Novel Therapeutic Targets and Drug Development in Retinal Diseases

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (10 June 2023) | Viewed by 13794

Special Issue Editor


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Guest Editor
Institute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of Tübingen, 72076 Tübingen, Germany
Interests: photoreceptors; retinal degeneration; proteostasis; neuroprotection; drug delivery; animal models; organotypic cultures

Special Issue Information

Dear Colleagues,

Many ocular diseases caused by endogenous or exogenous insults lead to photoreceptor cell death, the ultimate cause of vision loss in various retinal diseases, which are currently not properly treated despite the increasing prevalence. The light-sensitive photoreceptor cells are terminally differentiated neurons that are not regenerated after degeneration or injury in adult mammals. The high heterogeneity of factors inducing photoreceptor degeneration hampers the development of effective therapeutic interventions. Several cellular and biochemical processes can contribute to photoreceptor death, including endoplasmic reticulum stress and unfolded protein response, oxidative stress, and inflammation, offering a vast repertoire of potential therapeutic targets.

This Special Issue entitled “Novel Therapeutic Targets and Drug Development in Retinal Diseases” will contribute to understanding disease mechanisms better, opening novel avenues for targeting photoreceptor degeneration and accelerating the development and characterization of compounds for preclinical studies as a starting point for advanced drug development.

Dr. Blanca Arango-Gonzalez
Guest Editor

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Keywords

  • therapeutic target
  • retinitis pigmentosa
  • retinal degeneration
  • photoreceptor cell death
  • oxidative stress
  • neuroprotection
  • inflammation
  • ER stress
  • AMD

Published Papers (3 papers)

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Research

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22 pages, 4137 KiB  
Article
Photochemical Restoration of Light Sensitivity in the Degenerated Canine Retina
by Sergei Nikonov, Natalia Dolgova, Raghavi Sudharsan, Ivan Tochitsky, Simone Iwabe, Jose-Manuel Guzman, Russell N. Van Gelder, Richard H. Kramer, Gustavo D. Aguirre and William A. Beltran
Pharmaceutics 2022, 14(12), 2711; https://doi.org/10.3390/pharmaceutics14122711 - 03 Dec 2022
Cited by 1 | Viewed by 1405
Abstract
Photopharmacological compounds such as azobenzene-based photoswitches have been shown to control the conductivity of ionic channels in a light-dependent manner and are considered a potential strategy to restore vision in patients with end-stage photoreceptor degeneration. Here, we report the effects of DENAQ, a [...] Read more.
Photopharmacological compounds such as azobenzene-based photoswitches have been shown to control the conductivity of ionic channels in a light-dependent manner and are considered a potential strategy to restore vision in patients with end-stage photoreceptor degeneration. Here, we report the effects of DENAQ, a second-generation azobenzene-based photoswitch on retinal ganglion cells (RGC) in canine retinas using multi-electrode array (MEA) recordings (from nine degenerated and six WT retinas). DENAQ treatment conferred increased light sensitivity to RGCs in degenerated canine retinas. RGC light responses were observed in degenerated retinas following ex vivo application of 1 mM DENAQ (n = 6) or after in vivo DENAQ injection (n = 3, 150 μL, 3–10 mM) using 455 nm light at intensities as low as 0.2 mW/cm2. The number of light-sensitive cells and the per cell response amplitude increased with light intensity up to the maximum tested intensity of 85 mW/cm2. Application of DENAQ to degenerated retinas with partially preserved cone function caused appearance of DENAQ-driven responses both in cone-driven and previously non-responsive RGCs, and disappearance of cone-driven responses. Repeated stimulation slowed activation and accelerated recovery of the DENAQ-driven responses. The latter is likely responsible for the delayed appearance of a response to 4 Hz flicker stimulation. Limited aqueous solubility of DENAQ results in focal drug aggregates associated with ocular toxicity. While this limits the therapeutic potential of DENAQ, more potent third-generation photoswitches may be more promising, especially when delivered in a slow-release formulation that prevents drug aggregation. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets and Drug Development in Retinal Diseases)
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Review

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50 pages, 4601 KiB  
Review
Recent Advances of Ocular Drug Delivery Systems: Prominence of Ocular Implants for Chronic Eye Diseases
by Mahmoud Mostafa, Adel Al Fatease, Raid G. Alany and Hamdy Abdelkader
Pharmaceutics 2023, 15(6), 1746; https://doi.org/10.3390/pharmaceutics15061746 - 15 Jun 2023
Cited by 4 | Viewed by 3785
Abstract
Chronic ocular diseases can seriously impact the eyes and could potentially result in blindness or serious vision loss. According to the most recent data from the WHO, there are more than 2 billion visually impaired people in the world. Therefore, it is pivotal [...] Read more.
Chronic ocular diseases can seriously impact the eyes and could potentially result in blindness or serious vision loss. According to the most recent data from the WHO, there are more than 2 billion visually impaired people in the world. Therefore, it is pivotal to develop more sophisticated, long-acting drug delivery systems/devices to treat chronic eye conditions. This review covers several drug delivery nanocarriers that can control chronic eye disorders non-invasively. However, most of the developed nanocarriers are still in preclinical or clinical stages. Long-acting drug delivery systems, such as inserts and implants, constitute the majority of the clinically used methods for the treatment of chronic eye diseases due to their steady state release, persistent therapeutic activity, and ability to bypass most ocular barriers. However, implants are considered invasive drug delivery technologies, especially those that are nonbiodegradable. Furthermore, in vitro characterization approaches, although useful, are limited in mimicking or truly representing the in vivo environment. This review focuses on long-acting drug delivery systems (LADDS), particularly implantable drug delivery systems (IDDS), their formulation, methods of characterization, and clinical application for the treatment of eye diseases. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets and Drug Development in Retinal Diseases)
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32 pages, 2469 KiB  
Review
Retinitis Pigmentosa: Novel Therapeutic Targets and Drug Development
by Kevin Y. Wu, Merve Kulbay, Dana Toameh, An Qi Xu, Ananda Kalevar and Simon D. Tran
Pharmaceutics 2023, 15(2), 685; https://doi.org/10.3390/pharmaceutics15020685 - 17 Feb 2023
Cited by 18 | Viewed by 7695
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets and Drug Development in Retinal Diseases)
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