Medicinal cannabis plant extract (NTI164) modifies epigenetic, ribosomal, and immune pathways in paediatric acute-onset neuropsychiatric syndrome
Brooke A Keating 1, Velda X Han 2, Hiroya Nishida 3, Nader Aryamanesh 4, Lee L Marshall 5, Brian S Gloss 6, Xianzhong Lau 7, Ruwani Dissanayake 8, Suat Dervish 9, Mark E Graham 10, Shekeeb S Mohammad 11, Manoj Kanhangad 12, Michael C Fahey 12, Shrujna Patel 11, Russell C Dale 13
- 1Kids Neuroscience Centre, The Children’s Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; Fenix Innovation Group Pty Ltd, Mount Waverley, VIC 3149, Australia.
- 2Kids Neuroscience Centre, The Children’s Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; Khoo Teck Puat-National University Children’s Medical Institute, National University Health System, Singapore, Singapore; Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
- 3Kids Neuroscience Centre, The Children’s Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.
- 4Bioinformatics Group, Children’s Medical Research Institute, University of Sydney, Westmead, NSW, Australia; Faculty of Medicine and Health, Sydney Medical School, University of Sydney, Camperdown, NSW, Australia.
- 5Bioinformatics Group, Children’s Medical Research Institute, University of Sydney, Westmead, NSW, Australia.
- 6Westmead Research Hub, Westmead Institute for Medical Research, Westmead, NSW, Australia.
- 7Australian Genome Research Facility Ltd, Melbourne, VIC, Australia.
- 8Australian Genome Research Facility Ltd, Westmead, NSW, Australia.
- 9Westmead Institute for Medical Research, Sydney, Australia.
- 10Biomedical Proteomics, Children’s Medical Research Institute, The University of Sydney, NSW, Australia.
- 11Kids Neuroscience Centre, The Children’s Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; The Children’s Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
- 12Department of Neurology, Monash Children’s Hospital, Monash Health, Clayton, VIC, Australia.
- 13Kids Neuroscience Centre, The Children’s Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; The Children’s Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; The University of Sydney, School of Medical Sciences and Discipline of Child and Adolescent Health, Faculty of Medicine and Health, Sydney, NSW, Australia. Electronic address: russell.dale@sydney.edu.au.
Affiliationer
Paediatric acute-onset neuropsychiatric syndrome (PANS) is a syndrome of infection-provoked abrupt-onset obsessive-compulsive disorder (OCD) or eating restriction. Based on the hypothesis that PANS is an epigenetic disorder of immune and brain function, a full-spectrum medicinal cannabinoid-rich low-THC cannabis (NTI164) was selected for its known epigenetic and immunomodulatory properties. This open-label trial of 14 children with chronic-relapsing PANS (mean age 12·1 years; range 4-17; 71 % male) investigated the safety and efficacy of 20 mg/kg/day NTI164 over 12 weeks. Clinical outcomes were assessed using gold standard tools. To define the biological effects of NTI164, blood samples were collected pre- and post-treatment for bulk and single-cell transcriptomics, proteomics, phosphoproteomics, and DNA methylation. NTI164 was well-tolerated, and 12 weeks of treatment decreased the mean Clinical Global Impression-Severity (CGI-S) score from 4·8 to 3·3 (p = 0·002). Significant improvements were observed in emotional regulation (RCADS-P, p < 0·0001), obsessive-compulsive disorder (CYBOCS-II, p = 0·0001), tics (YGTSS, p < 0·0001), attention-deficit hyperactivity disorder (Conner’s, p = 0·028), and overall quality of life (EQ-5D-Y, p = 0·011). At baseline, the multi-omic approach revealed that leucocytes from patients with PANS had dysregulated epigenetic (chromatin structure, DNA methylation, histone modifications, transcription factors), ribosomal, mRNA processing, immune, and signalling pathways. These pathways were significantly modulated by NTI164 treatment. NTI164 shows promise as a disease-modifying therapeutic for PANS. Multi-omics reveal broad epigenetic and immune dysregulation in patients, which was modified by NTI164, presenting epigenetic machinery as a therapeutic target in PANS.
