Treatment of glutaric aciduria type I(GA-I)via intracerebroventricular delivery of GCDH  

作　　者：Lu Guo Zhikun Li Yuhuan Li Bin Qu Guanyi Jiao Chen Liang Zongbao Lu Xin-Ge Wang Cheng Huang Hongwei Du Jianmin Liang Qi Zhou Wei Li 

机构地区：[1]State Key Laboratory of Stem Cell and Reproductive Biology,Institute of Zoology,Chinese Academy of Sciences,Beijing 100101,China [2]Beijing Institute for Stem Cell and Regenerative Medicine,Beijing 100101,China [3]University of Chinese Academy of Sciences,Beijing 100049,China [4]The First Hospital of Jilin University,Changchun,Jilin 130021,China

出　　处：《Fundamental Research》2022年第6期836-842,共7页自然科学基础研究（英文版）

基　　金：the National Key Research and Development Program(2019YFA0110800 and 2020YFA0707900 to W.L.,and 2018YFA0108400 and 2019YFA0903800 to Q.Z.);Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16030403 to W.L.);National Natural Science Foundation of China(31621004 to Q.Z.and W.L.);CAS Project for Young Scientists in Basic Research(YSBR-012 to W.L.).

摘　　要：Glutaric aciduria type I(GA-I)is an autosomal recessive genetic disorder caused by a deficiency in glutaryl-CoA dehydrogenase(GCDH).Patients who do not receive proper treatment may die from acute encephalopathic crisis.Current treatments for GA-I include a low-lysine diet combined with oral supplementation of L-carnitine.A mouse model of Gcdh^(c.422_428del/c.422_428del)(Gcdh^(−/−))was generated in our laboratory using CRISPR/Cas9.Gcdh^(−/−)mice had significantly higher levels of glutaric acid(GA)in the plasma,liver,and brain than those in wild-type C57BL/6 mice.When given a high-protein diet(HPD)for two days,approximately 60%of Gcdh^(−/−)mice did not survive the metabolic stress.To evaluate whether GCDH gene replacement therapy could be used to provide sustained treatment for patients with GA-1,we prepared a recombinant adeno-associated virus(rAAV)carrying a human GCDH expression cassette and injected it into Gcdh^(−/−)neonates for a proof-of-concept(PoC)study.Our study demonstrated that delivering rAAV to the central nervous system(CNS),but not the peripheral system,significantly increased the survival rate under HPD exposure.Our study also demonstrated that rAAVPHP.eB mediated a higher efficiency than that of rAAV9 in increasing the survival rate.Surviving mice showed dose-dependent GCDH protein expression in the CNS and downregulation of GA levels.Our study demonstrated that AAV-based gene replacement therapy was effective for GA-I treatment and provided a feasible solution for this unmet medical need.

关 键 词：Glutaric aciduria type I(GA-I) Glutaryl-CoA dehydrogenase(GCDH) Adeno-associated virus(AAV) Gene therapy Neurometabolic disease 

分 类 号：R596[医药卫生—内科学]