Research status at the Rett Clinic at Children’s Hospital Colorado
It’s been over 10 years that RMRA has helped set up the Rett Clinic at Children’s Hospital Colorado, and the entire RMRA team is very proud of what the team at the Rett Clinic has achieved!
The Rett Clinic at Children's Hospital Colorado is a beacon of excellence. Distinguished with the prestigious Center of Excellence designations by the International Rett Syndrome Foundation, International Foundation for CDKL5 research and the FOXG1 Research Foundation, this clinic holds a special place. Focused on Rett Syndrome, MECP2 disorders, CDKL5 deletion disorder and FOXG1 syndrome, its researchers have contributed extensively to understanding these conditions, showing a wealth of study findings that delve into its intricacies. We want to give you an overview of Published papers and past and current studies in which the Rett Clinic at Children’s Hospital Colorado was involved.
PUBLISHED PAPERS
Check out the long list of published papers as of October 2023:
Trofinetide for the treatment of Rett syndrome: a randomized phase 3 study
Neul, J. L., Percy, A. K., Benke, T. A., Berry-Kravis, E. M., Glaze, D. G., Marsh, E. D., ... & Youakim, J. M. (2023). Nature Medicine, 1-8.
Design and outcome measures of LAVENDER
Neul, J. L., Percy, A. K., Benke, T. A., Berry-Kravis, E. M., Glaze, D. G., Peters, S. U., ... & Youakim, J. M. (2022)., a phase 3 study of trofinetide for Rett syndrome. Contemporary clinical trials, 114, 106704.
Improving clinical trial readiness to accelerate development of new therapeutics for Rett syndrome
Leonard, H., Gold, W., Samaco, R., Sahin, M., Benke, T., & Downs, J. (2022). Orphanet Journal of Rare Diseases, 17(1), 1-15.
Parental age effects and Rett syndrome
Fang, X., Baggett, L. M., Caylor, R. C., Percy, A. K., Neul, J. L., Lane, J. B., ... & Skinner, S. A. (2023). American Journal of Medical Genetics Part A.
Analysis of X‐inactivation status in a Rett syndrome natural history study cohort
Fang, X., Butler, K. M., Abidi, F., Gass, J., Beisang, A., Feyma, T., ... & Caylor, R. C. (2022). Molecular genetics & genomic medicine, 10(5), e1917.
Percy, A. K., Neul, J. L., Benke, T. A., Marsh, E. D., & Glaze, D. G. (2023). Frontiers in Pediatrics, 11.
Anxiety-like behavior and anxiolytic treatment in the Rett syndrome natural history study
Buchanan, C. B., Stallworth, J. L., Joy, A. E., Dixon, R. E., Scott, A. E., Beisang, A. A., ... & Percy, A. K. (2022). Journal of neurodevelopmental disorders, 14(1), 31.
Anthropometric Measures Correspond with Functional Motor Outcomes in Females with Rett Syndrome
Motil KJ, Geerts S, Annese F, Neul JL, Benke T, Marsh E, Lieberman D, Skinner SA, Glaze DG, Heydemann P, Beisang A, Standridge S, Ryther R, Lane JB, Edwards L, Percy AK.J Pediatr. 2022 Jan 18:S0022-3476(22)00010-5. doi: 10.1016/j.jpeds.2022.01.009. Online ahead of print.PMID: 35063470
Current neurologic treatment and emerging therapies in CDKL5 deficiency disorder
Olson HE, Daniels CI, Haviland I, Swanson LC, Greene CA, Denny AMM, Demarest ST, Pestana-Knight E, Zhang X, Moosa AN, Fidell A, Weisenberg JL, Suter B, Fu C, Neul JL, Percy AK, Marsh ED, Benke TA, Poduri A.J Neurodev Disord. 2021 Sep 16;13(1):40. doi: 10.1186/s11689-021-09384-z.PMID: 34530725
Multisite Study of Evoked Potentials in Rett Syndrome
Saby JN, Benke TA, Peters SU, Standridge SM, Matsuzaki J, Cutri-French C, Swanson LC, Lieberman DN, Key AP, Percy AK, Neul JL, Nelson CA, Roberts TPL, Marsh ED.Ann Neurol. 2021 Apr;89(4):790-802. doi: 10.1002/ana.26029. Epub 2021 Feb 4.PMID: 33480039
Cerebral Visual Impairment in CDKL5 Deficiency Disorder Correlates With Developmental Achievement
Brock D, Fidell A, Thomas J, Juarez-Colunga E, Benke TA, Demarest S.J Child Neurol. 2021 Oct;36(11):974-980. doi: 10.1177/08830738211019284.PMID: 34547934
Content Validation of Clinician-Reported Items for a Severity Measure for CDKL5 Deficiency Disorder
Saldaris J, Weisenberg J, Pestana-Knight E, Marsh ED, Suter B, Rajaraman R, Heidary G, Olson HE, Devinsky O, Price D, Jacoby P, Leonard H, Benke TA, Demarest S, Downs J.J Child Neurol. 2021 Oct;36(11):998-1006. doi: 10.1177/08830738211019576. Epub 2021 Aug 11.PMID: 34378447
Cerebral visual impairment in CDKL5 deficiency disorder: vision as an outcome measure
Olson HE, Costantini JG, Swanson LC, Kaufmann WE, Benke TA, Fulton AB, Hansen R, Poduri A, Heidary G.Dev Med Child Neurol. 2021 Nov;63(11):1308-1315. doi: 10.1111/dmcn.14908. Epub 2021 May 24.PMID: 34028805
Aledo-Serrano Á, Gómez-Iglesias P, Toledano R, Garcia-Peñas JJ, Garcia-Morales I, Anciones C, Soto-Insuga V, Benke TA, Del Pino I, Gil-Nagel A.Epilepsy Behav. 2021 May;118:107946. doi: 10.1016/j.yebeh.2021.107946. Epub 2021 Apr 10.PMID: 33848848
MacKay CI, Wong K, Demarest ST, Benke TA, Downs J, Leonard H.Clin Genet. 2021 Jan;99(1):157-165. doi: 10.1111/cge.13862. Epub 2020 Oct 20.PMID: 33047306
Raspa M, Bann CM, Gwaltney A, Benke TA, Fu C, Glaze DG, Haas R, Heydemann P, Jones M, Kaufmann WE, Lieberman D, Marsh E, Peters S, Ryther R, Standridge S, Skinner SA, Percy AK, Neul JL.Am J Intellect Dev Disabil. 2020 Nov 1;125(6):493-509. doi: 10.1352/1944-7558-125.6.493.PMID: 33211820
Phenotypic features in MECP2 duplication syndrome: Effects of age
Peters SU, Fu C, Marsh ED, Benke TA, Suter B, Skinner SA, Lieberman DN, Standridge S, Jones M, Beisang A, Feyma T, Heydeman P, Ryther R, Glaze DG, Percy AK, Neul JL.Am J Med Genet A. 2021 Feb;185(2):362-369. doi: 10.1002/ajmg.a.61956. Epub 2020 Nov 10.PMID: 33170557
Multisystem comorbidities in classic Rett syndrome: a scoping review
Fu C, Armstrong D, Marsh E, Lieberman D, Motil K, Witt R, Standridge S, Lane J, Dinkel T, Jones M, Hale K, Suter B, Glaze D, Neul J, Percy A, Benke T.BMJ Paediatr Open. 2020 Sep 22;4(1):e000731. doi: 10.1136/bmjpo-2020-000731. eCollection 2020.PMID: 33024833
Consensus guidelines on managing Rett syndrome across the lifespan
Fu C, Armstrong D, Marsh E, Lieberman D, Motil K, Witt R, Standridge S, Nues P, Lane J, Dinkel T, Coenraads M, von Hehn J, Jones M, Hale K, Suter B, Glaze D, Neul J, Percy A, Benke T.BMJ Paediatr Open. 2020 Sep 13;4(1):e000717. doi: 10.1136/bmjpo-2020-000717. eCollection 2020.PMID: 32984552
Comparison of Core Features in Four Developmental Encephalopathies in the Rett Natural History Study
Cutri-French C, Armstrong D, Saby J, Gorman C, Lane J, Fu C, Peters SU, Percy A, Neul JL, Marsh ED.Ann Neurol. 2020 Aug;88(2):396-406. doi: 10.1002/ana.25797. Epub 2020 Jun 29.PMID: 32472944
Severity Assessment in CDKL5 Deficiency Disorder
Demarest S, Pestana-Knight EM, Olson HE, Downs J, Marsh ED, Kaufmann WE, Partridge CA, Leonard H, Gwadry-Sridhar F, Frame KE, Cross JH, Chin RFM, Parikh S, Panzer A, Weisenberg J, Utley K, Jaksha A, Amin S, Khwaja O, Devinsky O, Neul JL, Percy AK, Benke TA.Pediatr Neurol. 2019 Aug;97:38-42. doi: 10.1016/j.pediatrneurol.2019.03.017. Epub 2019 Mar 27.PMID: 31147226
Demarest ST, Olson HE, Moss A, Pestana-Knight E, Zhang X, Parikh S, Swanson LC, Riley KD, Bazin GA, Angione K, Niestroj LM, Lal D, Juarez-Colunga E, Benke TA.Epilepsia. 2019 Aug;60(8):1733-1742. doi: 10.1111/epi.16285. Epub 2019 Jul 16.PMID: 31313283
Cyclin-Dependent Kinase-Like 5 Deficiency Disorder: Clinical Review
Olson HE, Demarest ST, Pestana-Knight EM, Swanson LC, Iqbal S, Lal D, Leonard H, Cross JH, Devinsky O, Benke TA.Pediatr Neurol. 2019 Aug;97:18-25. doi: 10.1016/j.pediatrneurol.2019.02.015. Epub 2019 Feb 23.PMID: 30928302
Characterizing the phenotypic effect of Xq28 duplication size in MECP2 duplication syndrome
Peters SU, Fu C, Suter B, Marsh E, Benke TA, Skinner SA, Lieberman DN, Standridge S, Jones M, Beisang A, Feyma T, Heydeman P, Ryther R, Kaufmann WE, Glaze DG, Neul JL, Percy AK.Clin Genet. 2019 May;95(5):575-581. doi: 10.1111/cge.13521. Epub 2019 Mar 15.PMID: 30788845
The array of clinical phenotypes of males with mutations in Methyl-CpG binding protein 2
Neul JL, Benke TA, Marsh ED, Skinner SA, Merritt J, Lieberman DN, Standridge S, Feyma T, Heydemann P, Peters S, Ryther R, Jones M, Suter B, Kaufmann WE, Glaze DG, Percy AK.Am J Med Genet B Neuropsychiatr Genet. 2019 Jan;180(1):55-67. doi: 10.1002/ajmg.b.32707. Epub 2018 Dec 7.PMID: 30536762
CDKL5 variants: Improving our understanding of a rare neurologic disorder
Hector RD, Kalscheuer VM, Hennig F, Leonard H, Downs J, Clarke A, Benke TA, Armstrong J, Pineda M, Bailey MES, Cobb SR.Neurol Genet. 2017 Dec 15;3(6):e200. doi: 10.1212/NXG.0000000000000200. eCollection 2017 Dec.PMID: 29264392
CURRENT & PAST STUDIES AT THE RETT CLINIC AT CHILDREN’S HOSPITAL COLORADO
The Rett Clinic at Children’s Hospital Colorado currently participates in several studies. Participation is limited and depends on the study guidelines. If you are interested in pursuing research as an avenue of treatment for your child, please contact the Rett clinic rettclinic@childrenscolorado.org
ACADIA Protocols 2019 - 2023
Acadia 003 (5-20yo. Double-Blind Placebo-Controlled Trial of Trofinetide)
Acadia 004 (5-20yo. Open-Label Trial of Trofinetide)
Acadia 005 (5-20yo. Open-Label Extension Trial of Trofinetide)
Acadia 009 (2-5yo. Open-Label Trial of Trofinetide)
The Rett Clinic at Children’s Hospital Colorado is excited that the ACADIA Protocols were concluded with the approval of Trofinedite by the FDA!
1. A Double-blind, Randomized, Placebo-controlled Trial of Adjunctive Ganaxolone Treatment in Children and Young Adults with Cyclindependent Kinase-like 5 (CDKL5) Deficiency Disorder (CDD) Followed by Long-term Open-label Treatment. Role: Site Co-PI. Status: closed. Sponsor: Marinus.
2. A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Study to Assess the Safety, Tolerability, and Efficacy of Oral Ketamine in Patients with Rett Syndrome. Role: Site PI. Status: recruiting. Sponsor: RSRT.
3. Open-Label Study in patients with CDKL5 deficiency disorder. Role: site Co-PI, Status: closed. Sponsor: Ovid/Takeda.
4. A Randomized, double-blind,placebo-controlled, trial to investigate the efficacy and safety of cannabidiol oral solution (GWP42003-P, CBD-OS) in patients with Rett Syndrome. Role Site PI. Status: closed. Sponsor: GW/Premier.
5. Lavendar and Lilac: Phase 3 trial of trofinetide in Rett Syndrome. Role: site PI, master-rater. Status: closing. Sponsor: Acadia/Neuren/Precision.
Research Support
U01NS114312-01A1 (Benke), 12/01/2020-11/30/2025
NIH/NINDS
Multi-site validation of biomarkers and core clinical outcome measures for clinical trials readiness in CDKL5 Deficiency Disorder
Role: PI/PD. Oversee clinical trial readiness network; oversee all aspects of the project.
The goal of this project is to validate biomarkers and clinical outcome measures for CDKL5 Disorder across multiple sites.
International Rett Syndrome Foundation, 12/15/2022-12/14/2024
Diagnostic experience of male Rett syndrome
Role: PI/PD. This award supports qualitative and quantitative studies of male Rett syndrome in partnership with IRSF Centers of Excellence and 3 clinical sites to advance understanding and treatment.
NINDS R61NS130216 (Marsh/Neul), 01/01/2023-12/31/2027
Development of translatable neurophysiological biomarkers to accelerate therapeutic development in Rett syndrome
Role: PI. Will develop neurophysiological biomarkers that can fulfil a specific primary Context of Use (COU), an early treatment.
DOD PR221983 (Neul), 07/01/2023– 06/30/2028
Umbrella Clinical Trial to Evaluate Repurpose Compounds in Rett Syndrome
Role: Site PI/MPI This proposal will focus on the PRMP Strategic Goal of Treatment: the evaluation of repurposed drugs to determine whether they are safe and efficacious to improve the health and quality of life in individuals living with RTT.
Person months per budget period:
R21 NS112770-01A1 (Benke), 04/01/2020-03/31/2022
NIH/NINDS
Role of CDKL5 kinase activity in modulating synaptic plasticity
Role: PI. The goal of this project is to characterize potential specific CDKL5 kinase inhibitors in order to determine their role in synaptic plasticity. Comparisons are made to CDKL5-knock out rodents to determine the role of the acute kinase function in this model of pediatric epileptic encephalopathy.
U54 HD061222 (Percy), 09/30/2003-07/31/2019
Rare Disease CRC for New Therapies and New Diagnostics
Role: Site PI. Rare Disease multisite initiative to provide natural history studies leading to possible therapies for Rett syndrome, MECP2 Duplication Disorder, and Rett-related Disorders Natural History.
Rett Syndrome Research Trust (Percy), 09/01/2016-08/31/2019
Outcome Measures and Biomarkers Development for Rett Syndrome: Multi-site development of standardized assessments for use in clinical trials
Role: Site PI. The goal of this project is to establish novel biomarkers for the assessment of treatment outcomes in patients with Rett syndrome.
UPenn Orphan Disease program (Marsh/Benke), 01/01/2017 - 12/31/2019
5212 Extension Study: AEP/VEP/EEG in CDKL5 deficiency syndrome
Role: co-PI. The goal of this project is to determine electrophysiologic biomarkers in CDKL5 deficiency syndrome.
UPenn Orphan Disease program (Benke), 05/01/2017 - 10/30/2018
Mechanisms and treatment of paradoxical hyperexcitability in CDKL5 deficiency syndrome. Role: PI. The goal of this project is to determine the mechanisms and possible treatment of CDKL5 deficiency syndrome.
RMRA is looking forward to many more years of studies and research findings. We are dedicated to supporting researchers to get a deeper understanding of this rare disease and, ultimately, a cure!
