disease in a murine model of mucopolysaccharidosis type I-Hurler
Xiu Jin 1, Jing Su 1, Qinyu Zhao 1, Ruiting Li 1, Jianlu Xiao 1, Xiaomei Zhong 1, Li Song 1, Yi Liu 1, Kaiqin She 1 2, Hongxin Deng 1, Yuquan Wei 1, Yang Yang 1 Affiliations
Free PMC article Abstract
Mucopolysaccharidosis type I-Hurler (MPS I-H) is a neurodegenerative lysosomal storage disorder (LSD) caused by inherited defects of the α-L-iduronidase (IDUA) gene. Current treatments are ineffective for treating central nervous system (CNS) manifestations because lysosomal enzymes do not effectively cross the blood-brain barrier (BBB). To enable BBB transport of the enzyme, we engineered a modified IDUA protein by adding a brain-targeting peptide from melanotransferrin. We demonstrated that fusion of melanotransferrin peptide (MTfp) at the N terminus of human IDUA (hIDUA) was enzymatically active and could efficiently cross the BBB in vitro. Then, liver-directed gene therapy using the adeno-associated virus 8 (AAV8) vector, which encoded the modified hIDUA cDNA driven by a liver-specific expression cassette was evaluated in an adult MPS I-H mouse model. The results showed that intravenous (i.v.) infusion of AAV8 resulted in sustained supraphysiological levels of IDUA activity and normalized glycosaminoglycan (GAG) accumulation in peripheral tissues. Addition of MTfp to the hIDUA N terminus allowed efficient BBB transcytosis and IDUA activity restoration in the brain, resulting in significant improvements in brain pathology and neurobehavioral deficits. Our results provide a novel strategy to develop minimally invasive therapies for treatment of MPS I-H and other neurodegenerative LSDs.