ArticleAmerican journal of human genetics2007
Propionic and methylmalonic acidemia: antisense therapeutics for intronic variations causing aberrantly spliced messenger RNA.
Article in American journal of human genetics, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 71 citations in OpenAlex.
- Targeted gene editing ofMolecular therapy. Nucleic acids · 2026Article
- From N-of-1 to versatility in propionic acidemia: Antisense oligonucleotide-mediated skipping of a constitutiveMolecular therapy. Nucleic acids · 2026Article
- Data-driven insights to inform splice-altering variant assessment.American journal of human genetics · 2025Article
- RegulatingMolecular therapy. Nucleic acids · 2024Article
- Splice-Modulating Antisense Oligonucleotides as Therapeutics for Inherited Metabolic Diseases.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2024Review
- Pathophysiological mechanisms of complications associated with propionic acidemia.Pharmacology & therapeutics · 2023Review
- The potential and limitations of intrahepatic cholangiocyte organoids to study inborn errors of metabolism.Journal of inherited metabolic disease · 2022Article
- Functional Analysis of theInternational journal of molecular sciences · 2021Article
- Opportunities and challenges for antisense oligonucleotide therapies.Journal of inherited metabolic disease · 2021Review
- Analysis of Pathogenic Pseudoexons Reveals Novel Mechanisms Driving Cryptic Splicing.Frontiers in genetics · 2021Article
- Gene Therapy for Methylmalonic Acidemia: Past, Present, and Future.Human gene therapy · 2019Review
- Article
- Improving the diagnosis of cobalamin and related defects by genomic analysis, plus functional and structural assessment of novel variants.Orphanet journal of rare diseases · 2018Article
- Deep intronic mutations and human disease.Human genetics · 2017Review
- Global identification of hnRNP A1 binding sites for SSO-based splicing modulation.BMC biology · 2016Article
- Splice-shifting oligonucleotide (SSO) mediated blocking of an exonic splicing enhancer (ESE) created by the prevalent c.903+469T>C MTRR mutation corrects splicing and restores enzyme activity in patient cells.Nucleic acids research · 2015Article
- Functional correction by antisense therapy of a splicing mutation in the GALT gene.European journal of human genetics : EJHG · 2015Article
- A sensitive assay system to test antisense oligonucleotides for splice suppression therapy in the mouse liver.Molecular therapy. Nucleic acids · 2014Article
- Antisense mediated splicing modulation for inherited metabolic diseases: challenges for delivery.Nucleic acid therapeutics · 2014Review
- Generation of a hypomorphic model of propionic acidemia amenable to gene therapy testing.Molecular therapy : the journal of the American Society of Gene Therapy · 2013Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
We describe the use of antisense morpholino oligonucleotides (AMOs) to restore normal splicing caused by intronic molecular defects identified in methylmalonic acidemia (MMA) and propionic acidemia (PA). The three new point mutations described in deep intronic regions increase the splicing scores of pseudoexons or generate consensus binding motifs for splicing factors, such as SRp40, which favor the intronic inclusions in MUT (r.1957ins76), PCCA (r.1284ins84), or PCCB (r.654ins72) messenger RNAs (mRNAs). Experimental confirmation that these changes are pathogenic and cause the activation of the pseudoexons was obtained by use of minigenes. AMOs were targeted to the 5? or 3? cryptic splice sites to block access of the splicing machinery to the pseudoexonic regions in the pre-mRNA. Using this antisense therapeutics, we have obtained correctly spliced mRNA that was effectively translated, and propionyl coenzyme A (CoA) carboxylase (PCC) or methylmalonylCoA mutase (MCM) activities were rescued in patients' fibroblasts. The effect of AMOs was sequence and dose dependent. In the affected patient with MUT mutation, close to 100% of MCM activity, measured by incorporation of (14)C-propionate, was obtained after 48 h, and correctly spliced MUT mRNA was still detected 15 d after treatment. In the PCCA-mutated and PCCB-mutated cell lines, 100% of PCC activity was measured after 72 h of AMO delivery, and the presence of biotinylated PCCA protein was detected by western blot in treated PCCA-deficient cells. Our results demonstrate that the aberrant inclusions of the intronic sequences are disease-causing mutations in these patients. These findings provide a new therapeutic strategy in these genetic disorders, potentially applicable to a large number of cases with deep intronic changes that, at the moment, remain undetected by standard mutation-detection techniques.
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