Gene Therapy for Retinitis Pigmentosa: Current Challenges and New Progress

Biomolecules, Год журнала: 2024, Номер 14(8), С. 903 - 903

Опубликована: Июль 25, 2024

Retinitis pigmentosa (RP) poses a significant threat to eye health worldwide, with prevalence rates of 1 in 5000 worldwide. This genetically diverse retinopathy is characterized by the loss photoreceptor cells and atrophy retinal pigment epithelium. Despite involvement more than 3000 mutations across approximately 90 genes its onset, finding an effective treatment has been challenging for considerable time. However, advancements scientific research, especially gene therapy, are significantly expanding options this most prevalent inherited disease, discovery new compounds, gene-editing techniques, loci offering hope treatments. Gene promising technology, utilizes viral or non-viral vectors correct genetic defects either replacing silencing disease-causing genes, potentially leading complete recovery. In review, we primarily focus on latest applications editing research RP. We delve into associated RP discuss genome-editing strategies currently employed various mutations.

Язык: Английский

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Modeling sacsin depletion in Danio Rerio offers new insight on retinal defects in ARSACS

Neurobiology of Disease, Год журнала: 2025, Номер unknown, С. 106793 - 106793

Опубликована: Янв. 1, 2025

Biallelic mutations in the SACS gene, encoding sacsin, cause early-onset autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a neurodegenerative disease also characterized by unique and poorly understood retinal abnormalities. While two murine models replicate phenotypic neuronal features observed patients, no phenotype has been described so far. In zebrafish knock-out strain that faithfully mirrors main aspects ARSACS, we impaired visual function due to photoreceptor degeneration, likely caused cell cycle defects progenitor cells. RNA-seq analysis embryos revealed dysfunction proteins related fat-soluble vitamins (e.g., TTPA, RDH5, VKORC) suggested key role neuroinflammation driving defects. Our findings indicate studying pathology ARSACS could be crucial for understanding impact sacsin depletion may offer insights into halting progression.

Язык: Английский

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A Y178C rhodopsin mutation causes aggregation and comparatively severe retinal degeneration

Cell Death Discovery, Год журнала: 2025, Номер 11(1)

Опубликована: Янв. 29, 2025

Abstract Rhodopsin is the light-activated G protein-coupled receptor that initiates vision in photoreceptor cells of retina. Numerous mutations rhodopsin promote misfolding and aggregation, causing autosomal dominant retinitis pigmentosa, a progressive retinal degenerative disease. The mechanism by which these cause cell death, role aggregation plays this process still unclear. We recently demonstrated with P23H G188R mutants severity observed vitro also reflected vivo impacts rate degeneration. A Y178C mutant was investigated here to determine if relationship applies broadly among receptor. In characterization indicated exhibits similar properties more severely aggregating mutant, where mislocalized endoplasmic reticulum HEK293 form aggregates cannot be rescued treatment retinoid 9- cis retinal. Despite similarities vitro, promoted severe degeneration compared mice. Aggregates labeled dye PROTEOSTAT were morphologically those formed both mutants. There was, however, significantly greater death occurring independently PROTEOSTAT-labeled mice expressing either or Here, we demonstrate are not sole mutation vivo, there may alternate aggregate forms contributing

Язык: Английский

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Female sex hormones exacerbate retinal neurodegeneration

Science Advances, Год журнала: 2025, Номер 11(15)

Опубликована: Апрель 11, 2025

Neurodegenerative disorders such as Alzheimer’s disease and macular degeneration represent major sources of human suffering, yet factors influencing severity remain poorly understood. Sex has been implicated one modifying factor. Here, we show that female sex is a risk factor for worsened outcomes in model retinal this susceptibility caused by the presence female-specific hormones. The adverse effect hormones was specific to diseased neurons, depletion these ameliorated phenotypic effect, while reintroduction rates females. Transcriptional analysis retinas showed significant differences between genes involved pyroptosis, inflammatory responses, endoplasmic reticulum stress–induced apoptosis males females with degeneration. These findings provide crucial insights into pathogenesis neurodegenerative diseases how can affect severity. have far-reaching implications clinical trial design use hormonal therapy certain disorders.

Язык: Английский

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Mutant mice with rod-specific VPS35 deletion exhibit retinal α-synuclein pathology-associated degeneration

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Июль 23, 2024

Abstract Vacuolar protein sorting 35 (VPS35), the core component of retromer complex which regulates endosomal trafficking, is genetically linked with Parkinson’s disease (PD). Impaired vision a common non-motor manifestation PD. Here, we show mouse retinas VPS35-deficient rods exhibit synapse loss and visual deficit, followed by progressive degeneration concomitant emergence Lewy body-like inclusions phospho-α-synuclein (P-αSyn) aggregation. Ultrastructural analyses reveal accumulate aggregates in late endosomes, deposited as lipofuscins bound to P-αSyn. Mechanistically, uncover network VPS35 its interaction HSC70. deficiency promotes sequestration HSC70 P-αSyn aggregation endosomes. Microglia engulf are activated, displaying autofluorescence, observed bright dots fundus imaging live animals, coinciding pathology onset progression. The Rod ∆ Vps35 line valuable tool for further mechanistic investigation αSyn lesions retinal degenerative diseases.

Язык: Английский

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Autosomal dominant Retinitis Pigmentosa caused by the rhodopsin isoleucine 255 deletion features rapid neuroretinal degeneration, decreased synaptic connectivity, and neuroinflammation.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 30, 2024

Abstract Retinitis Pigmentosa (RP) is a group of inherited retinal diseases that initially affects rod photoreceptors and causes progressive vision loss blindness. Mutations in rhodopsin ( RHO ) can cause both autosomal recessive (ar) dominant (ad) forms RP, yet, the underlying degenerative mechanisms remain largely unknown, rendering disease untreatable. Here, we focus on an in-frame, 3-base pair deletion, eliminating isoleucine residue at codon 255 i.e., ΔI255 resulting adRP. We generated novel knock-in mouse homologous to human mutation. This new model displays severe disruption photoreceptor structure function, as seen patients. Our results indicate this form RP systems neuroretina also impacts neuronal connectivity bipolar- horizontal cells, initiates neuroinflammation, reduces structural functional integrity retina. Typical for adRP, Rho mice exhibit primary loss, followed by secondary cone degeneration, protein (RHO) mislocalization, shortening outer segments (OS), disorganized OS structures. Subsequently, increasing gliosis, morphologic abnormalities inner retina, impaired cone-driven visual function developed. In single mutated allele sufficient disease, confirmed here ΔI255/+ heterozygous animals, where most were lost within two months after birth. Compared this, homozygous ΔI255/ΔI255 mutants accelerated onset even faster progression degeneration. The degeneration -mutant was linked activation caspase- calpain-type proteases, well poly(ADP-ribose) polymerase (PARP), indicating parallel execution apoptotic non-apoptotic processes. conclusion, our data beyond cell sharing features typical other central nervous diseases, insight, which may bear critical impact understand eventually develop treatment these currently untreatable Author summary Dominant mutations gene are among common blinding retinitis pigmentosa (RP). To date, pathophysiological still unknown remains introduce carrying Δ I255 As humans, suffers from rapid subsequent death complete function. sign neuroinflammation concomitant mechanisms. These will likely stimulate further studies into processes governing facilitate future therapy development day.

Язык: Английский

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In vitro high-content screening reveals miR-429 as a protective molecule in photoreceptor degeneration

Molecular Therapy — Nucleic Acids, Год журнала: 2024, Номер 36(1), С. 102434 - 102434

Опубликована: Дек. 22, 2024

Inherited retinal diseases (IRDs) are clinically and genetically heterogeneous disorders characterized by progressive photoreceptor degeneration irreversible vision loss. MicroRNAs (miRNAs), a class of endogenous non-coding RNAs with post-transcriptional regulatory properties, known to play major role in function, both physiological pathological conditions. Given their ability simultaneously modulate multiple molecular pathways, miRNAs represent promising therapeutic tools for high genetic heterogeneity, such as IRDs. In the present study, we performed high-content imaging (HCI) screening assess impact miRNA overexpression on cell line undergoing light-induced degeneration. More than 1,200 were assayed putative protective effects light-stressed 661W photoreceptor-like cells, top-performing further validated independent vitro assays. miR-429 showed strongest cell-protective effect vitro. Adeno-associated viral vector-mediated subretinal delivery Rho P23H/+ IRD mouse model preserved electrophysiological responses was associated reduced inflammatory processes retina. We demonstrate that HCI assay devised is reliable method select candidate molecules mutation-independent approaches disorders. Moreover, our data indicate represents potential target against

Язык: Английский

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ER Aggregation Causes Synaptic Protein Imbalance in Retinitis Pigmentosa Mutant Photoreceptor Neurons

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Окт. 22, 2024

Abstract Rod photoreceptor neurons in the retina detect scotopic light by packaging large quantities of visual pigment protein rhodopsin (Rho) into stacked membrane discs within their outer segments (OS). Efficient Rho trafficking to OS through inner rod compartments is critical for long-term health since diseases like retinitis pigmentosa (RP) induce mislocalization these compartments, including presynaptic terminals (i.e., “spherules”). Given importance OS, less known about synaptic proteins that maintain synapses between rods and neurons. Furthermore, subcellular impact on spherules has not been investigated. In this study we used super-resolution electron microscopies, along with proteomic measurements proteins, perform an intensive analysis P23H-Rho-RFP RP mutant mice both sexes. We discovered mislocalized distinct ER aggregations spherule cytoplasm which confirmed wild type (WT) overexpressing P23H-Rho-RFP. Additionally, found significant abundance differences Dystrophin, BASSOON, ELFN1 other mice. By comparison, plasma WT rd10 rods, there was no disruption. Throughout study, also identified a network membranes spherules. Together, our findings establish previously uncharacterized ER-based secretory system mediates normal turnover at mouse synapses. Significance Statement retina, essential vision; however, form downstream retinal Stressors inherited cause widespread terminals. This examines region caused P23H-Rho mutation contexts. Mutant fusion endoplasmic reticulum (ER) aggregation disrupted rod-specific levels, combined detection endogenous supports disease-relevant mechanism

Язык: Английский

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