2019
DOI: 10.3390/ijms20123036
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Molecular Mechanisms and Determinants of Innovative Correction Approaches in Coagulation Factor Deficiencies

Abstract: Molecular strategies tailored to promote/correct the expression and/or processing of defective coagulation factors would represent innovative therapeutic approaches beyond standard substitutive therapy. Here, we focus on the molecular mechanisms and determinants underlying innovative approaches acting at DNA, mRNA and protein levels in inherited coagulation factor deficiencies, and in particular on: (i) gene editing approaches, which have permitted intervention at the DNA level through the specific recognition… Show more

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Cited by 11 publications
(9 citation statements)
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References 218 publications
(256 reference statements)
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“…Among them, the use of the small nuclear ribonucleoprotein U1 (U1snRNP) that, in the earliest splicing step, plays a key role in the exon definition by mediating the recognition of the 5 ss through base pair complementarity with its RNA component (U1snRNA) [3]. Variants of the U1snRNA with increased complementarity with the 5 ss of the defective exon (compensatory U1snRNA), or targeting the downstream intronic sequences (Exon specific U1snRNA, ExSpeU1), have shown the ability to rescue mRNA splicing in the presence of disease-causing mutations at 5 ss, 3 ss or within exons [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. While the correction effect has been clearly shown in several cellular models of human disease the evaluation of their therapeutic potential requires investigations in animal models harboring the disease-causing splicing mutations, which are very rare.…”
Section: Introductionmentioning
confidence: 99%
“…Among them, the use of the small nuclear ribonucleoprotein U1 (U1snRNP) that, in the earliest splicing step, plays a key role in the exon definition by mediating the recognition of the 5 ss through base pair complementarity with its RNA component (U1snRNA) [3]. Variants of the U1snRNA with increased complementarity with the 5 ss of the defective exon (compensatory U1snRNA), or targeting the downstream intronic sequences (Exon specific U1snRNA, ExSpeU1), have shown the ability to rescue mRNA splicing in the presence of disease-causing mutations at 5 ss, 3 ss or within exons [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. While the correction effect has been clearly shown in several cellular models of human disease the evaluation of their therapeutic potential requires investigations in animal models harboring the disease-causing splicing mutations, which are very rare.…”
Section: Introductionmentioning
confidence: 99%
“…In present study, a TC model by using HUVECs, EA.hy926 cells and rabbits was established to explore the role of CAA and VB6. Amino acids, including essential amino acids (EAAs), conditionally essential amino acids (CEAAs) and nonessential amino acids (NEAAs), can promote the expression and processing of defective coagulation factors, increase the expression of anti-inflammatory cytokines, and reduces apoptosis and pro-inflammatory cytokine expression in oxidative stress and inflammation [25,26]. VB6 is a necessary coenzyme for a variety of enzymes.…”
Section: Discussionmentioning
confidence: 99%
“…However, ~1% of U2-type introns have the GC dinucleotide at position +1/+2 of 5′ss and it is recognized that a higher complementarity with the U1snRNA is required to compensate the U to C substitution [26,27]. Moreover, while different studies demonstrated that changes within the canonical GT 5′ss can be efficiently rescued by engineered U1snRNAs [8,11,12,16,28], to our knowledge no attempt has been provided so far for nucleotide changes occurring within the GC 5′ss variant. Therefore, to investigate further the U1snRNA-mediated rescue at protein and activity level of splicing mutations in the peculiar GC context, we focused on CDKL5 exon 3 c.99+5G>A mutation and developed a splicing-competent full-length CDKL5 transgene.…”
Section: Discussionmentioning
confidence: 99%