Molecular genetics and emerging therapies for retinitis pigmentosa: Basic research and clinical perspectives
Graphical abstract
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.
References (270)
- et al.
Rod-derived cone viability factor promotes cone survival by stimulating aerobic glycolysis
Cell
(2015) - et al.
Transplantation of embryonic and induced pluripotent stem cell-derived 3D retinal sheets into retinal degenerative mice
Stem Cell Rep.
(2014) - et al.
The cell stress machinery and retinal degeneration
FEBS Lett.
(2013) - et al.
In vivo CRISPR/Cas9 gene editing corrects retinal dystrophy in the S334ter-3 rat model of autosomal dominant retinitis pigmentosa
Mol. Ther.
(2016) - et al.
Safety and durability of effect of contralateral-eye administration of AAV2 gene therapy in patients with childhood-onset blindness caused by RPE65 mutations: a follow-on phase 1 trial
Lancet
(2016) - et al.
Reversal of blindness in animal models of leber congenital amaurosis using optimized AAV2-mediated gene transfer
Mol. Ther.
(2008) - et al.
The molecular basis of human retinal and vitreoretinal diseases
Prog. Retin Eye Res.
(2010) - et al.
Natural course of retinitis pigmentosa over a three-year interval
Am. J. Ophthalmol.
(1985) - et al.
Yearly rates of rod and cone functional loss in retinitis pigmentosa and cone-rod dystrophy
Ophthalmology
(1999) - et al.
Long-term follow-up of patients with retinitis pigmentosa receiving intraocular ciliary neurotrophic factor implants
Am. J. Ophthalmol.
(2016)
The spectrum of retinal dystrophies caused by mutations in the peripherin/RDS gene
Prog. Retin Eye Res.
Unravelling the genetics of inherited retinal dystrophies: past, present and future
Prog. Retin Eye Res.
In contrast to AAV-mediated Cntf expression, AAV-mediated Gdnf expression enhances gene replacement therapy in rodent models of retinal degeneration
Mol. Ther.
Using CRISPR-Cas9 to generate gene-corrected autologous iPSCs for the treatment of inherited retinal degeneration
Mol. Ther.
Effect of shape and coating of a subretinal prosthesis on its integration with the retina
Exp. Eye Res.
Restoration of vision with ectopic expression of human rod opsin
Curr. Biol.
Improved retinal function in a mouse model of dominant retinitis pigmentosa following AAV-delivered gene therapy
Mol. Ther.
Endoplasmic reticulum stress in human photoreceptor diseases
Brain Res.
Apoptosis: final common pathway of photoreceptor death in rd, rds, and rhodopsin mutant mice
Neuron
Valproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide-induced dopaminergic neurotoxicity
Neuroscience
Leber congenital amaurosis due to RPE65 mutations and its treatment with gene therapy
Prog. Retin Eye Res.
Cellular responses following retinal injuries and therapeutic approaches for neurodegenerative diseases
Prog. Retin Eye Res.
Inner limiting membrane barriers to AAV-mediated retinal transduction from the vitreous
Mol. Ther.
Gene therapy for inherited retinal degenerations
C R. Biol.
Mutations in the PDE6B gene in autosomal recessive retinitis pigmentosa
Genomics
Leber congenital amaurosis: genes, proteins and disease mechanisms
Prog. Retin Eye Res.
Virally delivered channelrhodopsin-2 safely and effectively restores visual function in multiple mouse models of blindness
Mol. Ther.
Valproic acid induces caspase 3-mediated apoptosis in microglial cells
Neuroscience
Topical dorzolamide for the treatment of cystoid macular edema in patients with retinitis pigmentosa
Am. J. Ophthalmol.
Rate of visual field loss in retinitis pigmentosa
Ophthalmology
Pharmacological approaches to retinitis pigmentosa: a laboratory perspective
Prog. Retin Eye Res.
Retinitis pigmentosa
Lancet
Gene therapy and transplantation in CNS repair: the visual system
Prog. Retin Eye Res.
Intravitreal injection of adeno-associated viral vectors results in the transduction of different types of retinal neurons in neonatal and adult rats: a comparison with lentiviral vectors
Mol. Cell Neurosci.
Prevalence of cystoid macular edema and stability in oct retinal thickness in eyes with retinitis pigmentosa during a 48-week lutein trial
Retina
The retinal ciliopathies
Ophthalmic Genet.
The effect of an intravitreal dexamethasone implant for cystoid macular edema in retinitis pigmentosa: a case report and literature review
Ophthalmic Surg. lasers imaging retina
Macular pigment and lutein supplementation in retinitis pigmentosa and Usher syndrome
Invest Ophthalmol. Vis. Sci.
Restoration of photoreceptor ultrastructure and function in retinal degeneration slow mice by gene therapy
Nat. Genet.
Novel adeno-associated virus serotypes efficiently transduce murine photoreceptors
J. Virol.
Intravitreal ranibizumab in the treatment of cystoid macular edema associated with retinitis pigmentosa
J. Ocul. Pharmacol. Ther.
Exchange of surface proteins impacts on viral vector cellular specificity and transduction characteristics: the retina as a model
Hum. Mol. Genet.
First-in-human trial of a novel suprachoroidal retinal prosthesis
PLoS One
Long-term effect of gene therapy on Leber's congenital amaurosis
N. Engl. J. Med.
Effect of gene therapy on visual function in Leber's congenital amaurosis
N. Engl. J. Med.
Precision medicine: genetic repair of retinitis pigmentosa in patient-derived stem cells
Sci. Rep.
In vivo analysis of disease-associated point mutations unveils profound differences in mRNA splicing of Peripherin-2 in rod and cone photoreceptors
PLoS Genet.
Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease
Proc. Natl. Acad. Sci. U. S. A.
A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa
Arch. Ophthalmol.
Clinical trial of lutein in patients with retinitis pigmentosa receiving vitamin A
Arch. Ophthalmol.
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