Molecular genetics and emerging therapies for retinitis pigmentosa: Basic research and clinical perspectives

https://doi.org/10.1016/j.preteyeres.2017.10.004Get rights and content

Highlights

  • Diverse genetic pathophysiology in retinitis pigmentosa.

  • Gene therapy as the most promising, molecular therapy for retinitis pigmentosa.

  • Emerging technologies such as gene editing for retinitis pigmentosa therapy.

Abstract

Retinitis Pigmentosa (RP) is a hereditary retinopathy that affects about 2.5 million people worldwide. It is characterized with progressive loss of rods and cones and causes severe visual dysfunction and eventual blindness in bilateral eyes. In addition to more than 3000 genetic mutations from about 70 genes, a wide genetic overlap with other types of retinal dystrophies has been reported with RP. This diversity of genetic pathophysiology makes treatment extremely challenging. Although therapeutic attempts have been made using various pharmacologic agents (neurotrophic factors, antioxidants, and anti-apoptotic agents), most are not targeted to the fundamental cause of RP, and their clinical efficacy has not been clearly proven. Current therapies for RP in ongoing or completed clinical trials include gene therapy, cell therapy, and retinal prostheses. Gene therapy, a strategy to correct the genetic defects using viral or non-viral vectors, has the potential to achieve definitive treatment by replacing or silencing a causative gene. Among many clinical trials of gene therapy for hereditary retinal diseases, a phase 3 clinical trial of voretigene neparvovec (AAV2-hRPE65v2, Luxturna) recently showed significant efficacy for RPE65-mediated inherited retinal dystrophy including Leber congenital amaurosis and RP. It is about to be approved as the first ocular gene therapy biologic product. Despite current limitations such as limited target genes and indicated patients, modest efficacy, and the invasive administration method, development in gene editing technology and novel gene delivery carriers make gene therapy a promising therapeutic modality for RP and other hereditary retinal dystrophies in the future.

Introduction

Retinal cells are interconnected neuronal cells forming the photosensitive tissue that lines the inner surface of the eye. These cells are responsible for the early stages of visual processing. Retinopathies and resultant retinal dysfunction are common causes of blindness (Jo et al., 2010). Hereditary retinopathy or hereditary retinal dystrophy is one of the blinding retinopathies, and it is characterized by slow and progressive degeneration of the retina (Coco et al., 2009). Most cases are due to mutations in a single gene, representing a significant cause of blindness. These mutations occur mainly in the photoreceptor cells (rods and cones) and, to a lesser extent, in the retinal pigment epithelium (RPE) cells (Trapani et al., 2014). The hereditary retinopathies are classified according to the genetic defect (when identified), the type of inheritance (autosomal dominant, autosomal recessive, or X-linked), the type of visual impairment, the rate of disease progression, and changes on the appearance of ocular fundus examination. Inherited retinal dystrophies can also be classified by the affected cells as: 1. rod-dominant abnormality (rod-cone dystrophy [retinitis pigmentosa]), 2. cone-dominant abnormality (cone or cone-rod dystrophy, achromatopsia), 3. macular dystrophy (Stargardt disease, Best macular dystrophy, Pattern dystrophy, Sorsby fundus dystrophy, etc.), 4. abnormality of photoreceptors and bipolar cells (X-linked retinoschisis, congenital stationary night blindness), 5. vitreoretinopathies (Wagner syndrome, Stickler syndrome, etc.), 6. hereditary choroidal diseases (choroideremia, central areolar choroidal atrophy, gyrate atrophy of the choroid and retina, etc.). Among the most frequent and severe forms of these retinopathies is retinitis pigmentosa (RP).

Each of these diseases has a different biochemical cause and mechanism. However, in all of them, the final common response is the morphological and functional damage of retinal cells including controlled cell death and tissue remodeling (Cuenca et al., 2014). The therapeutic use of pharmacological agents such as neuroprotective factors seems to be able to prevent further loss of photoreceptors and thereby reduce the rate of disease progression. However, the results of clinical trials of pharmacologic agents are still controversial and further studies are required. Cutting-edge treatments including gene therapy, cell transplantation (stem or retinal cells), and artificial retinal prosthesis have been researched through preclinical and clinical studies and have shown significant progress during the recent decade. Currently, two retinal prosthesis devices are commercially available, and one gene therapy product is about to be approved by FDA for hereditary retinal dystrophies. But there are still many challenges to overcome for these therapeutic devices/vectors, and the treatment of RP is still extremely challenging.

In this article, we review the genetic mechanisms, the current treatment methods focusing on clinical trial results, and future therapeutic strategies of RP. This review may be helpful for both clinicians and researchers to understand the current updated treatment for RP and their drawbacks. It can also provide insight for the development of future treatment technology for RP and hereditary retinal dystrophies.

Section snippets

Eye anatomy and physiology

The eye is an extremely specialized organ and has individual structures that work together to capture and process visual information. It can be divided into anterior and posterior segments. The anterior segment is formed by the cornea, conjunctiva, aqueous humor, iris, ciliary body, and lens. The posterior part consists of sclera, choroid, Bruch's membrane, RPE, neural retina, and vitreous. The most important cells that suffer from degeneration and atrophy in RP and other hereditary retinal

Clinical features of RP

For RP and allied diseases, a unified classification system has yet to be established amongst clinicians, cell biologists, and molecular geneticists. Clinically, RP is a retinal degenerative disease characterized by pigmented deposits called bone spicules, which are a result of a degeneration of the photoreceptors, predominantly in the peripheral retina. The RP is genetically and phenotypically heterogeneous (van Soest et al., 1999) with mutations affecting between 0.025 and 0.04% of the

Pharmacological approaches in the treatment for retinitis pigmentosa

There is no pharmacological therapy that has been clearly proven to prevent the development and progression of RP or to restore vision. Most pharmacological agents attempt to slow the progression of disease through neuroprotection and to conserve useful vision of the affected individuals during their lifetime (Jayakody et al., 2015). Such strategies do not correct the underlying causes of RP but aim to provide a supportive and conservative treatment. There are also ancillary treatments for

Challenges of current treatments according to disease stages

Finding an effective and safe therapy for RP is extremely challenging since this disease has great genetic heterogeneity, a wide variation of biological functions of the mutated proteins, and different molecular triggers for disease manifestations. Generally, therapeutic strategies for RP are chosen according to the disease stage of the individual patient (Fig. 9). As the more advanced the disease becomes, a lesser number of viable photoreceptors are present in the retina. The most effective

Declaration of interest

Se Joon Woo is a consultant of Samsung Bioepis Co., Suwon, South Korea and a founder of Retimark Co. Seoul, South Korea. The companies have no relationship with the contents of this paper.

Acknowledgment

MFD and YJK was financially supported by CNPq/Brazil (grant No. 401511/2014-6) and FAPEMIG/Brazil (grant No. APQ-01695-1; PPM-00456-17) for this work.

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