372. U1 snRNA-Mediated Correction of a Splicing Error of the Dopa Decarboxylase Gene

Abstract

Aromatic l-amino acid decarboxylase (AADC) deficiency is an inborn error of monoamine neurotransmitter synthesis that resulted in dopamine and serotonin deficiency. The DDC gene founder mutation IVS6+4A>T is highly prevalent in Chinese patients with AADC deficiency. In this study, we employed U1 snRNA to correct this splicing error. We first used a modified U1 snRNA sequence (IVS-AAA) that matched both the mutated nucleotide and exonic U1 binding sequences corrected the splicing error of both mutated human DDC minigene and mouse artificial splicing construct in vitro. We further injected an adeno-associated viral (AAV) vector to express IVS-AAA in the brain of a knock-in mouse model with either 1×1010 vg or 2×1010 vg per mouse. This treatment was well-tolerated and slightly improved the survival and brain dopamine levels of mice with AADC deficiency. Therefore, U1 snRNA-mediated gene therapy can be a promising method to treat genetic diseases caused by splicing errors, but the efficiency of such a treatment needs improvements.