Rescue of Advanced Pompe Disease in Mice with Hepatic Expression of Secretable Acid α-Glucosidase

被引：21

作者：

Cagin, Umut ^{[1
]}

Puzzo, Francesco ^{[1
,2
]}

Jose Gomez, Manuel ^{[3
]}

Moya-Nilges, Maryse ^{[4
]}

Sellier, Pauline ^{[1
]}

Abad, Catalina ^{[5
]}

Van Wittenberghe, Laetitia ^{[1
]}

Daniele, Nathalie ^{[1
]}

Guerchet, Nicolas ^{[1
]}

Gjata, Bernard ^{[1
]}

Collaud, Fanny ^{[1
]}

Charles, Severine ^{[1
]}

Sola, Marcelo Simon ^{[1
]}

Boyer, Olivier ^{[5
]}

Krijnse-Locker, Jacomina ^{[4
]}

Ronzitti, Giuseppe ^{[1
]}

Colella, Pasqualina ^{[1
]}

Mingozzi, Federico ^{[1
,2
,6
]}

机构：

[1] Univ Paris Saclay, Univ Evry, INSERM, INTEGRARE,Genethon, F-91002 Evry, France

[2] Sorbonne Univ, Paris, France

[3] Ctr Nacl Invest Cardiovasc Carlos III, Bioinformat Unit, Madrid 28029, Spain

[4] Pasteur Inst, Rue Dr Roux, F-75015 Paris, France

[5] Univ Rouen Normandie, IRIB, F-76183 Rouen, France

[6] Spk Therapeut, Philadelphia, PA 19103 USA

来源：

MOLECULAR THERAPY | 2020年 / 28卷 / 09期

基金：

欧洲研究理事会;

关键词：

ENZYME REPLACEMENT THERAPY; MEDIATED GENE-TRANSFER; NF-KAPPA-B; TARGETED DISRUPTION; EMERGING PHENOTYPE; MUSCLE; INFANTILE; GLYCOGEN; SAFETY; LONG;

D O I：

10.1016/j.ymthe.2020.05.025

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

Pompe disease is a neuromuscular disorder caused by disease-associated variants in the gene encoding for the lysosomal enzyme acid alpha-glucosidase (GAA), which converts lysosomal glycogen to glucose. We previously reported full rescue of Pompe disease in symptomatic 4-month-old Gaa knockout (Gaa(-/-)) mice by adeno-associated virus (AAV) vector-mediated liver gene transfer of an engineered secretable form of GAA (secGAA). Here, we showed that hepatic expression of secGAA rescues the phenotype of 4-month-old Gaa(-/-) mice at vector doses at which the native form of GAA has little to no therapeutic effect. Based on these results, we then treated severely affected 9-month-old Gaa mice with an AAV vector expressing secGAA and followed the animals for 9 months thereafter. AAV-treated Gaa(-/-) mice showed complete reversal of the Pompe phenotype, with rescue of glycogen accumulation in most tissues, including the central nervous system, and normalization of muscle strength. Transcriptomic profiling of skeletal muscle showed rescue of most altered pathways, including those involved in mitochondrial defects, a finding supported by structural and biochemical analyses, which also showed restoration of lysosomal function. Together, these results provide insight into the reversibility of advanced Pompe disease in the Gaa(-/-) mouse model via liver gene transfer of secGAA.

引用

页码：2056 / 2072

页数：17

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