Nat Commun: Gene editing during pregnancy to treat fatal childhood lysosomal storage disease

Lysosomal storage disease is a genetic disease that affects multiple organs, and current treatments are limited
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Existing studies have shown that pathological changes in patients with lysosomal storage disease begin before birth

Mucopolysaccharidosis type I (MPS-IH, Hurler syndrome) is a type of lysosomal storage disease (LSD)
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In MPS-IH, mutations in the IDUA gene lead to a lack of α-L-uridine enzyme (IDUA) and the accumulation of glycosaminoglycans (GAGs) in the lysosome

child

Although MPS-IH usually has symptoms at 6 months of age, it can be diagnosed prenatally through biochemical and genetic testing
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In histopathological examination, MPS-IH fetuses in the second trimester have disease phenotypes in multiple organs such as liver, heart, and brain

diagnosis

Current treatments include postpartum expensive, lifelong, immunity immunogenic enzyme replacement therapy (ERT), as well as hematopoietic stem cell transplantation (HSCT), which is also limited by the availability of donor, graft failure, graft versus host disease, and Complications of myelocytopenia/immunosuppression
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Immune Stem Cells

Base editing in the uterus may correct disease-causing mutations before tissue lesions occur
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Recently, researchers evaluated the therapeutic effect of using adeno-associated virus serotype 9 (AAV9) to deliver the adenine base editor (ABE) against the Idua G→A (W392X) mutation in the uterus of MPS-IH mice.

Base editing in the uterus may correct disease-causing mutations before tissue lesions occur

 In-utero cardinal editing improves heart function and viability of Idua-W392X mice

 Intrauterine cardinal editing improves the cardiac function and viabilityof Idua-W392X mice Intrauterine cardinal editing improves the cardiac function and viability of Idua-W392X mice 

The results showed that gene editing resulted in effective long-term W392X correction in liver cells and cardiomyocytes and low-level editing in the brain
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In utero editing is related to improving the survival of diseased mice, as well as improving metabolism, musculoskeletal and heart diseases

Hepatocytes and cardiomyocytes effective long-term W392X correction hepatocytes and cardiomyocytes effective long-term W392X correction in utero edit and improve survival disease in mice, as well as improving metabolic, musculoskeletal and heart disease in utero edit and improve disease in mice Survival and related to improving metabolism, musculoskeletal and heart disease

This proof-of-concept study shows that it is possible for us to effectively perform therapeutic base editing in multiple organs through clinically relevant delivery mechanisms before birth, highlighting the treatment of this approach in MPS-IH and other genetic diseases Potential

 

Original source:

Original source:

Sourav K.

Sourav K.

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