Gene therapy and antisense oligonucleotides (ASOs) are promising approaches to treating rare diseases by targeting specific genes. However, ASOs can have off-target effects that need careful consideration during development. Researchers can add moieties like peptide nucleic acid or methoxyethyl-modified ribose sugars to enhance specificity and reduce toxicity. Current research suggests that challenges such as nonspecific action, interference at various stages, adverse reactions, and nuclease degradation may soon be manageable with advanced technologies. ASOs show particular promise in treating rare conditions like Duchenne Muscular Dystrophy (DMD) and Timothy syndrome. Stereopure ASOs with repeated left-right patterns offer increased potency and half-life due to their resistance to nuclease activity and improved cellular uptake. This review explores how technological advancements can enhance the use of ASOs to manage various rare disease conditions effectively. Despite challenges in development and application, ASO therapy holds the potential to become a viable treatment option for a wide range of rare diseases. Advances in technology offer the possibility of increasing specificity and reducing toxicity, making ASO therapy a more effective and safe treatment option for patients with rare diseases.
References
[1]
Doxakis, E. (2020) Therapeutic Antisense Oligonucleotides for Movement Disorders. MedicinalResearchReviews, 41, 2656-2688. https://doi.org/10.1002/med.21706
[2]
Kuijper, E.C., Bergsma, A.J., Pijnappel, W.W.M.P. and Aartsma‐Rus, A. (2020) Opportunities and Challenges for Antisense Oligonucleotide Therapies. JournalofInheritedMetabolicDisease, 44, 72-87. https://doi.org/10.1002/jimd.12251
[3]
Scoles, D.R., Minikel, E.V. and Pulst, S.M. (2019) Antisense Oligonucleotides: A Primer. NeurologyGenetics, 5, e323. https://doi.org/10.1212/nxg.0000000000000323
[4]
Aymé, S., Kole, A. and Groft, S. (2008) Empowerment of Patients: Lessons from the Rare Diseases Community. TheLancet, 371, 2048-2051. https://doi.org/10.1016/s0140-6736(08)60875-2
[5]
Dias, N. and Stein, C.A. (2002) Antisense Oligonucleotides: Basic Concepts and Mechanisms. MolecularCancerTherapeutics, 1, 347-355.
[6]
Lauffer, M.C., van Roon-Mom, W. and Aartsma-Rus, A. (2024) Possibilities and Limitations of Antisense Oligonucleotide Therapies for the Treatment of Monogenic Disorders. CommunicationsMedicine, 4, Article No. 6. https://doi.org/10.1038/s43856-023-00419-1
[7]
Roberts, T.C., Langer, R. and Wood, M.J.A. (2020) Advances in Oligonucleotide Drug Delivery. NatureReviewsDrugDiscovery, 19, 673-694. https://doi.org/10.1038/s41573-020-0075-7
[8]
Zheng, Y.Y., Wu, Y., Begley, T.J. and Sheng, J. (2021) Sulfur Modification in Natural RNA and Therapeutic Oligonucleotides. RSCChemicalBiology, 2, 990-1003. https://doi.org/10.1039/d1cb00038a
[9]
Giles, R.V., Spiller, D.G., Clark, R.E. and Tidd, D.M. (1999) Antisense Morpholino Oligonucleotide Analog Induces Missplicing of C-myc mRNA. Antisense and NucleicAcidDrugDevelopment, 9, 213-220. https://doi.org/10.1089/oli.1.1999.9.213
Barresi, V., Musmeci, C., Rinaldi, A. and Condorelli, D.F. (2022) Transcript-Targeted Therapy Based on RNA Interference and Antisense Oligonucleotides: Current Applications and Novel Molecular Targets. InternationalJournalofMolecularSciences, 23, Article No. 8875. https://doi.org/10.3390/ijms23168875
[12]
Holm, A., Hansen, S.N., Klitgaard, H. and Kauppinen, S. (2022) Clinical Advances of RNA Therapeutics for Treatment of Neurological and Neuromuscular Diseases. RNABiology, 19, 594-608. https://doi.org/10.1080/15476286.2022.2066334
[13]
Stein, C.A. (2001) The Experimental Use of Antisense Oligonucleotides: A Guide for the Perplexed. JournalofClinicalInvestigation, 108, 641-644. https://doi.org/10.1172/jci13885
[14]
Aslesh, T. and Yokota, T. (2020) Development of Antisense Oligonucleotide Gapmers for the Treatment of Huntington’s Disease. In: Yokota, T. and Maruyama, R., Eds., Gapmers: Methods and Protocols, Springer US, 57-67. https://doi.org/10.1007/978-1-0716-0771-8_4
[15]
Owoyemi, J.O., Traficante, M.K., Bamgboye, M.A., DiSilvestre, D., Vieira, D.C.O. and Dick, I.E. (2022) Antisense Oligonucleotides as a Treatment Strategy for Timothy Syndrome. BiophysicalJournal, 121, 99a-100a. https://doi.org/10.1016/j.bpj.2021.11.2233
[16]
Phillips, M., Costales, J., Lee, R., Oliveira, E. and Burns, A. (2015) Antisense Therapy for Cardiovascular Diseases. CurrentPharmaceuticalDesign, 21, 4417-4426. https://doi.org/10.2174/1381612821666150803150402
[17]
Benson, M.D., Waddington-Cruz, M., Berk, J.L., Polydefkis, M., Dyck, P.J., Wang, A.K., et al. (2018) Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis. NewEnglandJournalofMedicine, 379, 22-31. https://doi.org/10.1056/nejmoa1716793
[18]
Gaudet, D., Alexander, V.J., Baker, B.F., Brisson, D., Tremblay, K., Singleton, W., et al. (2015) Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia. NewEnglandJournalofMedicine, 373, 438-447. https://doi.org/10.1056/nejmoa1400283
[19]
InSilico Medicine Hong Kong Limited (2022) A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Oral Single and Multiple Ascending Doses, Parallel Group Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of INS018_055 in Healthy Subjects (Clinical Trial Registration No. NCT05154240). https://clinicaltrials.gov/ct2/show/NCT05154240
[20]
Mombelli, G. and Pavanello, C. (2013) Novel Therapeutic Strategies for the Homozygous Familial Hypercholesterolemia. RecentPatentsonCardiovascularDrugDiscovery, 8, 143-150. https://doi.org/10.2174/15748901112079990001
[21]
Kumar, A., Acharya, A., Nandi, D., Sharma, N. and Chitkara, E. (n.d.) Mipomersen: A Novel Therapeutic Drug for the Treatment of Familial Hypercholesterolemia, Hyperlipidaemia, and Hypercholesterolemia.
[22]
Miller, T., Cudkowicz, M., Shaw, P.J., Andersen, P.M., Atassi, N., Bucelli, R.C., et al. (2020) Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. NewEnglandJournalofMedicine, 383, 109-119. https://doi.org/10.1056/nejmoa2003715
[23]
Singh, R.N. and Singh, N.N. (2018) Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes. In: Sattler, R. and Donnelly, C.J., Eds., RNA Metabolism in Neurodegenerative Diseases, Springer International Publishing, 31-61. https://doi.org/10.1007/978-3-319-89689-2_2
[24]
Knowles, J.K., Helbig, I., Metcalf, C.S., Lubbers, L.S., Isom, L.L., Demarest, S., et al. (2022) Precision Medicine for Genetic Epilepsy on the Horizon: Recent Advances, Present Challenges, and Suggestions for Continued Progress. Epilepsia, 63, 2461-2475. https://doi.org/10.1111/epi.17332
[25]
Chi, K.N., Higano, C.S., Blumenstein, B., Ferrero, J., Reeves, J., Feyerabend, S., et al. (2017) Custirsen in Combination with Docetaxel and Prednisone for Patients with Metastatic Castration-Resistant Prostate Cancer (SYNERGY Trial): A Phase 3, Multicentre, Open-Label, Randomised Trial. TheLancetOncology, 18, 473-485. https://doi.org/10.1016/s1470-2045(17)30168-7
[26]
Sandweiss, A.J., Brandt, V.L. and Zoghbi, H.Y. (2020) Advances in Understanding of Rett Syndrome and MECP2 Duplication Syndrome: Prospects for Future Therapies. TheLancetNeurology, 19, 689-698. https://doi.org/10.1016/s1474-4422(20)30217-9
[27]
Cavalieri, S., Pozzi, E., Gatti, R.A. and Brusco, A. (2012) Deep-Intronic ATM Mutation Detected by Genomic Resequencing and Corrected inVitro by Antisense Morpholino Oligonucleotide (AMO). EuropeanJournalofHumanGenetics, 21, 774-778. https://doi.org/10.1038/ejhg.2012.266
[28]
Vega, A.I., Pérez-Cerdá, C., Desviat, L.R., Matthijs, G., Ugarte, M. and Pérez, B. (2009) Functional Analysis of Three Splicing Mutations Identified in the PMM2 Gene: Toward a New Therapy for Congenital Disorder of Glycosylation Type Ia. HumanMutation, 30, 795-803. https://doi.org/10.1002/humu.20960
[29]
Tsuboi, Y. (2009) Clinical, Pathological, and Genetic Characteristics of Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17 with Mutations in the MAPT and PGRN. BrainandNerve, 61, 1285-1291.
[30]
Kalbfuss, B., Mabon, S.A. and Misteli, T. (2001) Correction of Alternative Splicing of Tau in Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17. JournalofBiologicalChemistry, 276, 42986-42993. https://doi.org/10.1074/jbc.m105113200
[31]
Peacey, E., Rodriguez, L., Liu, Y. and Wolfe, M.S. (2012) Targeting a Pre-mRNA Structure with Bipartite Antisense Molecules Modulates Tau Alternative Splicing. NucleicAcidsResearch, 40, 9836-9849. https://doi.org/10.1093/nar/gks710
[32]
Mukherjee, S. and Maxfield, F.R. (2004) Lipid and Cholesterol Trafficking in NPC. BiochimicaetBiophysicaActa (BBA)—MolecularandCellBiologyofLipids, 1685, 28-37. https://doi.org/10.1016/j.bbalip.2004.08.009
[33]
Friedman, J.M. (1999) Epidemiology of Neurofibromatosis Type 1. AmericanJournalofMedicalGenetics, 89, 1-6.
[34]
Fernández-Rodríguez, J., Castellsagué, J., Benito, L., Benavente, Y., Capellá, G., Blanco, I., et al. (2011) A Mild Neurofibromatosis Type 1 Phenotype Produced by the Combination of the Benign Nature of a Leaky Nf1-Splice Mutation and the Presence of a Complex Mosaicism. HumanMutation, 32, 705-709. https://doi.org/10.1002/humu.21500
[35]
Castellanos, E., Rosas, I., Solanes, A., Bielsa, I., Lázaro, C., Carrato, C., et al. (2013) Erratum: In Vitro Antisense Therapeutics for a Deep Intronic Mutation Causing Neurofibromatosis Type 2. EuropeanJournalofHumanGenetics, 22, 153-153. https://doi.org/10.1038/ejhg.2013.224
[36]
Mancini, C., Vaula, G., Scalzitti, L., Cavalieri, S., Bertini, E., Aiello, C., et al. (2012) Megalencephalic Leukoencephalopathy with Subcortical Cysts Type 1 (MLC1) Due to a Homozygous Deep Intronic Splicing Mutation (c.895-226T > G) Abrogated inVitro Using an Antisense Morpholino Oligonucleotide. Neurogenetics, 13, 205-214. https://doi.org/10.1007/s10048-012-0331-z
[37]
Regis, S., Corsolini, F., Grossi, S., Tappino, B., Cooper, D.N. and Filocamo, M. (2013) Restoration of the Normal Splicing Pattern of the PLP1 Gene by Means of an Antisense Oligonucleotide Directed against an Exonic Mutation. PLOSONE, 8, e73633. https://doi.org/10.1371/journal.pone.0073633
[38]
Valenzuela, A., Tardiveau, C., Ayuso, M., Buyssens, L., Bars, C., Van Ginneken, C., et al. (2021) Safety Testing of an Antisense Oligonucleotide Intended for Pediatric Indications in the Juvenile Göttingen Minipig, Including an Evaluation of the Ontogeny of Key Nucleases. Pharmaceutics, 13, Article No. 1442. https://doi.org/10.3390/pharmaceutics13091442
[39]
McDowall, S., Aung-Htut, M., Wilton, S. and Li, D. (2024) Antisense Oligonucleotides and Their Applications in Rare Neurological Diseases. FrontiersinNeuroscience, 18, Article ID: 1414658. https://doi.org/10.3389/fnins.2024.1414658
[40]
Valenzuela, A., Tardiveau, C., Ayuso, M., Buyssens, L., Bars, C., Van Ginneken, C., et al. (2021) Safety Testing of an Antisense Oligonucleotide Intended for Pediatric Indications in the Juvenile Göttingen Minipig, Including an Evaluation of the Ontogeny of Key Nucleases. Pharmaceutics, 13, Article No. 1442. https://doi.org/10.3390/pharmaceutics13091442
[41]
Burbano, L.E., Li, M., Jancovski, N., Jafar-Nejad, P., Richards, K., Sedo, A., Soriano, A., Rollo, B., Jia, L. and Gazina, E. (2020) Antisense Oligonucleotide Therapy for KCNT1 Encephalopathy.
[42]
Siva, K., Covello, G. and Denti, M.A. (2014) Exon-Skipping Antisense Oligonucleotides to Correct Missplicing in Neurogenetic Diseases. NucleicAcidTherapeutics, 24, 69-86. https://doi.org/10.1089/nat.2013.0461
[43]
Jason, T.L.H., Koropatnick, J. and Berg, R.W. (2004) Toxicology of Antisense Therapeutics. ToxicologyandAppliedPharmacology, 201, 66-83. https://doi.org/10.1016/j.taap.2004.04.017
[44]
Diesbach, P.d. (2000) Identification, Purification and Partial Characterisation of an Oligonucleotide Receptor in Membranes of Hepg2 Cells. NucleicAcidsResearch, 28, 868-874. https://doi.org/10.1093/nar/28.4.868
[45]
Bennett, C.F., Dean, N.M. and Monia, B.P. (1998) Antisense Oligonucleotide. Advances in Drug Discovery Techniques, 173.
[46]
Vaerman, J.L., Moureau, P., Deldime, F., Lewalle, P., Lammineur, C., Morschhauser, F., et al. (1997) Antisense Oligodeoxyribonucleotides Suppress Hematologic Cell Growth through Stepwise Release of Deoxyribonucleotides. Blood, 90, 331-339. https://doi.org/10.1182/blood.v90.1.331.331_331_339
[47]
Benimetskaya, L. (1997) Formation of a G-Tetrad and Higher Order Structures Correlates with Biological Activity of the Rela (NF-κB p65) “Antisense” Oligodeoxynucleotide. NucleicAcidsResearch, 25, 2648-2656. https://doi.org/10.1093/nar/25.13.2648
[48]
Krieg, A.M. (2004) Antitumor Applications of Stimulating Toll-Like Receptor 9 with CpG Oligodeoxynucleotides. CurrentOncologyReports, 6, 88-95. https://doi.org/10.1007/s11912-004-0019-0
