Eupatilin Improves Cilia Defects in Human CEP290 Ciliopathy Models

The photoreceptor outer segment is a highly specialized primary cilium that is essential for phototransduction and vision. Biallelic pathogenic variants in the cilia-associated gene CEP290 cause non-syndromic Leber congenital amaurosis 10 (LCA10) and syndromic diseases, where the retina is also affected. While RNA antisense oligonucleotides and gene editing are potential treatment options for the common deep intronic variant c.2991+1655A>G in CEP290, there is a need for variant-independent approaches that could be applied to a broader spectrum of ciliopathies. Here, we generated several distinct human models of CEP290-related retinal disease and investigated the effects of the flavonoid eupatilin as a potential treatment. Eupatilin improved cilium formation and length in CEP290 LCA10 patient-derived fibroblasts, in gene-edited CEP290 knockout (CEP290 KO) RPE1 cells, and in both CEP290 LCA10 and CEP290 KO iPSCs-derived retinal organoids. Furthermore, eupatilin reduced rhodopsin retention in the outer nuclear layer of CEP290 LCA10 retinal organoids. Eupatilin altered gene transcription in retinal organoids by modulating the expression of rhodopsin and by targeting cilia and synaptic plasticity pathways. This work sheds light on the mechanism of action of eupatilin and supports its potential as a variant-independent approach for CEP290-associated ciliopathies

Antibody levels following vaccination against SARS-CoV-2: associations with post-vaccination infection and risk factors

SARS-CoV-2 antibody levels can be used to assess humoral immune responses following SARS-CoV-2 infection or vaccination, and may predict risk of future infection. From cross-sectional antibody testing of 9,361 individuals from TwinsUK and ALSPAC UK population-based longitudinal studies (jointly in April-May 2021, and TwinsUK only in November 2021-January 2022), we tested associations between antibody levels following vaccination and: (1) SARS-CoV-2 infection following vaccination(s); (2) health, socio-demographic, SARS-CoV-2 infection and SARS-CoV-2 vaccination variables. Within TwinsUK, single-vaccinated individuals with the lowest 20% of anti-Spike antibody levels at initial testing had 3-fold greater odds of SARS-CoV-2 infection over the next six to nine months, compared to the top 20%. In TwinsUK and ALSPAC, individuals identified as at increased risk of COVID-19 complication through the UK "Shielded Patient List" had consistently greater odds (2 to 4-fold) of having antibody levels in the lowest 10%. Third vaccination increased absolute antibody levels for almost all individuals, and reduced relative disparities compared with earlier vaccinations. These findings quantify the association between antibody level and risk of subsequent infection, and support a policy of triple vaccination for the generation of protective antibodies

Delineating the expanding phenotype associated with SCAPER gene mutation

This letter is freely available via Open Access. Click on the Publisher URL to access the full-text via the publisher's site

Eupatilin Improves Cilia Defects in Human CEP290 Ciliopathy Models

The photoreceptor outer segment is a highly specialized primary cilium that is essential for phototransduction and vision. Biallelic pathogenic variants in the cilia-associated gene CEP290 cause non-syndromic Leber congenital amaurosis 10 (LCA10) and syndromic diseases, where the retina is also affected. While RNA antisense oligonucleotides and gene editing are potential treatment options for the common deep intronic variant c.2991+1655A>G in CEP290, there is a need for variant-independent approaches that could be applied to a broader spectrum of ciliopathies. Here, we generated several distinct human models of CEP290-related retinal disease and investigated the effects of the flavonoid eupatilin as a potential treatment. Eupatilin improved cilium formation and length in CEP290 LCA10 patient-derived fibroblasts, in gene-edited CEP290 knockout (CEP290 KO) RPE1 cells, and in both CEP290 LCA10 and CEP290 KO iPSCs-derived retinal organoids. Furthermore, eupatilin reduced rhodopsin retention in the outer nuclear layer of CEP290 LCA10 retinal organoids. Eupatilin altered gene transcription in retinal organoids by modulating the expression of rhodopsin and by targeting cilia and synaptic plasticity pathways. This work sheds light on the mechanism of action of eupatilin and supports its potential as a variant-independent approach for CEP290-associated ciliopathies

Metabolomic and gut microbiome profiles across the spectrum of community-based COVID and non-COVID disease

Abstract Whilst most individuals with SARS-CoV-2 infection have relatively mild disease, managed in the community, it was noted early in the pandemic that individuals with cardiovascular risk factors were more likely to experience severe acute disease, requiring hospitalisation. As the pandemic has progressed, increasing concern has also developed over long symptom duration in many individuals after SARS-CoV-2 infection, including among the majority who are managed acutely in the community. Risk factors for long symptom duration, including biological variables, are still poorly defined. Here, we examine post-illness metabolomic profiles, using nuclear magnetic resonance (Nightingale Health Oyj), and gut-microbiome profiles, using shotgun metagenomic sequencing (Illumina Inc), in 2561 community-dwelling participants with SARS-CoV-2. Illness duration ranged from asymptomatic (n = 307) to Post-COVID Syndrome (n = 180), and included participants with prolonged non-COVID-19 illnesses (n = 287). We also assess a pre-established metabolomic biomarker score, previously associated with hospitalisation for both acute pneumonia and severe acute COVID-19 illness, for its association with illness duration. We found an atherogenic-dyslipidaemic metabolic profile, including biomarkers such as fatty acids and cholesterol, was associated with longer duration of illness, both in individuals with and without SARS-CoV-2 infection. Greater values of a pre-existing metabolomic biomarker score also associated with longer duration of illness, regardless of SARS-CoV-2 infection. We found no association between illness duration and gut microbiome profiles in convalescence. This highlights the potential role of cardiometabolic dysfunction in relation to the experience of long duration symptoms after symptoms of acute infection, both COVID-19 as well as other illnesses