Neonatal nonviral gene editing with the CRISPR/Cas9 system improves some cardiovascular, respiratory, and bone disease features of the mucopolysaccharidosis I phenotype in mice

Schuh, Roselena Silvestri; Gonzalez, Esteban Alberto; Tavares, Ângela Maria Vicente; Seolin, Bruna Gazzi de Lima; Elias, Lais de Souza; Vera, Luisa Natalia Pimentel; Kubaski, Francyne; Poletto, Édina; Giugliani, Roberto; Teixeira, Hélder Ferreira; Matte, Úrsula da Silveira; Baldo, Guilherme

doi:10.1038/s41434-019-0113-4

Cited by 27 publications

(24 citation statements)

References 46 publications

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“…Similarly, AAV-mediated zinc-finger nuclease editing to express Idua in the hepatocyte Albumin locus of adult mice caused enhanced IDUA secretion, decreased tissue GAGs, and improved neurobehaviour 21 . Finally, neonatal hydrodynamic intravascular liposomal delivery of CRISPR-Cas9 targeting the hepatocyte Rosa26 locus for homology-directed repair (HDR) with Idua integration partially improved GAGs, serum IDUA, and skeletal and cardiac disease 22 . Although encouraging, postnatal CRISPR-HDR is inefficient and requires double-stranded DNA breaks (DSBs) that are associated with unwanted mutagenesis, large deletions, and complex rearrangements at on- and off-target sites 23 , 24 .…”

Section: Introductionmentioning

confidence: 99%

In utero adenine base editing corrects multi-organ pathology in a lethal lysosomal storage disease

et al. 2021

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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.

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Section: Introductionmentioning

confidence: 99%

In utero adenine base editing corrects multi-organ pathology in a lethal lysosomal storage disease

et al. 2021

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“…Milder clinical manifestations include dyspnea, difficulty clearing secretions, cough, wheezing, and recurrent bronchitis or pneumonia [22]. Despite the obvious importance of respiratory issues, these are rarely investigated in the animal models of MPS I. Schuh et al used plethysmography to establish that lung function is significantly compromised in MPS I mice, however, no histopathological analysis was conducted [30].…”

Section: Introductionmentioning

confidence: 99%

Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology

Hampe

Eisengart

Lund

et al. 2020

Cells

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Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive inherited disease, caused by deficiency of the enzyme α-L-iduronidase, resulting in accumulation of the glycosaminoglycans (GAGs) dermatan and heparan sulfate in organs and tissues. If untreated, patients with the severe phenotype die within the first decade of life. Early diagnosis is crucial to prevent the development of fatal disease manifestations, prominently cardiac and respiratory disease, as well as cognitive impairment. However, the initial symptoms are nonspecific and impede early diagnosis. This review discusses common phenotypic manifestations in the order in which they develop. Similarities and differences in the three animal models for MPS I are highlighted. Earliest symptoms, which present during the first 6 months of life, include hernias, coarse facial features, recurrent rhinitis and/or upper airway obstructions in the absence of infection, and thoracolumbar kyphosis. During the next 6 months, loss of hearing, corneal clouding, and further musculoskeletal dysplasias develop. Finally, late manifestations including lower airway obstructions and cognitive decline emerge. Cardiac symptoms are common in MPS I and can develop in infancy. The underlying pathogenesis is in the intra- and extracellular accumulation of partially degraded GAGs and infiltration of cells with enlarged lysosomes causing tissue expansion and bone deformities. These interfere with the proper arrangement of collagen fibrils, disrupt nerve fibers, and cause devastating secondary pathophysiological cascades including inflammation, oxidative stress, and other disruptions to intracellular and extracellular homeostasis. A greater understanding of the natural history of MPS I will allow early diagnosis and timely management of the disease facilitating better treatment outcomes.

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“…Newborn MPS I mice receiving the treatment had a modest increase in serum IDUA activity, GAG reduction in different tissues and partial prevention of bone disease. The treatment, however, had no effect on neurological manifestations 128 . An alternative approach is ex vivo genome editing.…”

Section: Challenges In Treating Mps I Bone Disease: Emerging Therapiesmentioning

confidence: 97%

MPS I: Early diagnosis, bone disease and treatment, where are we now?

Kingma

Jonckheere

2021

J of Inher Metab Disea

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Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder characterized by α‐L‐iduronidase deficiency. Patients present with a broad spectrum of disease severity ranging from the most severe phenotype (Hurler) with devastating neurocognitive decline, bone disease and early death to intermediate (Hurler‐Scheie) and more attenuated (Scheie) phenotypes, with a normal life expectancy. The most severely affected patients are preferably treated with hematopoietic stem cell transplantation, which halts the neurocognitive decline. Patients with more attenuated phenotypes are treated with enzyme replacement therapy. There are several challenges to be met in the treatment of MPS I patients. First, to optimize outcome, early recognition of the disease and clinical phenotype is needed to guide decisions on therapeutic strategies. Second, there is thus far no effective treatment available for MPS I bone disease. The pathophysiological mechanisms behind bone disease are largely unknown, limiting the development of effective therapeutic strategies. This article is a state of the art that comprehensively discusses three of the most urgent open issues in MPS I: early diagnosis of MPS I patients, pathophysiology of MPS I bone disease, and emerging therapeutic strategies for MPS I bone disease.

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Neonatal nonviral gene editing with the CRISPR/Cas9 system improves some cardiovascular, respiratory, and bone disease features of the mucopolysaccharidosis I phenotype in mice

Cited by 27 publications

References 46 publications

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

Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology

MPS I: Early diagnosis, bone disease and treatment, where are we now?

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