Neonatal umbilical cord blood transplantation halts skeletal disease progression in the murine model of MPS-I

Azario, Isabella; Pievani, Alice; Priore, Federica Del; Antolini, Laura; Santi, Ludovica; Corsi, Alessandro; Cardinale, Lucia; Sawamoto, Kazuki; Kubaski, Francyne; Gentner, Bernhard; Bernardo, Maria Ester; Valsecchi, Maria Grazia; Riminucci, Mara; Tomatsu, Shunji; Aiuti, Alessandro; Biondi, Andrea; Serafini, Marta

doi:10.1038/s41598-017-09958-9

Cited by 10 publications

(8 citation statements)

References 55 publications

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“…Current postnatal treatments include costly, lifelong, immunogenic enzyme replacement therapy (ERT), and hematopoietic stem cell transplantation (HSCT), which is limited by donor availability, graft failure, graft-versus-host disease, and complications of myeloablation/immunosuppression 3 . Both human and mouse studies have demonstrated improved outcomes following early initiation of ERT or HSCT compared to late treatment [12][13][14][15][16] . Importantly, in humans, neither treatment resolves preexisting musculoskeletal and cardiac pathologies 3,4,13 , which significantly contribute to MPS-IH clinical grade 17 .…”

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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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confidence: 99%

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

et al. 2021

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“…Two studies on the effect of neonatal HSCT in MPS I mice reported almost complete prevention of bone disease 101,102 . A third study showed that after neonatal HSCT, MPS I mice had a significant improvement of parameters of bone structure and remodeling measured by μCT.…”

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

confidence: 99%

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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“…Furthermore, many available treatments have demonstrated their increased efficacy when started early in life, identifying age at treatment as a predictive factor for a better clinical outcome [ 156 , 158 , 165 , 183 , 184 , 185 , 194 , 263 , 264 ]. In particular, both experiences in animal models and MPSI patients showed an improvement in bone defects in cases of early treatments, considering ERT [ 184 ] and/or HSCT [ 265 , 266 , 267 ]. In view of this, a neonatal GT approach could be helpful because it allows for a very early treatment and, in parallel, it is associated with a reduced risk of immunological complications (i.e., immune response against the therapeutic enzyme).…”

Section: Therapeutic Options For Mpsi and Focus On Bone Limitationsmentioning

confidence: 99%

MPSI Manifestations and Treatment Outcome: Skeletal Focus

Ponti

Donsante

Frigeni

et al. 2022

IJMS

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Mucopolysaccharidosis type I (MPSI) (OMIM #252800) is an autosomal recessive disorder caused by pathogenic variants in the IDUA gene encoding for the lysosomal alpha-L-iduronidase enzyme. The deficiency of this enzyme causes systemic accumulation of glycosaminoglycans (GAGs). Although disease manifestations are typically not apparent at birth, they can present early in life, are progressive, and include a wide spectrum of phenotypic findings. Among these, the storage of GAGs within the lysosomes disrupts cell function and metabolism in the cartilage, thus impairing normal bone development and ossification. Skeletal manifestations of MPSI are often refractory to treatment and severely affect patients’ quality of life. This review discusses the pathological and molecular processes leading to impaired endochondral ossification in MPSI patients and the limitations of current therapeutic approaches. Understanding the underlying mechanisms responsible for the skeletal phenotype in MPSI patients is crucial, as it could lead to the development of new therapeutic strategies targeting the skeletal abnormalities of MPSI in the early stages of the disease.

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Neonatal umbilical cord blood transplantation halts skeletal disease progression in the murine model of MPS-I

Cited by 10 publications

References 55 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

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

MPSI Manifestations and Treatment Outcome: Skeletal Focus

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