{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:47:28Z","timestamp":1791920848674,"version":"4.3.4"},"reference-count":75,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2023,8,4]],"date-time":"2023-08-04T00:00:00Z","timestamp":1691107200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Rett syndrome (RTT) is a rare disability causing female-oriented pediatric neurodevelopmental unmet medical need. RTT was recognized in 1966. However, over the past 56 years, the United States Food and Drug Administration (USFDA) has authorized no effective treatment for RTT. Recently, Trofinetide was approved by the USFDA on 10 March 2023 as the first RTT treatment. This article underlines the pharmaceutical advancement, patent literature, and prospects of Trofinetide. The data for this study were gathered from the PubMed database, authentic websites (Acadia Pharmaceuticals, Neuren Pharmaceuticals, and USFDA), and free patent databases. Trofinetide was first disclosed by Neuren Pharmaceuticals in 2000 as a methyl group containing analog of the naturally occurring neuroprotective tripeptide called glycine-proline-glutamate (GPE). The joint efforts of Acadia Pharmaceuticals and Neuren Pharmaceuticals have developed Trofinetide. The mechanism of action of Trofinetide is not yet well established. However, it is supposed to improve neuronal morphology and synaptic functioning. The patent literature revealed a handful of inventions related to Trofinetide, providing excellent and unexplored broad research possibilities with Trofinetide. The development of innovative Trofinetide-based molecules, combinations of Trofinetide, patient-compliant drug formulations, and precise MECP2-mutation-related personalized medicines are foreseeable. Trofinetide is in clinical trials for some neurodevelopmental disorders (NDDs), including treating Fragile X syndrome (FXS). It is expected that Trofinetide may be approved for treating FXS in the future. The USFDA-approval of Trofinetide is one of the important milestones for RTT therapy and is the beginning of a new era for the therapy of RTT, FXS, autism spectrum disorder (ASD), brain injury, stroke, and other NDDs.<\/jats:p>","DOI":"10.3390\/jcm12155114","type":"journal-article","created":{"date-parts":[[2023,8,4]],"date-time":"2023-08-04T09:28:29Z","timestamp":1691141309000},"page":"5114","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Trofinetide for Rett Syndrome: Highlights on the Development and Related Inventions of the First USFDA-Approved Treatment for Rare Pediatric Unmet Medical Need"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5765-4580","authenticated-orcid":false,"given":"Shuaibu A.","family":"Hudu","sequence":"first","affiliation":[{"name":"Department of Basic Medical and Dental Sciences, Faculty of Dentistry, Zarqa University, Zarqa 13110, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fayig","family":"Elmigdadi","sequence":"additional","affiliation":[{"name":"Department of Basic Medical and Dental Sciences, Faculty of Dentistry, Zarqa University, Zarqa 13110, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1328-5493","authenticated-orcid":false,"given":"Aiman Al","family":"Qtaitat","sequence":"additional","affiliation":[{"name":"Department of Basic Medical and Dental Sciences, Faculty of Dentistry, Zarqa University, Zarqa 13110, Jordan"},{"name":"Department of Anatomy and Histology, Faculty of Medicine, Mutah University, Karak 61710, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7580-8667","authenticated-orcid":false,"given":"Mazen","family":"Almehmadi","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4117-5811","authenticated-orcid":false,"given":"Ahad Amer","family":"Alsaiari","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7929-7748","authenticated-orcid":false,"given":"Mamdouh","family":"Allahyani","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdulelah","family":"Aljuaid","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1827-3659","authenticated-orcid":false,"given":"Magdi","family":"Salih","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8063-0090","authenticated-orcid":false,"given":"Adel","family":"Alghamdi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Clinical Pharmacy, Al-Baha University, P.O. Box 1988, Al-Baha 65779, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad A.","family":"Alrofaidi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Clinical Pharmacy, Al-Baha University, P.O. Box 1988, Al-Baha 65779, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6186-461X","authenticated-orcid":false,"family":"Abida","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Northern Border University, Rafha 91911, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6064-1040","authenticated-orcid":false,"given":"Mohd","family":"Imran","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Northern Border University, Rafha 91911, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1111\/dmcn.15383","article-title":"State-of-the-art therapies for Rett syndrome","volume":"65","author":"Panayotis","year":"2023","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2813","DOI":"10.2147\/NDT.S371483","article-title":"Rett syndrome and MECP2 duplication syndrome: Disorders of MeCP2 dosage","volume":"18","author":"Collins","year":"2022","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1002\/ana.410140412","article-title":"A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett\u2019s syndrome: Report of 35 cases","volume":"14","author":"Hagberg","year":"1983","journal-title":"Ann. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/13810","article-title":"Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2","volume":"23","author":"Amir","year":"1999","journal-title":"Nat. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1007\/s10354-016-0491-9","article-title":"Progress in Rett Syndrome: From discovery to clinical trials","volume":"166","author":"Percy","year":"2016","journal-title":"Wien. Med. Wochenschr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"817195","DOI":"10.3389\/fneur.2022.817195","article-title":"Sleep Disorders in Rett Syndrome and Rett-Related Disorders: A Narrative Review","volume":"13","author":"Tascini","year":"2022","journal-title":"Front. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s13643-023-02169-6","article-title":"Global prevalence of Rett syndrome: Systematic review and meta-analysis","volume":"12","author":"Petriti","year":"2023","journal-title":"Syst. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e1912","DOI":"10.1212\/WNL.0000000000007316","article-title":"Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome","volume":"92","author":"Glaze","year":"2019","journal-title":"Neurology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1093\/brain\/awy323","article-title":"Towards a better diagnosis and treatment of Rett syndrome: A model synaptic disorder","volume":"142","author":"Banerjee","year":"2019","journal-title":"Brain"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"59","DOI":"10.12703\/r\/10-59","article-title":"Rett syndrome: Think outside the (skull) box","volume":"10","author":"Borloz","year":"2021","journal-title":"Fac. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/nrg3897","article-title":"Rett syndrome: A complex disorder with simple roots","volume":"16","author":"Lyst","year":"2015","journal-title":"Nat. Rev. Genet."},{"key":"ref_12","unstructured":"Chahil, G., and Bollu, P.C. (2023). StatPearls, StatPearls Publishing."},{"key":"ref_13","unstructured":"International Rett Syndrome Foundation (2023, May 06). About Rett Syndrome. Available online: https:\/\/www.rettsyndrome.org\/about-rett-syndrome\/."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"106704","DOI":"10.1016\/j.cct.2022.106704","article-title":"Design and outcome measures of LAVENDER, a phase 3 study of trofinetide for Rett syndrome","volume":"114","author":"Neul","year":"2022","journal-title":"Contemp. Clin. Trials."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2740","DOI":"10.1007\/s10803-020-04381-y","article-title":"Drug Studies on Rett Syndrome: From Bench to Bedside","volume":"50","author":"Gomathi","year":"2020","journal-title":"J. Autism. Dev. Disord."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"May, D., Kponee-Shovein, K., Mahendran, M., Downes, N., Sheng, K., Lefebvre, P., and Cheng, W.Y. (2023). Epidemiology and patient journey of Rett syndrome in the United States: A real-world evidence study. BMC Neurol., 23.","DOI":"10.1186\/s12883-023-03181-y"},{"key":"ref_17","first-page":"1142","article-title":"Trofinetide Receives FDA Approval as First Drug for Rett Syndrome","volume":"329","author":"Harris","year":"2023","journal-title":"JAMA"},{"key":"ref_18","unstructured":"United States Food and Drug Administration (2023, May 06). FDA Approves First Treatment for Rett Syndrome, Available online: https:\/\/www.fda.gov\/drugs\/news-events-human-drugs\/fda-approves-first-treatment-rett-syndrome."},{"key":"ref_19","unstructured":"United States Food and Drug Administration (2023, May 06). Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations, Available online: https:\/\/www.accessdata.fda.gov\/scripts\/cder\/ob\/index.cfm."},{"key":"ref_20","unstructured":"Acadia (2023, May 06). DAYBUE\u2122 (Trofinetide): The Only FDA-Approved Treatment for Rett Syndrome. Available online: https:\/\/acadia.com\/our-medicines\/daybue\/."},{"key":"ref_21","unstructured":"Neuren Pharmaceuticals (2023, May 06). DAYBUE\u2122 (Trofinetide). Available online: https:\/\/www.neurenpharma.com\/products\/daybue-trofinetide."},{"key":"ref_22","unstructured":"Center for Drug Evaluation and Research (2023, May 06). Product Quality Review(s), Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2023\/217026Orig1s000ChemR.pdf."},{"key":"ref_23","unstructured":"Center for Drug Evaluation and Research (2023, May 06). Clinical Pharmacology Review(s), Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2023\/217026Orig1s000ClinPharmR.pdf."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1089\/neu.2008.0629","article-title":"NNZ-2566, a glypromate analog, improves functional recovery and attenuates apoptosis and inflammation in a rat model of penetrating ballistic-type brain injury","volume":"26","author":"Lu","year":"2009","journal-title":"J. Neurotrauma"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/s12017-015-8341-2","article-title":"NNZ-2566, a novel analog of (1\u20133) IGF-1, as a potential therapeutic agent for fragile X syndrome","volume":"17","author":"Deacon","year":"2015","journal-title":"Neuromolecular Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.jns.2008.12.003","article-title":"NNZ-2566: A Gly-Pro-Glu analogue with neuroprotective efficacy in a rat model of acute focal stroke","volume":"278","author":"Bickerdike","year":"2009","journal-title":"J. Neurol. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Pejhan, S., and Rastegar, M. (2021). Role of DNA Methyl-CpG-Binding Protein MeCP2 in Rett Syndrome Pathobiology and Mechanism of Disease. Biomolecules, 11.","DOI":"10.3390\/biom11010075"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1602","DOI":"10.1016\/j.jmb.2019.10.004","article-title":"The Molecular Basis of MeCP2 Function in the Brain","volume":"432","author":"Tillotson","year":"2020","journal-title":"J. Mol. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1097\/nen.0b013e3180302078","article-title":"Methyl CpG-binding protein 2 (a mutation of which causes Rett syndrome) directly regulates insulin-like growth factor binding protein 3 in mouse and human brains","volume":"66","author":"Itoh","year":"2007","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1924","DOI":"10.1038\/jcbfm.2009.109","article-title":"NNZ-2566, a glypromate analog, attenuates brain ischemia-induced non-convulsive seizures in rats","volume":"29","author":"Lu","year":"2009","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/1742-2094-6-19","article-title":"NNZ-2566 treatment inhibits neuroinflammation and pro-inflammatory cytokine expression induced by experimental penetrating ballistic-like brain injury in rats","volume":"6","author":"Wei","year":"2009","journal-title":"J. Neuroinflamm."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1007\/s12017-013-8236-z","article-title":"Mechanism of action for NNZ-2566 anti-inflammatory effects following PBBI involves upregulation of immunomodulator ATF3","volume":"15","author":"Cartagena","year":"2013","journal-title":"Neuromol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.pediatrneurol.2020.04.019","article-title":"A Double-Blind, Randomized, Placebo-Controlled Clinical Study of Trofinetide in the Treatment of Fragile X Syndrome","volume":"110","author":"Horrigan","year":"2020","journal-title":"Pediatr. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.pediatrneurol.2017.07.002","article-title":"A Double-Blind, Randomized, Placebo-Controlled Clinical Study of Trofinetide in the Treatment of Rett Syndrome","volume":"76","author":"Glaze","year":"2017","journal-title":"Pediatr. Neurol."},{"key":"ref_35","unstructured":"Center for Drug Evaluation and Research (2023, May 06). Clinical Review(s), Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2023\/217026Orig1s000MedR.pdf."},{"key":"ref_36","unstructured":"Center for Drug Evaluation and Research (2023, May 06). Non-Clinical Review(s), Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2023\/217026Orig1s000PharmR.pdf."},{"key":"ref_37","unstructured":"Center for Drug Evaluation and Research (2023, May 06). Summary Review, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2023\/217026Orig1s000SumR.pdf."},{"key":"ref_38","unstructured":"Center for Drug Evaluation and Research (2023, May 06). Labeling, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2023\/217026Orig1s000lbl.pdf."},{"key":"ref_39","unstructured":"(2023, May 06). United States National Library of Medicine, Available online: https:\/\/www.clinicaltrials.gov\/."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1007\/s40261-022-01156-4","article-title":"A Phase 1, Open-Label Study to Evaluate the Effects of Food and Evening Dosing on the Pharmacokinetics of Oral Trofinetide in Healthy Adult Subjects","volume":"42","author":"Darwish","year":"2022","journal-title":"Clin. Drug Investig."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"S98","DOI":"10.1016\/j.ejps.2017.05.032","article-title":"Population pharmacokinetics of NNZ-2566 in healthy subjects","volume":"109","author":"Oosterholt","year":"2017","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_42","unstructured":"Center for Drug Evaluation and Research (2023, May 06). Risk Assessment and Risk Mitigation Review(s), Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2023\/217026Orig1s000RiskR.pdf."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Almehmadi, M., Allahyani, M., Alsaiari, A.A., Alshammari, M.K., Alharbi, A.S., Hussain, K.H., Alsubaihi, L.I., Kamal, M., Alotaibi, S.S., and Alotaibi, A.N. (2022). A Glance at the Development and Patent Literature of Tecovirimat: The First-in-Class Therapy for Emerging Monkeypox Outbreak. Viruses, 14.","DOI":"10.3390\/v14091870"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Ashour, M.A., Fatima, W., Imran, M., Ghoneim, M.M., Alshehri, S., and Shakeel, F. (2022). A Review on the Main Phytoconstituents, Traditional Uses, Inventions, and Patent Literature of Gum Arabic Emphasizing Acacia seyal. Molecules, 27.","DOI":"10.3390\/molecules27041171"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1080\/13543776.2022.2045948","article-title":"Small molecules as kinetoplastid specific proteasome inhibitors for leishmaniasis: A patent review from 1998 to 2021","volume":"32","author":"Imran","year":"2022","journal-title":"Expert. Opin. Ther. Pat."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1016\/j.jiph.2022.08.016","article-title":"An insight into the discovery, clinical studies, compositions, and patents of macozinone: A drug targeting the DprE1 enzyme of Mycobacterium tuberculosis","volume":"15","author":"Imran","year":"2022","journal-title":"J. Infect. Public Health"},{"key":"ref_47","unstructured":"Sara, V.R. (1990). Neuromodulatory Peptide. (Application Publication Number EP0366638A2), European Patent."},{"key":"ref_48","unstructured":"Gluckman, P.D., and Williams, C.E. (1995). Composition and Methods to Improve Neural Outcome. (Application Publication Number WO9517204A1), PCT Patent."},{"key":"ref_49","unstructured":"Gluckman, P.D., Williams, C.E., and Guan, J. (1998). Regulation of Neural Enzymes. (Application Publication Number WO9814202A1), PCT Patent."},{"key":"ref_50","unstructured":"Gluckman, P.D., Guan, J., and Alexi, T. (1999). Regulation of tyrosine hydroxylase. (Application Publication Number WO9965509A1), PCT Patent."},{"key":"ref_51","unstructured":"Scheepens, A., Williams, C.E., Gluckman, P.D., and Clark, R.G. (2007). Neuroprotective Effect of Growth Hormone. (Number US7304029B1), United States Patent."},{"key":"ref_52","unstructured":"Gluckman, P., and Alexi, T. (2002). GPE Analogs. (Application Publication Number WO0216408A2), PCT Patent."},{"key":"ref_53","unstructured":"Abood, N.A., and Brimble, M.A. (2006). GPE Analogs and Peptidomimetics. (Number US7041314B2), United States Patent."},{"key":"ref_54","unstructured":"Gluckman, P.D., Thomas, G.B., Guan, J., Dragunow, M., Anand, A.K., Sieg, F., and Brimble, M.A. (2009). Effects of Glycyl-2 Methyl Prolyl Glutamate on Neurodegeneration. (Number US7605177B2), United States Patent."},{"key":"ref_55","unstructured":"Gluckman, P.D., Brimble, M.A., Wilson, D., Tortella, F.C., Williams, A.J., Lu, X.M., Hartings, J.A., and Gryder, D. (2010). Treatment of Non-Convulsive Seizures in Brain Injury Using G-2-Methyl-Prolyl Glutamate. (Number US7714020B2), United States Patent."},{"key":"ref_56","unstructured":"Wen, J., Thomas, G.B., and Bickerdike, M.J. (2011). Oral Formulations of Glycyl-2-Methylprolyl-Glutamate. (Number US7887839B2), United States Patent."},{"key":"ref_57","unstructured":"Wen, J., Thomas, G.B., and Bickerdike, M.J. (2012). Oral Formulations of Glycyl-2-Methylprolyl-Glutamate. (Number US8178125B2), United States Patent."},{"key":"ref_58","unstructured":"Wen, J., Thomas, G.B., and Bickerdike, M.J. (2013). Oral Formulations of Glycyl-2-Methylprolyl-Glutamate. (Number US8496963B2), United States Patent."},{"key":"ref_59","unstructured":"Glass, L., Bickerdike, M.J., and Snape, M.F. (2017). Treatment of Fragile X Syndrome Using Glycyl-L-2-Methylprolyl-L-Glutamate. (Number US9708366B2), United States Patent."},{"key":"ref_60","unstructured":"Glass, L.I., Bickerdike, M.J., Snape, M.F., and De Cogram, P.P. (2015). Treatment of Autism Spectrum Disorders Using Glycyl-l-2-Methylprolyl-l-Glumatic Acid. (Application Publication Number US2015224164A1), United States Patent."},{"key":"ref_61","unstructured":"Glass, L.I., Bickerdike, M.J., and Snape, M.F. (2015). Treatment of Rett Syndrome Using Glycyl-L-2-Methylprolyl-L-Glutamic Acid. (Number US9212204B2), United States Patent."},{"key":"ref_62","unstructured":"Kole, R., Marshall, J., and Owen, M. (2023). Enhanced Delivery of Antioxidants for Treatment of Central Nervous System Disorders Involving Oxidative Stress. (Number US11612642B2), United States Patent."},{"key":"ref_63","unstructured":"Blower, C., Peterson, M., Shaw, J.M., Bonnar, J.A., Moniotte, E.D.F.P., Bousmanne, M.B.C., Betti, C., Decroos, K.W.L., and Ayoub, M. (2022). Compositions of Trofinetide. (Number US11370755B2), United States Patent."},{"key":"ref_64","unstructured":"Blower, C., Peterson, M., Shaw, J.M., Bonnar, J.A., Moniotte, E.D.F.P., Bousmanne, M.B.C., Betti, C., Decroos, K.W.L., and Ayoub, M. (2022). Compositions of Trofinetide. (Application Publication Number US2022324799A1), United States Patent."},{"key":"ref_65","unstructured":"Peterson, M., Carlos, M., Bousmanne, M.B.C., Betti, C., Jonaitis, D.T., Mccracken, L.M., and Grove, L. (2023). Crystalline Forms of Trofinetide. (Application Publication Number US2023023114A1), United States Patent."},{"key":"ref_66","unstructured":"Darwish, M., Youakim, J.M., Glass, L.I., Jones, N.E., Oosterholt, S.P., and Pasqua, O.D. (2022). Methods and Compositions for Treatment of Rett Syndrome. (Application Publication Number US2022339138A1), United States Patent."},{"key":"ref_67","unstructured":"Vigneault, F., Levin, M., Ingber, D., and Novak, R. (2022). Drugs for Treating Neurodevelopmental Disorders. (Application Publication Number WO2022246277A2), PCT Patent."},{"key":"ref_68","unstructured":"Page, D., and Levy, J. (2022). Treating Disorders Associated with DYRK1A Dysfunction. (Application Publication Number WO2022165250A1), PCT Patent."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1021\/acschemneuro.2c00675","article-title":"Concise Overview of Glypromate Neuropeptide Research: From Chemistry to Pharmacological Applications in Neurosciences","volume":"14","author":"Costa","year":"2023","journal-title":"ACS Chem. Neurosci."},{"key":"ref_70","unstructured":"Lee, R.T., Patwari, P., and Pancoast, J. (2017). Compounds and Methods for Modulating Pharmacokinetics. (Number US9790264B2), United States Patent."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"247","DOI":"10.2217\/epi.14.80","article-title":"Genetic alterations of DNA methylation machinery in human diseases","volume":"7","author":"Hamidi","year":"2015","journal-title":"Epigenomics"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2029","DOI":"10.1073\/pnas.0812394106","article-title":"Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice","volume":"106","author":"Tropea","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"4596","DOI":"10.1073\/pnas.1311141111","article-title":"Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome","volume":"111","author":"Khwaja","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1016\/j.jiph.2022.09.011","article-title":"Selenium and COVID-19: A spotlight on the clinical trials, inventive compositions, and patent literature","volume":"15","author":"Alshammari","year":"2022","journal-title":"J. Infect. Public Health"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Imran, M., Arora, M.K., Chaudhary, A., Khan, S.A., Kamal, M., Alshammari, M.M., Alharbi, R.M., Althomali, N.A., Alzimam, I.M., and Alshammari, A.A. (2022). MmpL3 Inhibition as a Promising Approach to Develop Novel Therapies against Tuberculosis: A Spotlight on SQ109, Clinical Studies, and Patents Literature. 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