The U4 small nuclear RNA (snRNA) forms a duplex with the U6 snRNA and, together with U5 and ∼30 proteins, is part of the U4/U6.U5 tri-snRNP complex, located at the core of the major spliceosome. Recently, recurrent de novo variants in the U4 RNA, transcribed from the RNU4-2 gene, and in at least two other RNU genes were discovered to cause neurodevelopmental disorder. We detected inherited and de novo heterozygous variants in RNU4-2 (n.18_19insA and n.56T>C) and in four out of the five RNU6 paralogues (n.55_56insG and n.56_57insG) in 135 individuals from 62 families with non-syndromic retinitis pigmentosa (RP), a rare form of hereditary blindness. We show that these variants are recurrent among RP families and invariably cluster in close proximity within the three-way junction (between stem-I, the 5’ stem-loop and stem-II) of the U4/U6 duplex, affecting its natural conformation. Interestingly, this region binds to numerous splicing factors of the tri-snRNP complex including PRPF3, PRPF8 and PRPF31, previously associated with RP as well. The U4 and U6 variants identified seem to affect snRNP biogenesis, namely the U4/U6 di-snRNP, which is an assembly intermediate of the tri-snRNP. Based on the number of positive cases observed, deleterious variants in RNU4-2 and in RNU6 paralogues could be a significant cause of isolated or dominant RP, accounting for up to 1.2% of all undiagnosed RP cases. This study highlights the role of non-coding genes in rare Mendelian disorders and uncovers pleiotropy in RNU4-2 , where different variants underlie neurodevelopmental disorder and RP.

Resort to medications dates back million years ago with the use of medicinal plants. In the nineteenth century, significant contributions in medicine appeared in different domains, among which the invention of a specific drug delivery device; the syringe. Nowadays, injection therapy of bio-manufactured drugs is routine practice for chronic diseases but remains constraining and painful. New emerging advanced therapies invest in genetic, electronics and cell-based therapy for addressing unmet needs for the caregivers and the patient. As digital process in health (eHealth) gains momentum, connected advanced bio-electronic devices now offer new strategies for personalized injection therapies. In this review, we take a journey along the genesis path of a new drug delivery system: the Optogenerapy, a synergy between optogenetic and gene therapy. Inside a bio-electronic implant, electronics and optogenetics are interfaced by light as a traceless inducer signal. By controlling a synthetic optogenetic pathway in the cell, therapeutics delivery can be fine-tuned with a precise spatiotemporal control. The technology holds promise of a new modern syringe era capable of producing a drug of interest at will directly inside the patient.

In the framework of the UK 100 000 Genomes Project, we investigated the genetic origin of a previously undescribed recessive dermatological condition, which we named LIPHAK (LTV1-associated Inflammatory Poikiloderma with Hair abnormalities and Acral Keratoses), in four affected individuals from two UK families of Pakistani and Indian origins, respectively. Our analysis showed that only one gene, LTV1, carried rare biallelic variants that were shared in all affected individuals, and specifically they bore the NM_032860.5:c.503A > G, p.(Asn168Ser) change, found homozygously in all of them. In addition, high-resolution homozygosity mapping revealed the presence of a small 652-kb stretch on chromosome 6, encompassing LTV1, that was haploidentical and common to all affected individuals. The c.503A > G variant was predicted by in silico tools to affect the correct splicing of LTV1’s exon 5. Minigene-driven splicing assays in HEK293T cells and in a skin sample from one of the patients confirmed that this variant was indeed responsible for the creation of a new donor splice site, resulting in aberrant splicing and in a premature termination codon in exon 6 of this gene. LTV1 encodes one of the ribosome biogenesis factors that promote the assembly of the small (40S) ribosomal subunit. In yeast, defects in LTV1 alter the export of nascent ribosomal subunits to the cytoplasm; however, the role of this gene in human pathology is unknown to date. Our data suggest that LIPHAK could be a previously unrecognized ribosomopathy.

Wireless powered optogenetic cell-based implant provides a strategy to deliver subcutaneously therapeutic proteins. Immortalize Human Mesenchymal Stem Cells (hMSC-TERT) expressing the bacteriophytochrome diguanylate cyclase (DGCL) were validated for optogenetic controlled interferon-β delivery (Optoferon cells) in a bioelectronic cell-based implant. Optoferon cells transcriptomic profiling was used to elaborate an in-silico model of the recombinant interferon-β production. Wireless optoelectronic device integration was developed using additive manufacturing and injection molding. Implant cell-based optoelectronic interface manufacturing was established to integrate industrial flexible compact low-resistance screen-printed Near Field Communication (NFC) coil antenna. Optogenetic cell-based implant biocompatibility, and device performances were evaluated in the Experimental Autoimmune Encephalomyelitis (EAE) mouse model of multiple sclerosis.

Background Current first-line disease-modifying therapies (DMT) for multiple sclerosis (MS) patients are injectable or oral treatments. The Optogenerapy consortium is developing a novel bioelectronic cell-based implant for controlled release of beta-interferon (IFNβ1a) protein into the body. The current study estimated the potential cost effectiveness of the Optogenerapy implant (hereafter: Optoferon) compared with injectable IFNβ1a (Avonex). Methods A Markov model simulating the costs and effects of Optoferon compared with injectable 30 mg IFNβ1a over a 9-year time horizon from a Dutch societal perspective. Costs were reported in 2019 Euros and discounted at a 4% annual rate; health effects were discounted at a 1.5% annual rate. The cohort consisted of 35-year-old, relapsing–remitting MS patients with mild disability. The device is implanted in a daycare setting, and is replaced every 3 years. In the base-case analysis, we assumed equal input parameters for Optoferon and Avonex regarding disability progression, health effects, adverse event probabilities, and acquisition costs. We assumed reduced annual relapse rates and withdrawal rates for Optoferon compared with Avonex. Sensitivity, scenario, value of information, and headroom analysis were performed. Results Optoferon was the dominant strategy with cost reductions (− €26,966) and health gains (0.45 quality-adjusted life-years gained). A main driver of cost differences are the acquisition costs of Optoferon being 2.5 times less than the costs of Avonex. The incremental cost-effectiveness ratio was most sensitive to variations in the annual acquisition costs of Avonex, the annual withdrawal rate of Avonex and Optoferon, and the disability progression of Avonex. Conclusion Innovative technology such as the Optoferon implant may be a cost-effective therapy for patients with MS. The novel implantable mode of therapeutic protein administration has the potential to become a new mode of treatment administration for MS patients and in other disease areas. However, trials are needed to establish safety and effectiveness.