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Advances in Sphingolipidoses: CRISPR-Cas9 Editing as an Option for Modelling and Therapy

Published on Nov 24, 2019in International Journal of Molecular Sciences4.183
· DOI :10.3390/ijms20235897
Renato Santos1
Estimated H-index: 1
,
Olga Amaral9
Estimated H-index: 9
Abstract
Sphingolipidoses are inherited genetic diseases characterized by the accumulation of glycosphingolipids. Sphingolipidoses (SP), which usually involve the loss of sphingolipid hydrolase function, are of lysosomal origin, and represent an important group of rare diseases among lysosomal storage disorders. Initial treatments consisted of enzyme replacement therapy, but, in recent decades, various therapeutic approaches have been developed. However, these commonly used treatments for SP fail to be fully effective and do not penetrate the blood–brain barrier. New approaches, such as genome editing, have great potential for both the treatment and study of sphingolipidoses. Here, we review the most recent advances in the treatment and modelling of SP through the application of CRISPR-Cas9 genome editing. CRISPR-Cas9 is currently the most widely used method for genome editing. This technique is versatile; it can be used for altering the regulation of genes involved in sphingolipid degradation and synthesis pathways, interrogating gene function, generating knock out models, or knocking in mutations. CRISPR-Cas9 genome editing is being used as an approach to disease treatment, but more frequently it is utilized to create models of disease. New CRISPR-Cas9-based tools of gene editing with diminished off-targeting effects are evolving and seem to be more promising for the correction of individual mutations. Emerging Prime results and CRISPR-Cas9 difficulties are also discussed.
  • References (68)
  • Citations (1)
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References68
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#1Yvonne L. Latour (NIH: National Institutes of Health)H-Index: 7
#2Robin Yoon (NIH: National Institutes of Health)H-Index: 1
Last. Cynthia J. Tifft (NIH: National Institutes of Health)H-Index: 33
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Abstract GM1 gangliosidosis is an autosomal recessive neurodegenerative disorder caused by the deficiency of lysosomal β-galactosidase (β-gal) and resulting in accumulation of GM1 ganglioside. The disease spectrum ranges from infantile to late onset and is uniformly fatal, with no effective therapy currently available. Although animal models have been useful for understanding disease pathogenesis and exploring therapeutic targets, no relevant human central nervous system (CNS) model system has b...
1 CitationsSource
β-glucosidases [GBA1 (glucocerebrosidase) and GBA2] are ubiquitous essential enzymes. Lysosomal GBA1 and cytosol-facing GBA2 degrade glucosylceramide (GlcCer); GBA1 deficiency causes Gaucher disease, a lysosomal storage disorder characterized by lysosomal accumulation of GlcCer, which is partly converted to glucosylsphingosine (GlcSph). GBA1 and GBA2 also may transfer glucose from GlcCer to cholesterol, yielding glucosylated cholesterol (GlcChol). Here, we aimed to clarify the role of zebrafish ...
2 CitationsSource
#1Andrew V. Anzalone (Broad Institute)H-Index: 1
#2Peyton B. Randolph (Broad Institute)H-Index: 2
Last. David R. Liu (Broad Institute)H-Index: 73
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Most genetic variants that contribute to disease1 are challenging to correct efficiently and without excess byproducts2–5. Here we describe prime editing, a versatile and precise genome editing method that directly writes new genetic information into a specified DNA site using a catalytically impaired Cas9 fused to an engineered reverse transcriptase, programmed with a prime editing guide RNA (pegRNA) that both specifies the target site and encodes the desired edit. We performed more than 175 ed...
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#1Espen Melum (Oslo University Hospital)H-Index: 23
#2Xiaojun Jiang (Oslo University Hospital)H-Index: 3
Last. Richard S. Blumberg (Brigham and Women's Hospital)H-Index: 87
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Invariant natural killer T (iNKT) cells recognize activating self and microbial lipids presented by CD1d. CD1d can also bind non-activating lipids, such as sphingomyelin. We hypothesized that these serve as endogenous regulators and investigated humans and mice deficient in acid sphingomyelinase (ASM), an enzyme that degrades sphingomyelin. We show that ASM absence in mice leads to diminished CD1d-restricted antigen presentation and iNKT cell selection in the thymus, resulting in decreased iNKT ...
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#1Jenny Do (NIH: National Institutes of Health)H-Index: 1
#2Cindy E. McKinney (NIH: National Institutes of Health)H-Index: 7
Last. Ellen Sidransky (NIH: National Institutes of Health)H-Index: 55
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Mutations in GBA1, the gene encoding the lysosomal enzyme glucocerebrosidase, are among the most common known genetic risk factors for the development of Parkinson disease and related synucleinopathies. A great deal is known about GBA1, as mutations in GBA1 are causal for the rare autosomal storage disorder Gaucher disease. Over the past decades, significant progress has been made in understanding the genetics and cell biology of glucocerebrosidase. A least 495 different mutations, found through...
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#1Tamar Farfel-Becker (NIH: National Institutes of Health)H-Index: 9
#2Jenny Do (NIH: National Institutes of Health)H-Index: 1
Last. Ellen Sidransky (NIH: National Institutes of Health)H-Index: 55
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Homozygous and heterozygous mutations in GBA1 , the gene implicated in Gaucher disease, increase the risk and severity of Parkinson disease (PD). We evaluated the design, phenotype, strengths, and limitations of current GBA1 -associated PD mouse models. Although faithful modeling of a genetic risk factor poses many challenges, the different approaches taken were successful in revealing predisposing abnormalities in heterozygotes for GBA1 mutations and demonstrating the deleterious effects of GBA...
3 CitationsSource
#1Bence György (Harvard University)H-Index: 20
#2Carl Nist-Lund (Boston Children's Hospital)H-Index: 3
Last. David P. Corey (Harvard University)H-Index: 75
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Since most dominant human mutations are single nucleotide substitutions1,2, we explored gene editing strategies to disrupt dominant mutations efficiently and selectively without affecting wild-type alleles. However, single nucleotide discrimination can be difficult to achieve3 because commonly used endonucleases, such as Streptococcus pyogenes Cas9 (SpCas9), can tolerate up to seven mismatches between guide RNA (gRNA) and target DNA. Furthermore, the protospacer-adjacent motif (PAM) in some Cas9...
6 CitationsSource
#1Gali Maor (TAU: Tel Aviv University)H-Index: 4
#2Debora Rapaport (TAU: Tel Aviv University)H-Index: 13
Last. Mia Horowitz (TAU: Tel Aviv University)H-Index: 30
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#1Daniel P. Dever (Stanford University)H-Index: 12
#2Samantha G. Scharenberg (Stanford University)H-Index: 1
Last. Matthew H. Porteus (Stanford University)H-Index: 46
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Summary Human neural stem cells (NSCs) offer therapeutic potential for neurodegenerative diseases, such as inherited monogenic nervous system disorders, and neural injuries. Gene editing in NSCs (GE-NSCs) could enhance their therapeutic potential. We show that NSCs are amenable to gene targeting at multiple loci using Cas9 mRNA with synthetic chemically modified guide RNAs along with DNA donor templates. Transplantation of GE-NSC into oligodendrocyte mutant shiverer-immunodeficient mice showed t...
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Inherited retinal dystrophies (IRDs) are a clinically and genetically heterogeneous group of diseases with more than 250 causative genes. The most common form is retinitis pigmentosa. IRDs lead to vision impairment for which there is no universal cure. Encouragingly, a first gene supplementation therapy has been approved for an autosomal recessive IRD. However, for autosomal dominant IRDs, gene supplementation therapy is not always pertinent because haploinsufficiency is not the only cause. Dise...
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#1Fatemeh Khatami (Tehran University of Medical Sciences)H-Index: 3
#2Maryam Aghaii (Tehran University of Medical Sciences)
Last. Seyed Mohammad Kazem Aghamir (Tehran University of Medical Sciences)H-Index: 7
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Abstract Several diseases are the consequence of genetic alterations in normal DNA sequences. Solving the problem of these alterations can be possible through genome editing which exactly means replacing the wrong sequence with the correct ones. One of the common tools for this repair is clustered regularly interspaced short palindromic repeats (CRISPR) ( Joung et al., 2018 ). In fact CRISPER is a family of DNA sequences originated from the prokaryotic genome. Cas9 (or “CRISPR-associated protein...
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