ArticleHuman molecular genetics2011
Arginine-rich cell-penetrating peptide dramatically enhances AMO-mediated ATM aberrant splicing correction and enables delivery to brain and cerebellum.
Article in Human molecular genetics, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers, 1 of them a synthesis that pooled it.
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Who cites it
45 citing papers in PubMed, 1 synthesis or guideline pooled it, 75 citations in OpenAlex.
- Gene Suppression Therapies in Hereditary Cerebellar Ataxias: A Systematic Review of Animal Studies.Cells · 2023Pooled it
- Antisense and Functional Nucleic Acids in Rational Drug Development.Antibiotics (Basel, Switzerland) · 2024Review
- Down syndrome and DYRK1A overexpression: relationships and future therapeutic directions.Frontiers in molecular neuroscience · 2024Review
- Therapeutic Strategies for Spinocerebellar Ataxia Type 1.Biomolecules · 2023Review
- Peptides as Pharmacological Carriers to the Brain: Promises, Shortcomings and Challenges.Molecular pharmaceutics · 2022Review
- Recent Progress and Challenges in the Development of Antisense Therapies for Myotonic Dystrophy Type 1.International journal of molecular sciences · 2022Review
- Deliver the promise: RNAs as a new class of molecular entities for therapy and vaccination.Pharmacology & therapeutics · 2022Review
- Review
- RNA-based therapeutics for neurological diseases.RNA biology · 2022Review
- The promise of microRNA-based therapies in Alzheimer's disease: challenges and perspectives.Molecular neurodegeneration · 2021Review
- Article
- Delivery of oligonucleotide-based therapeutics: challenges and opportunities.EMBO molecular medicine · 2021Review
- Advances of Antisense Oligonucleotide Technology in the Treatment of Hereditary Neurodegenerative Diseases.Evidence-based complementary and alternative medicine : eCAM · 2021Review
- Advances in oligonucleotide drug delivery.Nature reviews. Drug discovery · 2020Review
- Targeting Alternative Splicing as a Potential Therapy for Episodic Ataxia Type 2.Biomedicines · 2020Review
- Peptide-conjugate antisense based splice-correction for Duchenne muscular dystrophy and other neuromuscular diseases.EBioMedicine · 2019Review
- Article
- Synthetic molecular evolution of hybrid cell penetrating peptides.Nature communications · 2018Article
- Cell-Penetrating Peptides to Enhance Delivery of Oligonucleotide-Based Therapeutics.Biomedicines · 2018Review
- Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Antisense morpholino oligonucleotides (AMOs) can reprogram pre-mRNA splicing by complementary binding to a target site and regulating splice site selection, thereby offering a potential therapeutic tool for genetic disorders. However, the application of this technology into a clinical scenario has been limited by the low correction efficiency in vivo and inability of AMOs to efficiently cross the blood brain barrier and target brain cells when applied to neurogenetic disorders such as ataxia-telangiecatasia (A-T). We previously used AMOs to correct subtypes of ATM splicing mutations in A-T cells; AMOs restored up to 20% of the ATM protein and corrected the A-T cellular phenotype. In this study, we demonstrate that an arginine-rich cell-penetrating peptide, (RXRRBR)(2)XB, dramatically improved ATM splicing correction efficiency when conjugated with AMOs, and almost fully corrected aberrant splicing. The restored ATM protein was close to normal levels in cells with homozygous splicing mutations, and a gene dose effect was observed in cells with heterozygous mutations. A significant amount of the ATM protein was still detected 21 days after a single 5 µm treatment. Systemic administration of an fluorescein isothiocyanate-labeled (RXRRBR)(2)XB-AMO in mice showed efficient uptake in the brain. Fluorescence was evident in Purkinje cells after a single intravenous injection of 60 mg/kg. Furthermore, multiple injections significantly increased uptake in all areas of the brain, notably in cerebellum and Purkinje cells, and showed no apparent signs of toxicity. Taken together, these results highlight the therapeutic potential of (RXRRBR)(2)XB-AMOs in A-T and other neurogenetic disorders.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.