Retinal Structure and Function in a Knock-in Mouse Model for the FAM161A-p.Arg523∗ Human Nonsense Pathogenic Variant

Matsevich, Chen; Gopalakrishnan, Prakadeeswari; Obolensky, Alexey; Banin, Eyal; Sharon, Dror; Beryozkin, Avigail

doi:10.1016/j.xops.2022.100229

Cited by 8 publications

(10 citation statements)

References 37 publications

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“…12 DISCUSSION Our previous study demonstrated improved retinal survival and preservation of retinal function in Fam161a tm1b/tm1b mice after gene transfer of the mouse Fam161a cDNA using AAV2/8-IRBP-GRK1 vector (19). In the present study, to translate this work into a FAM161A gene therapy for a future clinical application, we further examined the efficiency of AAV vectors to deliver the human FAM161A cDNA.…”

Section: Combined Fcbr1-f04-hs+fcbr1-f04-hl Administration Restores R...mentioning

confidence: 86%

“…We have previously shown that mFam161a expression of the longer isoform delivered by the AAV2/8-IRBP-GRK1 vector in the KO mouse retina preserves retinal structure and function (19). Here, we performed a similar study using the hFAM161A vectors.…”

Section: Aav2/8-irbp-grk1 Vectors Partially Preserve the Retina Integ...mentioning

confidence: 95%

“…After this validation, different vector constructs were generated to test gene transfer efficacy according to the promoter activity. In a previous study, the Interphotoreceptor Retinoid-Binding Protein enhancer combined with the G Protein-Coupled Receptor Kinase 1 promoter (IRBP-GRK1) drove efficient transgene expression in rod and cone photoreceptors but some ectopic FAM161A expression extending outside the CC was observed (19). Therefore, we reasoned that using the endogenous hFAM161A promoter in the vector design may better mimic the endogenous expression and would represent an asset for the gene augmentation strategy.…”

Section: Vector Designs For Photoreceptor Specific Expression Of Huma...mentioning

confidence: 99%

“…Seizing the opportunity of this mouse model which recapitulated human disease features with a relatively slow degenerative process (18), we investigated the possibility to restore the thin structure of the CC and tested different levels of gene expression to assess whether this CC formation necessitates critical control of FAM161A expression. In a previous study, the gene transfer of the long mouse Fam161a isoform under the control of the Interphotoreceptor Retinoid-Binding Protein enhancer combined with the G Protein-Coupled Receptor Kinase 1 promoter (IRBP-GRK1), showed efficient transgene expression in rod and cone photoreceptors leading to retina rescue and improved retinal function (19).…”

Section: Introductionmentioning

confidence: 99%

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Fine-tuning FAM161A gene augmentation therapy to restore retinal function

Arsenijevic,

Chang,

Mercey

et al. 2023

Preprint

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In 15 years, inherited retinal diseases have seen gene therapy as a springboard to hope. Many preclinical investigations focused on vectors with maximal gene expression capabilities. But despite an efficient gene transfer, little physiological improvement was noted for certain ciliopathies. FAM161A is an essential protein for the structure of photoreceptor connecting cilium (CC). In the absence of FAM161A, cilia disorganize resulting in outersegment collapses and vision impairment. Within the human retina,FAM161Aproduces two isoforms: the long with exon 4, and the short, lacking it. To restore CC inFam161a-deficient mice, we compared AAV vectors with different promoter activities, doses, and human isoforms injected subretinally in 14-daysFam161atm1b/tm1bmice, shortly after the onset of cilium disorganization. All vectors improved cell survival, but only combining both isoforms using the weak FCBR1-F0.4 promoter allowed precise FAM161A expression in the CC and enhanced retinal function.Our study onFAM161Agene replacement for RP28, a rod-cone-related disease, underscores the critical need for precise therapeutic gene regulation, appropriate vector dosing and delivery of both isoforms. Fine tuning of therapeutic gene expression, tailored to disease traits, is crucial for restoring retinal function. This precision is pivotal for secure gene therapy involving structural proteins like FAM161A.

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Section: Combined Fcbr1-f04-hs+fcbr1-f04-hl Administration Restores R...mentioning

confidence: 86%

Section: Aav2/8-irbp-grk1 Vectors Partially Preserve the Retina Integ...mentioning

confidence: 95%

Section: Vector Designs For Photoreceptor Specific Expression Of Huma...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Fine-tuning FAM161A gene augmentation therapy to restore retinal function

Arsenijevic,

Chang,

Mercey

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Recently, Beryozkin and his colleagues have successfully generated a knockout mice model for Fam161a deficiency; Fam161a knockout mice display retinal degeneration phenotype as well as enhanced molecular generative markers such as microglia [ 87 ]. Similarly, homozygous Fam161a p.Arg512∗ were shown to have altered visual acuity due to complete loss of the outer nuclear layer and photoreceptor cell death [ 88 ].…”

Section: Gene Therapymentioning

confidence: 99%

Retinitis Pigmentosa: Novel Therapeutic Targets and Drug Development

Kulbay

Toameh

et al. 2023

Pharmaceutics

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Retinitis pigmentosa (RP) is a heterogeneous group of hereditary diseases characterized by progressive degeneration of retinal photoreceptors leading to progressive visual decline. It is the most common type of inherited retinal dystrophy and has a high burden on both patients and society. This condition causes gradual loss of vision, with its typical manifestations including nyctalopia, concentric visual field loss, and ultimately bilateral central vision loss. It is one of the leading causes of visual disability and blindness in people under 60 years old and affects over 1.5 million people worldwide. There is currently no curative treatment for people with RP, and only a small group of patients with confirmed RPE65 mutations are eligible to receive the only gene therapy on the market: voretigene neparvovec. The current therapeutic armamentarium is limited to retinoids, vitamin A supplements, protection from sunlight, visual aids, and medical and surgical interventions to treat ophthalmic comorbidities, which only aim to slow down the progression of the disease. Considering such a limited therapeutic landscape, there is an urgent need for developing new and individualized therapeutic modalities targeting retinal degeneration. Although the heterogeneity of gene mutations involved in RP makes its target treatment development difficult, recent fundamental studies showed promising progress in elucidation of the photoreceptor degeneration mechanism. The discovery of novel molecule therapeutics that can selectively target specific receptors or specific pathways will serve as a solid foundation for advanced drug development. This article is a review of recent progress in novel treatment of RP focusing on preclinical stage fundamental research on molecular targets, which will serve as a starting point for advanced drug development. We will review the alterations in the molecular pathways involved in the development of RP, mainly those regarding endoplasmic reticulum (ER) stress and apoptotic pathways, maintenance of the redox balance, and genomic stability. We will then discuss the therapeutic approaches under development, such as gene and cell therapy, as well as the recent literature identifying novel potential drug targets for RP.

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Retinal Microenvironment‐Protected Rhein‐GFFYE Nanofibers Attenuate Retinal Ischemia‐Reperfusion Injury via Inhibiting Oxidative Stress and Regulating Microglial/Macrophage M1/M2 Polarization

Zhang,

Peng,

et al. 2023

Advanced Science

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Retinal ischemia is involved in the occurrence and development of various eye diseases, including glaucoma, diabetic retinopathy, and central retinal artery occlusion. To the best of our knowledge, few studies have reported self‐assembling peptide natural products for the suppression of ocular inflammation and oxidative stress. Herein, a self‐assembling peptide GFFYE is designed and synthesized, which can transform the non‐hydrophilicity of rhein into an amphiphilic sustained‐release therapeutic agent, and rhein‐based therapeutic nanofibers (abbreviated as Rh‐GFFYE) are constructed for the treatment of retinal ischemia‐reperfusion (RIR) injury. Rh‐GFFYE significantly ameliorates oxidative stress and inflammation in an in vitro oxygen‐glucose deprivation (OGD) model of retinal ischemia and a rat model of RIR injury. Rh‐GFFYE also significantly enhances retinal electrophysiological recovery and exhibits good biocompatibility. Importantly, Rh‐GFFYE also promotes the transition of M1‐type macrophages to the M2 type, ultimately altering the pro‐inflammatory microenvironment. Further investigation of the treatment mechanism indicates that Rh‐GFFYE activates the PI3K/AKT/mTOR signaling pathway to reduce oxidative stress and inhibits the NF‐κB and STAT3 signaling pathways to affect inflammation and macrophage polarization. In conclusion, the rhein‐loaded nanoplatform alleviates RIR injury by modulating the retinal microenvironment. The findings are expected to promote the clinical application of hydrophobic natural products in RIR injury‐associated eye diseases.

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Retinal Structure and Function in a Knock-in Mouse Model for the FAM161A-p.Arg523∗ Human Nonsense Pathogenic Variant

Cited by 8 publications

References 37 publications

Fine-tuning FAM161A gene augmentation therapy to restore retinal function

Fine-tuning FAM161A gene augmentation therapy to restore retinal function

Retinitis Pigmentosa: Novel Therapeutic Targets and Drug Development

Retinal Microenvironment‐Protected Rhein‐GFFYE Nanofibers Attenuate Retinal Ischemia‐Reperfusion Injury via Inhibiting Oxidative Stress and Regulating Microglial/Macrophage M1/M2 Polarization

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