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The UBE3A-ATS antisense oligonucleotide rugonersen in children with Angelman syndrome: a phase 1 trial

Nature Medicine volume 31, pages 2936–2945 (2025)Cite this article

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Abstract

Angelman syndrome (AS) is a severe genetic neurodevelopmental disorder with no disease-modifying treatments. AS is caused by deletion or mutation of the neuronally imprinted gene encoding the ubiquitin-protein ligase E3A (UBE3A). Rugonersen (RO7248824) is an antisense oligonucleotide that reinstates UBE3A by derepressing the silenced paternal allele. TANGELO was a phase 1, multicenter, open-label, multiple-ascending-dose trial with a long-term extension to investigate the safety and tolerability (primary) and pharmacokinetics (secondary) of rugonersen in children aged 1–12 years with AS (n = 61, F/M: 28/33). Key exploratory endpoints assessing changes following rugonersen treatment were electroencephalogram δ-power (2–4 Hz) and domains of the Bayley Scales of Infant and Toddler Development—Third Edition and Vineland Adaptive Behavior Scales—Third Edition. The primary endpoint was met; rugonersen had an acceptable safety and tolerability profile. Analysis of exploratory endpoints showed that rugonersen led to a dose-dependent partial normalization of the AS-associated electroencephalogram abnormality and revealed signals of clinical improvement in core AS symptom domains beyond expectation from natural history data. The results of the primary study objective support continued development of rugonersen for AS. ClinicalTrials.gov registration: NCT04428281.

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Fig. 1: Trial design and patient flow diagram.
Fig. 2: EEG responses to rugonersen.
Fig. 3: Clinical response in the MAD.
Fig. 4: Clinical response in the LTE.

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Data availability

Qualified researchers may request access to individual patient-level data through the clinical study data request platform (https://vivli.org/). Further details on Roche’s criteria for eligible studies are available at https://vivli.org/members/ourmembers/. For further details on Roche’s Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm.

Code availability

For the collection of EEG data, Curry 8 (Compumedics) was used. For data analyses, R (version 4.2.1, https://www.r-project.org/) and Matlab (version R2024b, https://matlab.mathworks.com/) were used. For EEG analyses, the Matlab FieldTrip toolbox53 (version 7ba023993, https://www.fieldtriptoolbox.org/) and the MEGLET code47,48 (https://roche.github.io/neuro-meeglet/) were used.

References

  1. Luk, H. M. & Lo, I. F. M. Angelman syndrome in Hong Kong Chinese: a 20 years’ experience. Eur. J. Med. Genet. 59, 315–319 (2016).

    CAS  PubMed  Google Scholar 

  2. Mertz, L. G. B. et al. Angelman syndrome in Denmark. Birth incidence, genetic findings, and age at diagnosis. Am. J. Med. Genet. A 161, 2197–2203 (2013).

    CAS  Google Scholar 

  3. Yakoreva, M. et al. A retrospective analysis of the prevalence of imprinting disorders in Estonia from 1998 to 2016. Eur. J. Hum. Genet. 27, 1649–1658 (2019).

    PubMed  PubMed Central  Google Scholar 

  4. Bird, L. Angelman syndrome: review of clinical and molecular aspects. Appl. Clin. Genet. https://doi.org/10.2147/TACG.S57386 (2014).

  5. Thibert, R. L., Larson, A. M., Hsieh, D. T., Raby, A. R. & Thiele, E. A. Neurologic manifestations of Angelman syndrome. Pediatr. Neurol. 48, 271–279 (2013).

    PubMed  Google Scholar 

  6. Willgoss, T. et al. Measuring what matters to individuals with Angelman syndrome and their families: development of a patient-centered disease concept model. Child Psychiatry Hum. Dev. https://doi.org/10.1007/s10578-020-01051-z (2020).

    Article  PubMed Central  Google Scholar 

  7. Williams, C. A. et al. Angelman syndrome 2005: updated consensus for diagnostic criteria. Am. J. Med. Genet. 140A, 413–418 (2006).

    Google Scholar 

  8. Laan, L. A. E. M. & Vein, A. A. Angelman syndrome: is there a characteristic EEG? Brain Dev. 27, 80–87 (2005).

    PubMed  Google Scholar 

  9. Boyd, S. G., Harden, A. & Patton, M. A. The EEG in early diagnosis of the Angelman (happy puppet) syndrome. Eur. J. Pediatr. 147, 508–513 (1988).

    CAS  PubMed  Google Scholar 

  10. Buiting, K., Williams, C. & Horsthemke, B. Angelman syndrome—insights into a rare neurogenetic disorder. Nat. Rev. Neurol. 12, 584–593 (2016).

    CAS  PubMed  Google Scholar 

  11. Chamberlain, S. J. & Lalande, M. Angelman syndrome, a genomic imprinting disorder of the brain. J. Neurosci. 30, 9958–9963 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Kishino, T., Lalande, M. & Wagstaff, J. UBE3A/E6-AP mutations cause Angelman syndrome. Nat. Genet. 15, 70–73 (1997).

    CAS  PubMed  Google Scholar 

  13. Clayton-Smith, J. & Laan, L. Angelman syndrome: a review of the clinical and genetic aspects. J. Med. Genet. 40, 87–95 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Yashiro, K. et al. Ube3a is required for experience-dependent maturation of the neocortex. Nat. Neurosci. 12, 777–783 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Greer, P. L. et al. The Angelman syndrome protein Ube3A regulates synapse development by ubiquitinating arc. Cell 140, 704–716 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Rougeulle, C., Cardoso, C., Fontés, M., Colleaux, L. & Lalande, M. An imprinted antisense RNA overlaps UBE3A and a second maternally expressed transcript. Nat. Genet. 19, 15–16 (1998).

    CAS  PubMed  Google Scholar 

  17. Meng, L., Person, R. E. & Beaudet, A. L. Ube3a-ATS is an atypical RNA polymerase II transcript that represses the paternal expression of Ube3a. Hum. Mol. Genet. 21, 3001–3012 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Chamberlain, S. J. & Brannan, C. I. The Prader–Willi syndrome imprinting center activates the paternally expressed murine Ube3a antisense transcript but represses paternal Ube3a. Genomics 73, 316–322 (2001).

    CAS  PubMed  Google Scholar 

  19. Huang, H.-S. et al. Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature 481, 185–189 (2012).

    CAS  Google Scholar 

  20. Meng, L. et al. Towards a therapy for Angelman syndrome by targeting a long non-coding RNA. Nature 518, 409–412 (2015).

    CAS  PubMed  Google Scholar 

  21. Vihma, H. et al. Ube3a unsilencer for the potential treatment of Angelman syndrome. Nat. Commun. 15, 5558 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Milazzo, C. et al. Antisense oligonucleotide treatment rescues UBE3A expression and multiple phenotypes of an Angelman syndrome mouse model. JCI Insight 6, e145991 (2021).

    PubMed  PubMed Central  Google Scholar 

  23. Spencer, E. R. et al. Longitudinal EEG model detects antisense oligonucleotide treatment effect and increased UBE3A in Angelman syndrome. Brain Commun. 4, fcac106 (2022).

    PubMed  PubMed Central  Google Scholar 

  24. Silva-Santos, S. et al. Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model. J. Clin. Invest. 125, 2069–2076 (2015).

    PubMed  PubMed Central  Google Scholar 

  25. Jagasia, R. et al. Angelman syndrome patient neuron screen identifies a potent and selective clinical ASO targeting UBE3A-ATS with long lasting effect in cynomolgus monkey. Preprint at bioRxiv https://doi.org/10.1101/2022.06.09.495066 (2022).

  26. Sidorov, M. S. et al. Delta rhythmicity is a reliable EEG biomarker in Angelman syndrome: a parallel mouse and human analysis. J. Neurodev. Disord. 9, 17 (2017).

    PubMed  PubMed Central  Google Scholar 

  27. Frohlich, J. et al. Electrophysiological phenotype in Angelman syndrome differs between genotypes. Biol. Psychiatry 85, 752–759 (2019).

    PubMed  PubMed Central  Google Scholar 

  28. Hipp, J. F., Frohlich, J., Keute, M., Tan, W.-H. & Bird, L. M. Electrophysiological abnormalities in Angelman syndrome correlate with symptom severity. Biol. Psychiatry Glob. Open Sci. https://doi.org/10.1016/j.bpsgos.2021.05.003 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Ostrowski, L. M. et al. Delta power robustly predicts cognitive function in Angelman syndrome. Ann. Clin. Transl. Neurol. 8, 1433–1445 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Bayley, N. Bayley Scales of Infant and Toddler Development, Third Edition, Pearson Assessments (2012); https://doi.org/10.1037/t14978-000

  31. Sparrow, S. S., Cicchetti, D. V. & Saulnier, C. A. Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) (NCS Pearson, 2016).

  32. Connor-Ahmad, S. et al. Developing Angelman syndrome-specific clinician-reported and caregiver-reported measures to support holistic, patient-centered drug development. Orphanet J. Rare Dis. 18, 156 (2023).

    PubMed  PubMed Central  Google Scholar 

  33. Keute, M. et al. Angelman syndrome genotypes manifest varying degrees of clinical severity and developmental impairment. Mol. Psychiatry https://doi.org/10.1038/s41380-020-0858-6 (2020).

  34. Tjeertes, J. et al. Enabling endpoint development for interventional clinical trials in individuals with Angelman syndrome: a prospective, longitudinal, observational clinical study (FREESIAS). J. Neurodev. Disord. 15, 22 (2023).

    PubMed  PubMed Central  Google Scholar 

  35. Cassater, D. et al. Clinical characterization of epilepsy in children with Angelman syndrome. Pediatr. Neurol. 124, 42–50 (2021).

    PubMed  PubMed Central  Google Scholar 

  36. Urits, I. et al. Postoperative nausea and vomiting in paediatric anaesthesia. Turk. J. Anaesthesiol. Reanim. 48, 88–95 (2020).

    PubMed  Google Scholar 

  37. Haché, M. et al. Intrathecal injections in children with spinal muscular atrophy: nusinersen clinical trial experience. J. Child Neurol. 31, 899–906 (2016).

    PubMed  PubMed Central  Google Scholar 

  38. Mousa, M. A. et al. A comprehensive institutional overview of intrathecal nusinersen injections for spinal muscular atrophy. Pediatr. Radiol. 48, 1797–1805 (2018).

    PubMed  Google Scholar 

  39. Janssens, E., Aerssens, P., Alliët, P., Gillis, P. & Raes, M. Post-dural puncture headaches in children. A literature review. Eur. J. Pediatr. 162, 117–121 (2003).

    PubMed  Google Scholar 

  40. Alhamadani, F. et al. Adverse drug reactions and toxicity of the FDA-approved antisense oligonucleotide drugs. Drug Metab. Dispos. 50, 879–887 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Wilkinson, C. L. & Nelson, C. A. Increased aperiodic gamma power in young boys with fragile X syndrome is associated with better language ability. Mol. Autism 12, 17 (2021).

    PubMed  PubMed Central  Google Scholar 

  42. Frohlich, J. et al. A quantitative electrophysiological biomarker of duplication 15q11.2-q13.1 syndrome. PLoS ONE 11, e0167179 (2016).

    PubMed  PubMed Central  Google Scholar 

  43. Roche, K. J. et al. Electroencephalographic spectral power as a marker of cortical function and disease severity in girls with Rett syndrome. J. Neurodev. Disord. 11, 15 (2019).

    PubMed  PubMed Central  Google Scholar 

  44. Hawellek, D. J. et al. Changes in brain activity with tominersen in early-manifest Huntington’s disease. Brain Commun. 4, fcac149 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. van der Vaart, T., Overwater, I. E., Oostenbrink, R., Moll, H. A. & Elgersma, Y. Treatment of cognitive deficits in genetic disorders: a systematic review of clinical trials of diet and drug treatments. JAMA Neurol. 72, 1052–1060 (2015).

    PubMed  Google Scholar 

  46. Berry-Kravis, E. M. et al. Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome. Nat. Rev. Drug Discovery 17, 280–299 (2017).

    PubMed  Google Scholar 

  47. Hipp, J. F., Hawellek, D. J., Corbetta, M., Siegel, M. & Engel, A. K. Large-scale cortical correlation structure of spontaneous oscillatory activity. Nat. Neurosci. 15, 884–890 (2012).

    CAS  PubMed  Google Scholar 

  48. Bomatter, P., Paillard, J., Garces, P., Hipp, J. & Engemann, D.-A. Machine learning of brain-specific biomarkers from EEG. eBioMedicine 106, 105259 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Jobert, M. Guidelines for the recording and evaluation of pharmaco-EEG data in man: the International Pharmaco-EEG Society (IPEG). Neuropsychobiology 66, 201–220 (2012).

    PubMed  Google Scholar 

  50. Bird, L. M. et al. The STARS Phase 2 Study: a randomized controlled trial of gaboxadol in Angelman syndrome. Neurology 96, e1024–e1035 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Sadhwani, A. Developmental Skills of Individuals with Angelman Syndrome Assessed Using the Bayley-III. J. Autism. Dev. Disord. https://doi.org/10.1007/s10803-020-04861-1 (2021).

  52. Daniel, M. & Vannier, L. Growth Scale Value (GSV): Theory, Development, and Applications Growth Scale Value Technical Report Number 1 (NCS Pearson, 2022).

  53. Oostenveld, R., Fries, P., Maris, E. & Schoffelen, J.-M. FieldTrip: open source software for advanced analysis of MEG, EEG, and invasive electrophysiological data. Comput. Intell. Neurosci. (2011).

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Acknowledgements

We thank the children and families who participated in this study and in the natural history studies for their generosity. Our work would not have been possible without their commitment to advancing the understanding of Angelman syndrome. We also want to thank patient organizations and scientific advisors for the input on the study protocol and during study conduction. We are particularly grateful to W.-H. Tan and A. Sadhwani, and the ABOM consortium, for sharing the latest NH data from the ongoing AS NH study. Finally, we want to thank all contributors that are not explicitly listed in the Article or Supplementary Information, foremost being the clinical site personnel. The EEG recordings and reviews were performed using the Biotrial EEG core lab platform. The work was sponsored by F. Hoffmann-La Roche Ltd.

Author information

Author notes

  1. These authors jointly supervised this work: Elizabeth Berry-Kravis, Azad Bonni.

  2. Lists of authors and their affiliations appear at the end of the paper.

Authors and Affiliations

  1. Roche Pharma Research and Early Development, Neuroscience and Rare Diseases, Roche Innovation Center Basel, F. Hoffmann-La Roche, Basel, Switzerland

    Jörg F. Hipp, Ina Bruenig-Traebert, Ravi Jagasia, Michelle L. Krishnan, Lorraine Murtagh, Julian Tillmann, Azad Bonni, Muhamed Barakovic, Ponghatai Boonsimma, Stormy Chamberlain, Sebastian Holst, Thomas Kremer, Stefano Magon & Thomas Wiese

  2. Department of Molecular and Human Genetics, Baylor College of Medicine and Baylor Genetics Laboratory, Texas Children’s Hospital, Houston, TX, USA

    Carlos A. Bacino

  3. Department of Pediatrics; Division of Genetics/Dysmorphology, Rady Children’s Hospital San Diego, University of California San Diego, San Diego, USA

    Lynne M. Bird

  4. Roche Pharma Research and Early Development (pRED), Strategy, Portfolio & Operations, Roche Innovation Center Basel, Basel, Switzerland

    Daniel Chan

  5. Department of Neurology and Pediatric Neurology and Erasmus MC center of expertise for neurodevelopmental disorders ENCORE, Erasmus MC, Rotterdam, The Netherlands

    Marie Claire de Wit

  6. NOVA Medical School, Lisbon, Portugal

    Paulo Fontoura

  7. Roche Products Ltd, Welwyn Garden City, UK

    Gregory Hooper & Amanda Messer

  8. Product Development Neuroscience, Roche Innovation Center Basel, F. Hoffmann-La Roche, Basel, Switzerland

    Alessandro Noci, Jorrit Tjeertes, Brenda Vincenzi, Katalin Buzasi, Oana Danila, Giuseppe Palermo & Lisa Squassante

  9. Division of Pediatric, Parc Taulí Hospital Universitari. Institut d’Investigació i Innovació Parc Taulí (I3PT-CERCA), Sabadell, Spain

    Ana Roche Martínez

  10. Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche, Basel, Switzerland

    Dietmar Schwab, Charlotte Bon & Philipp Daetwyler

  11. Pediatric Neurology Department, Hospital Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, Barcelona, Spain

    Mercedes Serrano

  12. UNC Carolina Institute for Developmental Disabilities (CIDD), Dept. of Psychiatry, and Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA

    Mark D. Shen

  13. Departments of Pediatrics, Neurological Sciences, Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL, USA

    Elizabeth Berry-Kravis

  14. Roche Pharma Research and Early Development, Data and Analytics, Roche Innovation Center Basel, F. Hoffmann–La Roche Ltd., Basel, Switzerland

    Mariana Bustamante, Florian Lipsmeier & David Nobbs

  15. Patient Centered Outcomes Research, Roche Products Ltd, Welwyn Garden City, UK

    Susanne Clinch & Siobhan Connor-Ahmad

  16. Columbia University Irving Medical Center, Department of Neurology, Division of Child Neurology, and NewYork Presbyterian Morgan Stanley Children’s Hospital of New York, New York, NY, USA

    Jennifer M. Bain

  17. Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Jamie Capal

  18. Department of Neurology and Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA

    Ralitza Gavrilova

  19. Pediatric Neurology Department, Hospital Virgen del Rocío, Sevilla, Spain

    María Muñoz Cabeza

  20. Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

    Nicola Pietrafusa

  21. UCLA Mattel Children’s Hospital, Los Angeles, Division of Pediatric Neurology, University of California, Los Angeles, California, USA

    Rajsekar Rajamaran

  22. Dept of Pediatrics and Neurology, USC Keck School of Medicine, Children’s Hospital Los Angeles, Los Angeles, USA

    Shafali Jeste

  23. Head of Developmental Disabilities Dpt IRCCS San Raffaele—Rome, Rome, Italy

    Federico Vigevano

Authors
  1. Jörg F. Hipp
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  2. Carlos A. Bacino
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  4. Ina Bruenig-Traebert
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Consortia

the Rugonersen Study Group

  • Muhamed Barakovic
  • , Charlotte Bon
  • , Azad Bonni
  • , Ponghatai Boonsimma
  • , Ina Bruenig-Traebert
  • , Mariana Bustamante
  • , Katalin Buzasi
  • , Stormy Chamberlain
  • , Daniel Chan
  • , Susanne Clinch
  • , Siobhan Connor-Ahmad
  • , Philipp Daetwyler
  • , Oana Danila
  • , Paulo Fontoura
  • , Jörg F. Hipp
  • , Sebastian Holst
  • , Gregory Hooper
  • , Ravi Jagasia
  • , Thomas Kremer
  • , Michelle L. Krishnan
  • , Florian Lipsmeier
  • , Stefano Magon
  • , Amanda Messer
  • , Lorraine Murtagh
  • , David Nobbs
  • , Alessandro Noci
  • , Giuseppe Palermo
  • , Dietmar Schwab
  • , Lisa Squassante
  • , Julian Tillmann
  • , Jorrit Tjeertes
  • , Brenda Vincenzi
  •  & Thomas Wiese

all TANGELO investigators

  • Carlos A. Bacino
  • , Jennifer M. Bain
  • , Elizabeth Berry-Kravis
  • , Lynne M. Bird
  • , Jamie Capal
  • , Ralitza Gavrilova
  • , Ana Roche Martínez
  • , María Muñoz Cabeza
  • , Nicola Pietrafusa
  • , Rajsekar Rajamaran
  • , Shafali Jeste
  • , Mercedes Serrano
  • , Mark D. Shen
  • , Federico Vigevano
  •  & Marie Claire de Wit

Contributions

Initial study design and protocol development: M.L.K., D.S., J.F.H., I.B.T., G.H. and J. Tjeertes. Protocol amendments: J. Tjeertes, B.V., D.S., J.F.H., A.N., G.H., I.B.T. and the TANGELO Investigators. Study conduct and data acquisition: B.V., J. Tjeertes, D.C., D.S., J.F.H., G.H., L.M.B., M.C.d.W., M.S., M.D.S., A.R.M., E.B.-K. and the TANGELO Investigators. Data analysis: J.F.H. (EEG and clinical scales), G.H. (safety) and D.S. (PK). Initial paper writing: J.F.H. with support from G.H., D.S., J. Tillmann and A.N. Interpretation of data and final review: all authors.

Corresponding author

Correspondence to Jörg F. Hipp.

Ethics declarations

Competing interests

J.F.H., D.C., G.H., L.M., A.N., D.S., J. Tillmann and A.B. are employees of F. Hoffmann-La Roche. I.B.T., M.L.K., J. Tjeertes, B.V., P.F. and R.J. are former employees of F. Hoffmann-La Roche. M.L.K. is currently an employee of Biomedical Research, Translational Medicine, Novartis AG, Basel, Switzerland. J. Tjeertes is currently an employee of Bayer AG, Basel Switzerland. P.F. is Chief Scientific and Clinical Development Advisor, Stalicla SA, Geneva, Switzerland. L.M.B. has received funding from Aardvark Therapeutics, Acadia Pharmaceuticals, Biogen, Ionis Pharmaceuticals, F. Hoffman-La Roche, Gedeon Richter, Neuren Pharmaceuticals, Ovid Therapeutics, PTC Therapeutics, Radius Health, Soleno Therapeutics and Ultragenyx to conduct clinical trials or consult on trial design or results. E.B.-K. has received funding from Acadia, Alcobra, AMO, Asuragen, Avexis, Biogen, BioMarin, Cydan, Engrail, Erydel, Fulcrum, GeneTx, GW, Healx, Ionis, Jaguar, Kisbee, Lumos, Marinus, Mazhi, Moment Biosciences, Neuren, Neurogene, Neurotrope, Novartis, Orphazyme/Kempharm/Zevra, Ovid, PTC Therapeutics, Retrophin, Roche, Seaside Therapeutics, Taysha, Tetra, Ultragenyx, Yamo, Zynerba and Vtesse/Sucampo/Mallinckrodt Pharmaceuticals, to consult on trial design or run clinical or lab validation trials in genetic neurodevelopmental or neurodegenerative disorders, all of which are directed to RUMC in support of rare disease programs. E.B.-K. receives no personal funds, and Rush University Medical Center has no relevant financial interest in any of the commercial entities listed. For M.C.d.W., Erasmus MC received compensation for participation in the Tangelo trial from Hoffmann-La Roche, and for consultation from Jazz Pharmaceuticals. M.D.S. has received research funding from Biogen, Ionis and Roche to conduct clinical trials or research studies. All funds were paid to the University of North Carolina; M.D.S. receives no personal funds and has no relevant financial interest in any of the commercial entities listed. The other authors declare no competing interests.

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Supplementary Information

Supplementary Figs. 1–9, Supplementary Tables 1–20, Supplementary Sections 1–16 and Supplementary References.

Reporting Summary

Supplementary Table 21

Angelman syndrome developmental trajectory of EEG delta-power derived from natural history data for Del and Mut genotypes; age range, 1–16 years.

Supplementary Table 22

Angelman syndrome developmental trajectory of all five BSID-III and five VABS-III domains derived from natural history data for Del and Mut genotypes; age range, 1–16 years.

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Hipp, J.F., Bacino, C.A., Bird, L.M. et al. The UBE3A-ATS antisense oligonucleotide rugonersen in children with Angelman syndrome: a phase 1 trial. Nat Med 31, 2936–2945 (2025). https://doi.org/10.1038/s41591-025-03784-7

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