Drug delivery to retinal photoreceptors

Himawan, Erico; Ekström, Per; Buzgo, Matěj; Gaillard, Pieter J.; Stefánsson, Einar; Marigo, Valeria; Loftsson, Þorsteinn; Paquet-Durand, François

doi:10.1016/j.drudis.2019.03.004

Cited by 55 publications

(52 citation statements)

References 46 publications

(51 reference statements)

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“…In general, there are three possible delivery methods to reach the eye: systemic, topical, and local. Each of these methods have their advantages and disadvantages [192]. Systemic delivery is often accompanied by systemic side effects and drugs need to pass the blood–retinal barrier first to perform their function, but it is less invasive compared to intraocular injections.…”

Section: Discussion and Outlookmentioning

confidence: 99%

Balancing the Photoreceptor Proteome: Proteostasis Network Therapeutics for Inherited Retinal Disease

Faber

Roepman

2019

Genes

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The light sensing outer segments of photoreceptors (PRs) are renewed every ten days due to their high photoactivity, especially of the cones during daytime vision. This demands a tremendous amount of energy, as well as a high turnover of their main biosynthetic compounds, membranes, and proteins. Therefore, a refined proteostasis network (PN), regulating the protein balance, is crucial for PR viability. In many inherited retinal diseases (IRDs) this balance is disrupted leading to protein accumulation in the inner segment and eventually the death of PRs. Various studies have been focusing on therapeutically targeting the different branches of the PR PN to restore the protein balance and ultimately to treat inherited blindness. This review first describes the different branches of the PN in detail. Subsequently, insights are provided on how therapeutic compounds directed against the different PN branches might slow down or even arrest the appalling, progressive blinding conditions. These insights are supported by findings of PN modulators in other research disciplines.

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Section: Discussion and Outlookmentioning

confidence: 99%

Balancing the Photoreceptor Proteome: Proteostasis Network Therapeutics for Inherited Retinal Disease

Faber

Roepman

2019

Genes

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“…While the last ten years have seen an important development and the appearance of many innovative materials, designs, and technologies for retinal drug delivery, efficient and sustained drug delivery to the photoreceptors remains a major challenge. Importantly, each compound or therapeutic agent may require highly-adapted DDS, which additionally must comply with regulatory requirements from the medicinal drug and product authorities [93]. Therefore, future research into new treatments for IRD should take the retinal delivery problem into consideration as early as possible, and synchronize the compound and delivery system development.…”

Section: Delivery Of Compounds To the Retinal Photoreceptorsmentioning

confidence: 99%

“…Among the disadvantages of intraocular application are the patients´ discomfort, the need for qualified doctors to perform the injections, and the low (but cumulative) risk for intraocular inflammation [96]. Unfortunately, topical drug application is usually not possible because of the various barriers surrounding the eye and retina, and the alternating lipophilic and hydrophilic nature of these barriers, preventing most drugs from reaching the retina via this route [93].…”

Section: Delivery Of Compounds To the Retinal Photoreceptorsmentioning

confidence: 99%

The cGMP Pathway and Inherited Photoreceptor Degeneration: Targets, Compounds, and Biomarkers

Tolone

Belhadj

Rentsch

et al. 2019

Genes

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Photoreceptor physiology and pathophysiology is intricately linked to guanosine-3’,5’-cyclic monophosphate (cGMP)-signaling. Here, we discuss the importance of cGMP-signaling for the pathogenesis of hereditary retinal degeneration. Excessive accumulation of cGMP in photoreceptors is a common denominator in cell death caused by a variety of different gene mutations. The cGMP-dependent cell death pathway may be targeted for the treatment of inherited photoreceptor degeneration, using specifically designed and formulated inhibitory cGMP analogues. Moreover, cGMP-signaling and its down-stream targets may be exploited for the development of novel biomarkers that could facilitate monitoring of disease progression and reveal the response to treatment in future clinical trials. We then briefly present the importance of appropriate formulations for delivery to the retina, both for drug and biomarker applications. Finally, the review touches on important aspects of future clinical translation, highlighting the need for interdisciplinary cooperation of researchers from a diverse range of fields.

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“…Our group has previously applied ASO-mediated exon skipping to rescue kidney phenotypes in a mouse ciliopathy model (Ramsbottom et al, 2018). Delivery of ASO via systemic administration to the kidney appears effective in contrast to the brain and retinal tissues where blood-brain and blood-retinal barriers respectively cause reduction in delivery (Daneman & Prat, 2015;Himawan et al, 2019;Pardridge, 2002;Yu et al, 2007). In rodents, systemic administration of ASOs revealed greatest accumulation in kidney and liver (Geary, Norris, Yu, & Bennett, 2015;Zhao et al, 1998) and abundant proximal tubular uptake (Janssen et al, 2019;Oberbauer, Schreiner, & Meyer, 1995).…”

Section: Discussionmentioning

confidence: 99%

Update of genetic variants in CEP120 and CC2D2A -- with an emphasis on genotype-phenotype correlations, tissue specific transcripts and exploring mutation specific exon skipping therapies

Gil

Olinger

Ramsbottom

et al. 2020

Preprint

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Mutations in ciliary genes cause a spectrum of both overlapping and distinct clinical syndromes (ciliopathies). CEP120 and CC2D2A are paradigmatic examples for this genetic heterogeneity and pleiotropy as mutations in both cause Joubert syndrome but are also associated with skeletal ciliopathies and Meckel syndrome, respectively. The molecular basis for this phenotypical variability is not understood but basal exon skipping likely contributes to tolerance for deleterious mutations via preservation of the amount of expressed functional protein. Here we systematically review and annotate genetic variants described in CEP120and CC2D2A-associated disease and confirm more severe clinical presentations with biallelic truncating CC2D2A mutations. Combining in silico and ex vivo studies, we identify alternative basal exon skipping in the kidney, with possible relevance for organ-specific disease manifestations. Finally, we propose a multimodal approach to classify exons amenable to exon skipping and by mapping reported variants, 14 truncating mutations in 7 CC2D2A exons were identified as potentially rescuable by targeted exon skipping, an approach that is already in clinical use for other inherited human diseases. We conclude that genotype-phenotype correlations for CC2D2A support the deleteriousness of null alleles and that CC2D2A, but not CEP120, offers potential for therapeutic exon skipping approaches.

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Drug delivery to retinal photoreceptors

Abstract: Highlights Routes of administration to retinal photoreceptors. The blood–retinal barrier as a challenge for photoreceptor drug delivery. Review of nanoparticle drug delivery systems used for intraocular applications. Perspectives for topical drug delivery to the retina.

Cited by 55 publications

References 46 publications

Balancing the Photoreceptor Proteome: Proteostasis Network Therapeutics for Inherited Retinal Disease

Balancing the Photoreceptor Proteome: Proteostasis Network Therapeutics for Inherited Retinal Disease

The cGMP Pathway and Inherited Photoreceptor Degeneration: Targets, Compounds, and Biomarkers

Update of genetic variants in CEP120 and CC2D2A -- with an emphasis on genotype-phenotype correlations, tissue specific transcripts and exploring mutation specific exon skipping therapies

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