Ex Vivo Gene Therapy Treats Bone Complications of Mucopolysaccharidosis Type II Mouse Models through Bone Remodeling Reactivation

Wada, Miho; Shimada, Yohta; Iizuka, Sayoko; Ishii, Natsumi; Hiraki, Hiromi; Tachibana, Toshiaki; Maeda, Kazuhiro; Saito, Mitsuru; Arakawa, Shoutaro; Ishimoto, Takuya; Nakano, Takayoshi; Ida, Hiroyuki; Ohashi, Toya; Kobayashi, Hiroshi

doi:10.1016/j.omtm.2020.09.012

Cited by 18 publications

(24 citation statements)

References 58 publications

(72 reference statements)

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“…Another method to achieve high levels of IDS is through ex vivo genetic modification of HSC. Transplantation of lentiviral transduced HSC resulted in an increase in serum IDS levels several-fold higher than wild type [167,236]. GAG accumulation in all tested tissues, including the brain, was resolved.…”

Section: Treatment In Animalsmentioning

confidence: 90%

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Differences in MPS I and MPS II Disease Manifestations

Hampe

Yund

Orchard

et al. 2021

IJMS

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Mucopolysaccharidosis (MPS) type I and II are two closely related lysosomal storage diseases associated with disrupted glycosaminoglycan catabolism. In MPS II, the first step of degradation of heparan sulfate (HS) and dermatan sulfate (DS) is blocked by a deficiency in the lysosomal enzyme iduronate 2-sulfatase (IDS), while, in MPS I, blockage of the second step is caused by a deficiency in iduronidase (IDUA). The subsequent accumulation of HS and DS causes lysosomal hypertrophy and an increase in the number of lysosomes in cells, and impacts cellular functions, like cell adhesion, endocytosis, intracellular trafficking of different molecules, intracellular ionic balance, and inflammation. Characteristic phenotypical manifestations of both MPS I and II include skeletal disease, reflected in short stature, inguinal and umbilical hernias, hydrocephalus, hearing loss, coarse facial features, protruded abdomen with hepatosplenomegaly, and neurological involvement with varying functional concerns. However, a few manifestations are disease-specific, including corneal clouding in MPS I, epidermal manifestations in MPS II, and differences in the severity and nature of behavioral concerns. These phenotypic differences appear to be related to different ratios between DS and HS, and their sulfation levels. MPS I is characterized by higher DS/HS levels and lower sulfation levels, while HS levels dominate over DS levels in MPS II and sulfation levels are higher. The high presence of DS in the cornea and its involvement in the arrangement of collagen fibrils potentially causes corneal clouding to be prevalent in MPS I, but not in MPS II. The differences in neurological involvement may be due to the increased HS levels in MPS II, because of the involvement of HS in neuronal development. Current treatment options for patients with MPS II are often restricted to enzyme replacement therapy (ERT). While ERT has beneficial effects on respiratory and cardiopulmonary function and extends the lifespan of the patients, it does not significantly affect CNS manifestations, probably because the enzyme cannot pass the blood–brain barrier at sufficient levels. Many experimental therapies, therefore, aim at delivery of IDS to the CNS in an attempt to prevent neurocognitive decline in the patients.

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Section: Treatment In Animalsmentioning

confidence: 90%

“…Moreover, bone manifestations were affected with significant reduction of zygomatic arch width. In-depth analysis of bone parameters revealed higher osteoclast number, suggesting activation of bone resorption [236].…”

Section: Treatment In Animalsmentioning

confidence: 95%

Differences in MPS I and MPS II Disease Manifestations

Hampe

Yund

Orchard

et al. 2021

IJMS

View full text Add to dashboard Cite

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“…Among various serotypes of adeno‐associated virus (AAV), AAV9 has been selected as the vector due to its brain tropism (Fu et al., 2018; Hinderer et al., 2016; Laoharawee et al., 2017; Motas et al., 2016). In addition to the AAV study, lentiviral vector‐mediated animal studies have been reported (Gleitz et al., 2018; Wada et al., 2020). As the novel mode of delivery, nanoparticle‐mediated administration of the IDS enzyme and gene has also been reported (Rigon et al., 2019).…”

Section: Discussionmentioning

confidence: 99%

“…An active IDS enzyme requires a biotransformation of cysteine to formylglycine for maximal catalytic activity (Demydchuk et al., 2017). To achieve this, the SUMF1 enzyme plays a key role (Gleitz et al., 2018; Wada et al., 2020). In the case of the IDS enzyme, a previous study reported that 68.1%–79.4% of cysteine in therapeutic enzyme preparation from mammalian cell culture systems has been converted into formylglycine (Chung et al., 2014).…”

Section: Discussionmentioning

confidence: 99%

Production of therapeutic iduronate‐2‐sulfatase enzyme with a novel single‐stranded RNA virus vector

Ohira

Kikuchi

Mizuta³

et al. 2021

Genes to Cells

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The Sendai virus vector has received a lot of attention due to its broad tropism for mammalian cells. As a result of efforts for genetic studies based on a mutant virus, we can now express more than 10 genes of up to 13.5 kilo nucleotides in a single vector with high protein expression efficiency. To prove this benefit, we examined the efficacy of the novel ribonucleic acid (RNA) virus vector harboring the human iduronate‐2‐sulfatase (IDS) gene with 1,653 base pairs, a causative gene for mucopolysaccharidosis type II, also known as a disorder of lysosomal storage disorders. As expected, this novel RNA vector with the human IDS gene exhibited its marked expression as determined by the expression of enhanced green fluorescent protein and IDS enzyme activity. While these cells exhibited a normal growth rate, the BHK‐21 transformant cells stably expressing the human IDS gene persistently generated an active human IDS enzyme extracellularly. The human IDS protein produced failed to be incorporated into the lysosome when cells were pretreated with mannose‐6‐phosphate, demonstrating that this human IDS enzyme has potential for therapeutic use by cross‐correction. These results suggest that our novel RNA vector may be applicable for further clinical settings.

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“…The limitation of retroviruses is their integration into the host genome, the risk of mutagenesis and immunogenicity. However, research using other viral vectors on model organisms was continued and showed promising results [ 46 , 47 , 48 ]. Further clinical trials are conducted using various forms of gene therapy, including genome editing systems such as zinc finger nucleases (ZFNs) or Clustered Regularly Interspaced Short Palindromic Repeat/Cas9 (CRISPR/Cas9) [ 48 ].…”

Section: Gene Therapymentioning

confidence: 99%

Gene Therapy for Mucopolysaccharidosis Type II—A Review of the Current Possibilities

Zapolnik

Pyrkosz

2021

IJMS

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Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder based on a mutation in the IDS gene that encodes iduronate 2-sulphatase. As a result, there is an accumulation of glycosaminoglycans—heparan sulphate and dermatan sulphate—in almost all body tissues, which leads to their dysfunction. Currently, the primary treatment is enzyme replacement therapy, which improves the course of the disease by reducing somatic symptoms, including hepatomegaly and splenomegaly. The enzyme, however, does not cross the blood–brain barrier, and no improvement in the function of the central nervous system has been observed in patients with the severe form of the disease. An alternative method of treatment that solves typical problems of enzyme replacement therapy is gene therapy, i.e., delivery of the correct gene to target cells through an appropriate vector. Much progress has been made in applying gene therapy for MPS II, from cellular models to human clinical trials. In this article, we briefly present the history and basics of gene therapy and discuss the current state of knowledge about the methods of this therapy in mucopolysaccharidosis type II.

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Ex Vivo Gene Therapy Treats Bone Complications of Mucopolysaccharidosis Type II Mouse Models through Bone Remodeling Reactivation

Cited by 18 publications

References 58 publications

Differences in MPS I and MPS II Disease Manifestations

Differences in MPS I and MPS II Disease Manifestations

Production of therapeutic iduronate‐2‐sulfatase enzyme with a novel single‐stranded RNA virus vector

Gene Therapy for Mucopolysaccharidosis Type II—A Review of the Current Possibilities

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