Development of an Antisense Oligonucleotide-Mediated Exon Skipping Therapeutic Strategy for Mucolipidosis II: Validation at RNA Level

Matos, Liliana; Vilela, Regina Maria; Rocha, Melissa; Santos, Juliana Inês; Coutinho, Maria Francisca; Gaspar, Paulo; Prata, Maria João; Alves, Sandra

doi:10.1089/hum.2020.034

Cited by 10 publications

(8 citation statements)

References 36 publications

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“…Recently, Matos et al have developed an antisense oligonucleotide-based exon skipping strategy to treat ML II [ 123 ]. A deletion of a dinucleotide (c.3503_3504del) on exon 19 of GNTAB makes truncated GlcNAc-1-phosphotransferase, resulting in a complete loss of enzyme activity.…”

Section: Therapy and Management Of ML Patientsmentioning

confidence: 99%

Mucolipidoses Overview: Past, Present, and Future

Khan

Tomatsu

2020

IJMS

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Mucolipidosis II and III (ML II/III) are caused by a deficiency of uridine-diphosphate N-acetylglucosamine: lysosomal-enzyme-N-acetylglucosamine-1-phosphotransferase (GlcNAc-1-phosphotransferase, EC2.7.8.17), which tags lysosomal enzymes with a mannose 6-phosphate (M6P) marker for transport to the lysosome. The process is performed by a sequential two-step process: first, GlcNAc-1-phosphotransferase catalyzes the transfer of GlcNAc-1-phosphate to the selected mannose residues on lysosomal enzymes in the cis-Golgi network. The second step removes GlcNAc from lysosomal enzymes by N-acetylglucosamine-1-phosphodiester α-N-acetylglucosaminidase (uncovering enzyme) and exposes the mannose 6-phosphate (M6P) residues in the trans-Golgi network, in which the enzymes are targeted to the lysosomes by M6Preceptors. A deficiency of GlcNAc-1-phosphotransferase causes the hypersecretion of lysosomal enzymes out of cells, resulting in a shortage of multiple lysosomal enzymes within lysosomes. Due to a lack of GlcNAc-1-phosphotransferase, the accumulation of cholesterol, phospholipids, glycosaminoglycans (GAGs), and other undegraded substrates occurs in the lysosomes. Clinically, ML II and ML III exhibit quite similar manifestations to mucopolysaccharidoses (MPSs), including specific skeletal deformities known as dysostosis multiplex and gingival hyperplasia. The life expectancy is less than 10 years in the severe type, and there is no definitive treatment for this disease. In this review, we have described the updated diagnosis and therapy on ML II/III.

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Section: Therapy and Management Of ML Patientsmentioning

confidence: 99%

Mucolipidoses Overview: Past, Present, and Future

Khan

Tomatsu

2020

IJMS

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“…The structure and mannose-binding mode of the γ subunit was also determined. These results may help assessing the impact of genetic mutations and facilitate the development of lysosomal enzyme replacement therapies ( 39 ) or other treatments for mucolipidosis ( 27 ). However, the most intriguing aspect of this complex—the basis for its ability to specifically recognize around 70 lysosomal hydrolases among the thousands of glycoproteins in the secretory pathway—remains largely unanswered.…”

Section: Resultsmentioning

confidence: 99%

“…Genetic mutations in GNPTAB and GNPTG cause the lysosomal storage diseases mucolipidosis type II, fatal in early childhood, and type III, a less severe form ( 16 , 22 – 24 ). There are currently no disease-specific treatments for these disorders ( 25 ), with preclinical investigations of gene therapy ( 26 ) and antisense oligonucleotides ( 27 ) in progress. These approaches, and others including pharmacological chaperones ( 28 ), could be facilitated by detailed structural information on GNPT.…”

mentioning

confidence: 99%

Structures of the mannose-6-phosphate pathway enzyme, GlcNAc-1-phosphotransferase

Gorelik

Illés

Bui

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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The mannose-6-phosphate (M6P) pathway is responsible for the transport of hydrolytic enzymes to lysosomes. N-acetylglucosamine-1-phosphotransferase (GNPT) catalyzes the first step of tagging these hydrolases with M6P, which when recognized by receptors in the Golgi diverts them to lysosomes. Genetic defects in the GNPT subunits, GNPTAB and GNPTG, cause the lysosomal storage diseases mucolipidosis types II and III. To better understand its function, we determined partial three-dimensional structures of the GNPT complex. The catalytic domain contains a deep cavity for binding of uridine diphosphate- N -acetylglucosamine, and the surrounding residues point to a one-step transfer mechanism. An isolated structure of the gamma subunit of GNPT reveals that it can bind to mannose-containing glycans in different configurations, suggesting that it may play a role in directing glycans into the active site. These findings may facilitate the development of therapies for lysosomal storage diseases.

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“…The plethora of innovative ideas on pharmacological approaches is growing at an incredible rate and different mechanisms of action are being exploited from mutation-specific approaches such as stop-codon read-through [ 63 , 64 , 65 ] and splicing modulation with antisense oligonucleotides [ 66 , 67 , 68 ] to more generic approaches, such as the use of anti-inflammatory or neuroprotective drugs, which address endpoints of the LSDs pathophysiological cascade [ 69 ]. Not all these approaches hold potential to address brain pathology, but the neurological dysfunction has not been forgotten.…”

Section: Lysosomal Storage Disordersmentioning

confidence: 99%

Lysosomal Storage Disease-Associated Neuropathy: Targeting Stable Nucleic Acid Lipid Particle (SNALP)-Formulated siRNAs to the Brain as a Therapeutic Approach

Coutinho

Santos

Mendonça

et al. 2020

IJMS

Self Cite

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More than two thirds of Lysosomal Storage Diseases (LSDs) present central nervous system involvement. Nevertheless, only one of the currently approved therapies has an impact on neuropathology. Therefore, alternative approaches are under development, either addressing the underlying enzymatic defect or its downstream consequences. Also under study is the possibility to block substrate accumulation upstream, by promoting a decrease of its synthesis. This concept is known as substrate reduction therapy and may be triggered by several molecules, such as small interfering RNAs (siRNAs). siRNAs promote RNA interference, a naturally occurring sequence-specific post-transcriptional gene-silencing mechanism, and may target virtually any gene of interest, inhibiting its expression. Still, naked siRNAs have limited cellular uptake, low biological stability, and unfavorable pharmacokinetics. Thus, their translation into clinics requires proper delivery methods. One promising platform is a special class of liposomes called stable nucleic acid lipid particles (SNALPs), which are characterized by high cargo encapsulation efficiency and may be engineered to promote targeted delivery to specific receptors. Here, we review the concept of SNALPs, presenting a series of examples on their efficacy as siRNA nanodelivery systems. By doing so, we hope to unveil the therapeutic potential of these nanosystems for targeted brain delivery of siRNAs in LSDs.

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Development of an Antisense Oligonucleotide-Mediated Exon Skipping Therapeutic Strategy for Mucolipidosis II: Validation at RNA Level

Cited by 10 publications

References 36 publications

Mucolipidoses Overview: Past, Present, and Future

Mucolipidoses Overview: Past, Present, and Future

Structures of the mannose-6-phosphate pathway enzyme, GlcNAc-1-phosphotransferase

Lysosomal Storage Disease-Associated Neuropathy: Targeting Stable Nucleic Acid Lipid Particle (SNALP)-Formulated siRNAs to the Brain as a Therapeutic Approach

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