Children's Medical Research Institute

Abstract Voltage-gated (Kv) potassium channels are critical for neuronal physiology, and their dysfunction can lead to serious consequences. For example, mutations in the silent modulatory Kv8.2 subunit are known to cause irreversible inherited blindness ( KCNV2 retinopathy). This is a currently incurable condition that causes lifelong visual loss, reduced visual acuity, photoaversion, night blindness and abnormal colour vision, alongside a distinctive supernormal electrophysiological (ERG) retinal response to light. In this study, we demonstrate that AAV-mediated gene replacement therapy delivering a codon-optimised human KCNV2 gene subretinally into Kv8.2 knock-out mice significantly restores retinal function. Treated mice exhibited improved ERG responses and correct expression of KCNV2 and its encoded Kv8.2 protein in photoreceptors. Recovery of visually guided scotopic and photopic optomotor responses to wildtype levels was achieved at lower vector doses, highlighting dose-dependent efficacy. Furthermore, treatment of human retinal organoids derived from a KCNV2 patient iPSC line resulted in substantial Kv8.2 protein rescue. This work provides the first preclinical proof-of-concept for the safety and therapeutic potential of gene therapy for KCNV2 retinopathy, laying a strong foundation for future clinical trials.

Protocols for deriving midbrain dopaminergic (mDA) neurons for Parkinson’s disease (PD) modeling and therapy remain incompletely benchmarked against in vivo references. To establish transcriptomic standards, we generated an integrated human fetal whole-brain atlas and a midbrain subatlas. Whole-brain analysis revealed strong region-specific signatures, underscoring the need for global mapping before refined midbrain annotation. We implemented this two-tier strategy, BrainSTEM (Brain Single-cell Two tiEr Mapping), to systematically reassess published single-cell datasets of human midbrain culture models. BrainSTEM confirmed the presence of bona fide midbrain cell types (“on-target”), but also revealed substantial populations aligning with nonmidbrain regions (“off-target”), inflating reported mDA yields across protocols. This unbiased framework enables rigorous evaluation of differentiation outcomes, clarifies current limitations of midbrain-directed models, and provides a foundation for refining protocols toward more faithful in vitro systems for PD research and regenerative applications.

Rett syndrome (RTT, OMIM #312750) is a severe genetic, neurodevelopmental disorder, primarily affecting females, that occurs due to pathogenic variants in MECP2. Clinical features include loss of acquired developmental milestones, such as purposeful hand movements and communicative abilities and the onset of stereotypic hand movements. Mitochondrial dysfunction/impairment, and inflammation have been reported in individuals with RTT. Despite numerous clinical trials and medications thought to be disease-modifying, treatment often remains purely symptomatic. A significant impediment in determining treatment efficacy has been the lack of clinical biomarkers that correlate with disease state. Mitokines, such as fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), have been established as biomarkers of cellular stress and mitochondrial dysfunction that may be of clinical utility for patients with RTT. We aimed to determine the suitability of these mitokines as biomarkers for RTT where we analysed their expression levels in blood samples from individuals with RTT as well as fromthe Mecp2T158A mouse model . Our data showed higher FGF21 and GDF15 levels in female Mecp2-deficient mice compared to their wild type littermates. Median FGF21 and GDF15 levels also trended higher in the affected human cohort compared to controls; however, these elevations did not reach statistical significance and appear to be correlated with sodium valproate therapy.

Abstract Introduction Studies have consistently demonstrated that hospitalised children sleep poorly, and that ward environments are disruptive, leading to poor quality sleep. To date, literature around potential interventions to improve sleep in hospitalised children has not been synthesised. This study aims to address this gap and provide guidance for future research. Methods A systematic review of the current literature pertaining to the interventions that have been evaluated to improve quality and duration of sleep for hospitalised children (age 0-18yrs) was undertaken, following PRIMSA guidelines. A detailed individual search strategy was developed and performed within PubMed, Embase, CINAHL, Web of Science and Cochrane Library databases. Title and abstract screening of identified articles was undertaken by one investigator, with a second investigator screening 50% (93% concordance between investigators). Results The initial search yielded 2474 studies regarding interventions to improve sleep in hospitalised children. 58 of these were deemed eligible for inclusion. Interventions studied included (i) Child focused interventions- use of music, mother’s voice, white noise, storybook reading, massage and acupressure (ii) Nursing focus interventions- decreasing overnight vital sign monitoring and clustering cares and (iii) Development of educational material to promote optimal sleep environments through reducing noise, light and screen time for patients. Full text screening of the included studies is now underway. Conclusion By providing a comprehensive review of the efficacy of existing interventions employed to improve sleep in hospitalised children, we hope to identify current gaps in knowledge and provide guidance around the optimal approach to reduce sleep disruption in hospitalised children.

PurposeVision plays a critical role in the performance of various functional tasks, and can also be an inherent source of enjoyment unrelated to a functional task. This study aimed to explore the sources and importance of visual enjoyment and how these might alter with vision loss.MethodsFourteen adults (26–81 years) with self‐reported healthy vision and 15 (37–84 years) with vision loss (inherited retinal disease, glaucoma, age‐related macular degeneration) participated. Across four focus groups (2 × healthy vision, 2 × vision loss), participants were asked about sources of visual enjoyment, attitudes around the distinction between vision to perform tasks versus vision as an inherent source of enjoyment, how sources of visual enjoyment may have changed through eye disease or aging, and experiences with eye care providers regarding visual enjoyment. Transcriptions were analysed using qualitative content analysis.ResultsAlmost all participants felt sources of visual enjoyment were important. Most could think of examples of visual enjoyment as distinct from visual function (e.g., appreciating leaf colour changes, stargazing), with a minority noting sources of enjoyment that either depended upon, or were facilitated by, good vision (e.g., playing golf, reading). Although around half believed the distinction between visual enjoyment and visual function was important, some were unclear whether there was a distinction or saw no distinction. Most felt that aging and vision loss with ocular disease had altered what they considered as sources of visual enjoyment. While direct experience of eye care practitioners considering personal sources of visual enjoyment when providing advice was mostly lacking, many respondents felt visual enjoyment would be important or beneficial to consider.ConclusionsSources of visual enjoyment are important to most people with and without vision loss. These results suggest that some patients may value having their personal sources of visual enjoyment considered by eye care providers.