In utero adenine base editing corrects multi-organ pathology in a lethal lysosomal storage disease.
In utero adenine base editing corrects multi-organ pathology in a lethal lysosomal storage disease.
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DOI：
10.1038/s41467-021-24443-8
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发表时间：
2021-07-13
影响因子：
16.6
通讯作者：
Peranteau WH
中科院分区：
文献类型：
--
作者：
Bose SK;White BM;Kashyap MV;Dave A;De Bie FR;Li H;Singh K;Menon P;Wang T;Teerdhala S;Swaminathan V;Hartman HA;Jayachandran S;Chandrasekaran P;Musunuru K;Jain R;Frank DB;Zoltick P;Peranteau WH
在子宫内，碱基编辑有可能在病理发生之前纠正致病突变。粘多糖病I型(MPS-IH，Hurler综合征)是一种累及多个器官的溶酶体蓄积性疾病，常导致出生后早期心肺功能衰竭。我们在宫内腺相关病毒血清9型(AAV9)中评估了针对MPS-IH小鼠中IDUA G→A(W392X)突变的腺嘌呤碱基编辑程序(ABE)的传递，对应于MPS-IH患者中常见的IDUA G→A(W402X)突变。在这里，我们展示了在肝细胞和心肌细胞中有效的长期W392X校正和在大脑中的低水平编辑。宫内编辑与改善新陈代谢、肌肉骨骼和心脏疾病的存活率和改善有关。这项概念验证研究证明了通过临床相关的传递机制在出生前有效地在多个器官中执行治疗性碱基编辑的可能性，强调了这种方法在MPS-IH和其他遗传性疾病中的潜力。溶酶体储存疾病，如粘多糖病I型(MPS I)，在出生前就会导致病理，并导致早期发病率和死亡率。在这里，作者表明，在子宫基础上的编辑中介多器官的表型和生存的益处在小鼠模型中概括了一个常见的人类MPSI突变。
In utero base editing has the potential to correct disease-causing mutations before the onset of pathology. Mucopolysaccharidosis type I (MPS-IH, Hurler syndrome) is a lysosomal storage disease (LSD) affecting multiple organs, often leading to early postnatal cardiopulmonary demise. We assessed in utero adeno-associated virus serotype 9 (AAV9) delivery of an adenine base editor (ABE) targeting the Idua G→A (W392X) mutation in the MPS-IH mouse, corresponding to the common IDUA G→A (W402X) mutation in MPS-IH patients. Here we show efficient long-term W392X correction in hepatocytes and cardiomyocytes and low-level editing in the brain. In utero editing was associated with improved survival and amelioration of metabolic, musculoskeletal, and cardiac disease. This proof-of-concept study demonstrates the possibility of efficiently performing therapeutic base editing in multiple organs before birth via a clinically relevant delivery mechanism, highlighting the potential of this approach for MPS-IH and other genetic diseases. Lysosomal storage diseases like mucopolysaccharidosis type I (MPS I) cause pathology before birth and result in early morbidity and mortality. Here, the authors show that in utero base editing mediates multi-organ phenotypic and survival benefits in a mouse model recapitulating a common human MPSI mutation.
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影响因子：
3.6
作者：
Choi JH;Yu NK;Baek GC;Bakes J;Seo D;Nam HJ;Baek SH;Lim CS;Lee YS;Kaang BK
通讯作者：
Kaang BK
影响因子：
82.9
作者：
Charlesworth, Carsten T.;Deshpande, Priyanka S.;Porteus, Matthew H.
通讯作者：
Porteus, Matthew H.
影响因子：
4.3
作者：
Boelig, Matthew M.;Kim, Aimee G.;Peranteau, William H.
通讯作者：
Peranteau, William H.
影响因子：
3
作者：
Bello-Arroyo E;Roque H;Marcos A;Orihuel J;Higuera-Matas A;Desco M;Caiolfa VR;Ambrosio E;Lara-Pezzi E;Gómez-Gaviro MV
通讯作者：
Gómez-Gaviro MV
DOI：
10.1073/pnas.1813952116
发表时间：
2019-03-05
影响因子：
11.1
作者：
Frank, David B.;Penkala, Ian J.;Morrisey, Edward E.
通讯作者：
Morrisey, Edward E.