RESUMEN
Endometriosis is a chronic inflammatory condition affecting one in 10 women and those assigned female at birth, defined by the presence of endometrial-like tissue outside the uterus. It is commonly associated with pain, infertility, and mood disorders, and often comorbid with other chronic pain conditions, such as irritable bowel syndrome. Recent research has identified a key role for the microbiota-gut-brain axis in health and a range of inflammatory and neurological disorders, prompting an exploration of its potential mechanistic role in endometriosis. Increased awareness of the impact of the gut microbiota within the patient community, combined with the often-detrimental side effects of current therapies, has motivated many to utilise self-management strategies, such as dietary modification and supplements, despite a lack of robust clinical evidence. Current research has characterised the gut microbiota in endometriosis patients and animal models. However, small cohorts and differing methodology has resulted in little consensus in the data. In this narrative review, we summarise research studies that have investigated the role of gut microbiota and their metabolic products in the development and progression of endometriosis lesions, before summarising insights from research into co-morbid conditions and discussing the reported impact of self-management strategies on symptoms of endometriosis. Finally, we suggest ways in which this promising field of research could be expanded to explore the role of specific bacteria, improve access to 'microbial' phenotyping, and to develop personalised patient advice for reduction of symptoms such as chronic pain and bloating.
RESUMEN
Cyclin-dependent kinase-like 5 disorder is a severe neurodevelopmental disorder caused by mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene. It predominantly affects females who typically present with severe early epileptic encephalopathy, global developmental delay, motor dysfunction, autistic features and sleep disturbances. To develop a gene replacement therapy, we initially characterized the human CDKL5 transcript isoforms expressed in the brain, neuroblastoma cell lines, primary astrocytes and embryonic stem cell-derived cortical interneurons. We found that the isoform 1 and to a lesser extent the isoform 2 were expressed in human brain, and both neuronal and glial cell types. These isoforms were subsequently cloned into recombinant adeno-associated viral (AAV) vector genome and high-titre viral vectors were produced. Intrajugular delivery of green fluorescence protein via AAV vector serotype PHP.B in adult wild-type male mice transduced neurons and astrocytes throughout the brain more efficiently than serotype 9. Cdkl5 knockout male mice treated with isoform 1 via intrajugular injection at age 28-30 days exhibited significant behavioural improvements compared to green fluorescence protein-treated controls (1012 vg per animal, n = 10 per group) with PHP.B vectors. Brain expression of the isoform 1 transgene was more abundant in hindbrain than forebrain and midbrain. Transgene brain expression was sporadic at the cellular level and most prominent in hippocampal neurons and cerebellar Purkinje cells. Correction of postsynaptic density protein 95 cerebellar misexpression, a major fine cerebellar structural abnormality in Cdkl5 knockout mice, was found in regions of high transgene expression within the cerebellum. AAV vector serotype DJ efficiently transduced CDKL5-mutant human induced pluripotent stem cell-derived neural progenitors, which were subsequently differentiated into mature neurons. When treating CDKL5-mutant neurons, isoform 1 expression led to an increased density of synaptic puncta, while isoform 2 ameliorated the calcium signalling defect compared to green fluorescence protein control, implying distinct functions of these isoforms in neurons. This study provides the first evidence that gene therapy mediated by AAV vectors can be used for treating CDKL5 disorder.
