EXTL2 and EXTL3 inhibition with siRNAs as a promising substrate reduction therapy for Sanfilippo C syndrome

Canals, Isaac; Benetó, Noelia; Cozar, Mónica; Vilageliu, Lluı̈sa; Grinberg, Daniel

doi:10.1038/srep13654

Cited by 26 publications

(32 citation statements)

References 9 publications

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“…In Sanfilippo disease (mucopolysaccharidosis III), there is an accumulation of heparan sulfate in the lysosomes due to an impaired function of one of several lysosomal enzymes. We have assayed the inhibition of the EXTL2 and EXTL3 genes, as a substrate reduction therapy for Sanfilippo C disease in patients' fibroblasts and we are currently performing a similar approach on Sanfilippo C neurons, derived from induced pluripotent stem cells (iPSC) generated by our group …”

Section: Osteochondromatosis or Multiple Hereditary Exostosismentioning

confidence: 99%

Bone development and remodeling in metabolic disorders

Serra-Vinardell

Roca-Ayats

De-Ugarte

et al. 2019

J of Inher Metab Disea

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There are many metabolic disorders that present with bone phenotypes. In some cases, the pathological bone symptoms are the main features of the disease whereas in others they are a secondary characteristic. In general, the generation of the bone problems in these disorders is not well understood and the therapeutic options for them are scarce. Bone development occurs in the early stages of embryonic development where the bone formation, or osteogenesis, takes place. This osteogenesis can be produced through the direct transformation of the pre‐existing mesenchymal cells into bone tissue (intramembranous ossification) or by the replacement of the cartilage by bone (endochondral ossification). In contrast, bone remodeling takes place during the bone's growth, after the bone development, and continues throughout the whole life. The remodeling involves the removal of mineralized bone by osteoclasts followed by the formation of bone matrix by the osteoblasts, which subsequently becomes mineralized. In some metabolic diseases, bone pathological features are associated with bone development problems but in others they are associated with bone remodeling. Here, we describe three examples of impaired bone development or remodeling in metabolic diseases, including work by others and the results from our research. In particular, we will focus on hereditary multiple exostosis (or osteochondromatosis), Gaucher disease, and the susceptibility to atypical femoral fracture in patients treated with bisphosphonates for several years.

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Section: Osteochondromatosis or Multiple Hereditary Exostosismentioning

confidence: 99%

Bone development and remodeling in metabolic disorders

Serra-Vinardell

Roca-Ayats

De-Ugarte

et al. 2019

J of Inher Metab Disea

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“…XYLT1, XYLT2, GALTI, and GALTII [49]), as well as enzymes specific to HS chain elongation (e.g. EXTL2 and EXTL3 [50,51]). These studies together demonstrated decrease in the targeted mRNA concomitant with reduced GAG biosynthesis and attenuated phenotypes in MPS I and III patient fibroblasts.…”

Section: Glycosaminoglycanmentioning

confidence: 99%

Substrate reduction therapy for inborn errors of metabolism

Yue

Mackinnon

Bezerra

2019

Emerging Topics in Life Sciences

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Inborn errors of metabolism (IEM) represent a growing group of monogenic disorders each associated with inherited defects in a metabolic enzyme or regulatory protein, leading to biochemical abnormalities arising from a metabolic block. Despite the well-established genetic linkage, pathophysiology and clinical manifestations for many IEMs, there remains a lack of transformative therapy. The available treatment and management options for a few IEMs are often ineffective or expensive, incurring a significant burden to individual, family, and society. The lack of IEM therapies, in large part, relates to the conceptual challenge that IEMs are loss-of-function defects arising from the defective enzyme, rendering pharmacologic rescue difficult. An emerging approach that holds promise and is the subject of a flurry of pre-/clinical applications, is substrate reduction therapy (SRT). SRT addresses a common IEM phenotype associated with toxic accumulation of substrate from the defective enzyme, by inhibiting the formation of the substrate instead of directly repairing the defective enzyme. This minireview will summarize recent highlights towards the development of emerging SRT, with focussed attention towards repurposing of currently approved drugs, approaches to validate novel targets and screen for hit molecules, as well as emerging advances in gene silencing as a therapeutic modality.

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“…A different SRT approach consists in the use of RNA interference (RNAi) to inhibit genes responsible for GAG synthesis. Patients' fibroblasts treated with siRNAs or shRNAs against two genes involved in HS synthesis showed a clear reduction in GAG production [23][24][25] and HS storage [25]. However, given the neurological symptoms seen in patients, it is crucial to study SRT in relevant human neural cells.…”

Section: Introductionmentioning

confidence: 99%

“…Here we combined these three iPSC lines with optimized protocols to obtain neurons [31] and astrocytes [32], creating novel and relevant disease models that recapitulate major Sanfilippo syndrome hallmarks. We then assayed an siRNA-based SRT strategy that was successful in treating patient fibroblasts [25] and showed that this strategy is not effective in neural cells, highlighting the importance of using disease-relevant cells in studies of disease mechanisms and drug screening.…”

Section: Introductionmentioning

confidence: 99%

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Neuronal and Astrocytic Differentiation from Sanfilippo C Syndrome iPSCs for Disease Modeling and Drug Development

Benetó

Cozar

Castilla‐Vallmanya

et al. 2020

JCM

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Sanfilippo syndrome type C (mucopolysaccharidosis IIIC) is an early-onset neurodegenerative lysosomal storage disorder, which is currently untreatable. The vast majority of studies focusing on disease mechanisms of Sanfilippo syndrome were performed on non-neural cells or mouse models, which present obvious limitations. Induced pluripotent stem cells (iPSCs) are an efficient way to model human diseases in vitro. Recently developed transcription factor-based differentiation protocols allow fast and efficient conversion of iPSCs into the cell type of interest. By applying these protocols, we have generated new neuronal and astrocytic models of Sanfilippo syndrome using our previously established disease iPSC lines. Moreover, our neuronal model exhibits disease-specific molecular phenotypes, such as increase in lysosomes and heparan sulfate. Lastly, we tested an experimental, siRNA-based treatment previously shown to be successful in patients’ fibroblasts and demonstrated its lack of efficacy in neurons. Our findings highlight the need to use relevant human cellular models to test therapeutic interventions and shows the applicability of our neuronal and astrocytic models of Sanfilippo syndrome for future studies on disease mechanisms and drug development.

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EXTL2 and EXTL3 inhibition with siRNAs as a promising substrate reduction therapy for Sanfilippo C syndrome

Cited by 26 publications

References 9 publications

Bone development and remodeling in metabolic disorders

Bone development and remodeling in metabolic disorders

Substrate reduction therapy for inborn errors of metabolism

Neuronal and Astrocytic Differentiation from Sanfilippo C Syndrome iPSCs for Disease Modeling and Drug Development

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