網膜色素変性症

INTRODUCTION: Bardet-Biedl syndrome (BBS) is a rare genetic disease caused by primary ciliary dysfunction leading to retinal degeneration, rod-cone dystrophy, polydactyly, hyperphagia, early-onset obesity, renal dysfunction, hypogonadism, and learning difficulties. Hyperphagia, a pathological insatiable hunger leading to excessive and unusual food intake and persistent, obsessive food-seeking behaviours, is a frequent symptom associated with BBS. This study assessed hyperphagia severity in adults with BBS living in the UK, using a standard structured questionnaire accompanied by an in-depth semi-structured interview. METHODS: This non-interventional, cross-sectional study included 51 adults with BBS (49.0% males; 56.9% aged 18-34 years; mean [SD] body mass index [) BMI] of 36.5 [8.8] kg/m2 [range 21.8-59.6]). Participants were excluded if they were currently prescribed or had previously taken setmelanotide. Most were of White ethnicity (82.4%), and age at diagnosis ranged from birth to 50 years. Participants completed a 14-item hyperphagia questionnaire comprising multiple-choice and open-ended questions; a subset (n=15) participated in semi-structured interviews. Interview transcripts were coded systematically by a qualitative researcher and reviewed with a BBS clinical expert to assign severity ratings. Semi-structured interviews were designed to address known limitations of self-reporting in this population, including the disability paradox, stigma, and cognitive difficulties. RESULTS: Questionnaire data classified hyperphagia as severe in 5.9% (3/51) of participants, moderate in 45.1% (23/51), and mild in 49.0% (25/51), whereas semi-structured interviews classified hyperphagia as severe in 66.7% (10/15) participants, moderate in 26.7% (4/15), and mild in 6.7% (1/15). Notably, 86.7% (13/15) participants were assigned a higher severity level via interviews than questionnaires, while only two participants had the same classification across both methods. In a sub-analysis of participants with BMI ≥30 kg/m2 (n=39), semi-structured interviews classified hyperphagia as severe in 69.2% (9/13) and moderate in 30.8% (4/13); none were classified as mild hyperphagia. CONCLUSIONS: This study reveals a high prevalence of severe hyperphagia in adults with BBS based on semi-structured interviews and highlights substantial underreporting of hyperphagia severity when relying on self-reported questionnaires alone. The findings support incorporating semi-structured interviews as a mixed-method approach to provide a more comprehensive assessment of hyperphagia burden in adults with BBS.

The biological functions and mechanisms of many cell-type-specific transcriptional cofactors remain unclear. We previously identified Panky (Ankrd33) as a repressive transcriptional co-factor that suppresses Crx-mediated transactivation of photoreceptor genes; however, the biological function of Panky remains unclarified. Here, we investigated the functions of Panky and its paralog, Panky-like (Ankrd33b), in mice of either sex. Single knockout (KO) mouse retinas of Panky or Panky-like did not show significant alterations at both histological and functional levels compared to those of control mice. We then established and examined Panky and Panky-like double knockout (PPL DKO) mice. PPL DKO mice exhibited decreased light-evoked activities detected by electroretinogram (ERG), impaired cone photoreceptor morphology revealed by immunohistochemistry, and structural deformity of cone outer segments and synaptic terminals indicated by transmission electron microscopy (TEM), followed by cone death at a later stage. Lipidomics analysis revealed elevated ganglioside levels in PPL DKO retinas, consistent with the increased immunoreactivity of GT1b and GD3 in the outer segment layer. RNA-seq analysis was conducted in a cone-enriched context resulting from Nrl deficiency and showed that the Cerkl gene, whose mutations in humans cause retinitis pigmentosa (RP26), was upregulated in Panky/Panky-like/Nrl triple KO mice. Transcriptional assays showed that PPL suppressed Crx-mediated transactivation of Cerkl In addition, AAV-mediated Cerkl overexpression in the mouse retina induced significant photoreceptor cell death. Taken together, these findings suggest that the repressive Panky and Panky-like co-factors, which modulate Crx transcriptional activities and thus ganglioside levels in the mouse retina, are essential for cone photoreceptor structure and maintenance.Significance statement The retina is a light-sensing neural tissue in the eye. Photoreceptor cells (PRs) in the retina receive light stimuli. Rod PRs mediate dim-light vision, whereas cone PRs are responsible for bright and color vision. The present study identified that Panky and Panky-like genes are predominantly expressed in PRs in the mouse retina. Panky and Panky-like double-knockout mice exhibit impaired cone cell morphology, cone cell death, and visual dysfunction. In addition, gangliosides, which are chemically bonded lipids and sugars essential for cell membrane stability and function, accumulate in the photoreceptor layer. This study showed that Panky and Panky-like genes regulate ganglioside levels in the retina and play essential roles in the structure and maintenance of cone photoreceptor cells.

Inherited retinal diseases (IRDs) are often associated with signs of low-grade intraocular inflammation. With gene therapy-associated uveitis (GTAU) being recognized as a critical determinant of the efficacy of retinal gene therapies for IRDs, it is unclear whether such background inflammation might compound any immune response to viral vectors. We explored the immunological state of the retinas of Rpgr -/y mice as a model of slow-progressive retinitis pigmentosa (RP) and RhoP23H mice as a model of rapid-progressive RP utilizing multicolor flow cytometry. We subsequently assessed the cellular immune response to subretinal adeno-associated virus (AAV) gene therapy in these mouse models versus age-matched wild-type controls. RhoP23H mice exhibit increased immune cells within the retina, suggesting a degree of blood-retinal barrier breakdown, while Rpgr -/y retina remained immunologically quiescent. Subretinal gene augmentation therapy with clinically relevant AAV vectors resulted in a Th1 cell-mediated immune response in both models, but significantly greater immune cell infiltration was seen in RhoP23H retinas while the response in Rpgr -/y mirrored that of wild-type controls. Our findings indicate that background immunological changes in rapid retinal degeneration could compound the immune response to gene therapy, thus leading to clinically significant GTAU.

Blinding diseases due to the degeneration of photoreceptors (PhRs), such as geographic atrophy (GA) secondary to dry age-related macular degeneration and retinitis pigmentosa (RP), leave the rest of the retinal circuitry largely intact, albeit unable to respond to light. Gene therapy has been able to revert PhR degeneration, but it can be applied only to a rare mutation affecting a small subset of RP patients. Alternatively, implanted electronic retinal prostheses aim at a larger population by electrically stimulating surviving neurons. However, the treatment is invasive and costly and provides limited resolution. Photopharmacology can develop photoswitchable small molecules to restore vision impairment by conferring light sensitivity to ion channels that are widely expressed in the remaining inner retinal neurons, and a first-in-human clinical trial is ongoing. Here, we have developed novel photoswitchable small-molecule ligands of metabotropic glutamate 6 (mGlu6) receptors, which are located exclusively at the dendrites of ON bipolar cells (postsynaptic to PhRs) and can leverage a privileged position to mimic physiological signals in the remnant retinal circuit. These photoswitchable ligands (prosthe6) thus act as "molecular prostheses" that can restore the light input to the retina via upstream-targeted control of the circuit after PhR degeneration. Prosthe6 compounds are allosteric, drug-like, water-soluble, and display outstanding in vitro properties including full efficacy, nanomolar potency, fast deactivation in ambient white light, and fast reactivation in the dark. In vivo experiments show that they readily recover the saccadic eye movements of blinded zebrafish larvae and restore the innate light-avoidance behavior in the mouse models of blindness (GA and RP). These effects are mediated by mGlu6 receptors in vivo. In addition, at least two compounds (prosthe6-12 and -15) can restore sight by topical administration and display promising safety properties to become potential drug candidates for sight restoration in patients with degenerative blinding diseases.

Photobiomodulation (PBM) is a non-invasive therapeutic strategy that uses red and near-infrared (NIR) light in the 590-950 nm range to modulate the cellular and molecular pathways involved in retinal homeostasis. At the molecular level, PBM acts primarily through photon absorption by cytochrome c oxidase (CcO, complex IV of the mitochondrial electron transport chain), whose four metal centres-two copper (CuA and CuB) and two heme groups (heme a and heme a3)-absorb light across approximately 600-1000 nm. Photon capture promotes photodissociation of inhibitory nitric oxide (NO) from the binuclear CuB-heme a3 centre, accelerates electron transfer, restores the proton-motive force and increases ATP synthesis. These primary events trigger a coordinated molecular programme that includes (i) transient mitochondrial reactive oxygen species (ROS) bursts that activate the Nrf2/Keap1/ARE axis and upregulate phase II antioxidant enzymes (HO-1, NQO1, GCLC, SOD2, catalase, GPx); (ii) calcium- and cAMP-dependent secondary signalling that converges on PI3K/Akt, MAPK/ERK, AMPK and mTOR pathways; (iii) suppression of NF-κB-driven cytokine production (TNF-α, IL-1β, IL-6) and of NLRP3 inflammasome activation; (iv) downregulation of the HIF-1α/VEGF axis, particularly at 590 nm; (v) anti-apoptotic remodelling of the Bcl-2/Bax ratio with reduced cytochrome c release and caspase-3/9 activation; and (vi) PGC-1α/TFAM/NRF1-driven mitochondrial biogenesis, alongside restoration of fission/fusion homeostasis (Drp1, Mfn1/2, Opa1) and PINK1/Parkin-mediated mitophagy. Wavelength specificity has a defined molecular basis: 590 nm modulates VEGF signalling and RPE pump activity, 660 nm interacts with the CuB centre and enhances O2 binding at CcO, and 850 nm is absorbed by CuA and supports electron entry into complex IV. A second molecular axis is the bidirectional crosstalk between PBM and the circadian system: mitochondrial respiration, ATP turnover and CcO activity oscillate over the 24 h cycle under the control of the BMAL1/CLOCK and PER/CRY core machinery, the NAD+/SIRT1-SIRT3 axis and REV-ERBα. Preliminary preclinical and human observations suggest that NIR-induced bioenergetic and functional gains may be coupled to this rhythm, with greater benefit reported when light is delivered in the morning window (≈08:00-11:00); this time dependence should be regarded as an emerging hypothesis rather than an established clinical principle. The clinical evidence is unevenly developed across indications. It is most robust for non-exudative age-related macular degeneration, where multiwavelength PBM (590/660/850 nm; Valeda Light Delivery System) has shown disease-modifying potential in randomized controlled trials (LIGHTSITE I-III and the LIGHTSITE IIIB extension), with sustained BCVA gains and reduced incidence of geographic atrophy over 24 months and beyond. Evidence for retinitis pigmentosa, central serous chorioretinopathy and, with red-light monotherapy, childhood myopia is at present limited to small or short-term studies and remains preliminary. This narrative review synthesizes the molecular machinery engaged by PBM, integrates clinical findings across retinal diseases and discusses how chronotherapeutic delivery of light, aligned with the molecular clock, may further optimize therapeutic efficacy.