Retinitis Pigmentosa: Novel Therapeutic Targets and Drug Development
Abstract
:1. Introduction
2. Overview of Retinitis Pigmentosa
2.1. Clinical Manifestations
2.2. Classification
2.3. Management and Prognosis
3. Conventional Treatments and Limitations
3.1. Dietary Supplements (Vitamin A, DHA, Lutein) [11]
3.2. Cystoid Macular Edema (CME) Treatment
3.3. Protection from Sunlight
3.4. Visual Aids
3.5. Surgical Intervention
4. Recent Therapeutic Advances
5. Gene Therapy
5.1. Overview of Gene Therapy Methods
5.1.1. Viral Vectors
5.1.2. CRISPR-Cas Gene Editing System
5.1.3. RNA Replacement
5.2. Targeting Retinitis Pigmentosa Pathogenesis
Inheritance Mode | Genes | Preclinical Phase Studies |
---|---|---|
Autosomal Dominant Retinitis Pigmentosa | RHO | CRISPR-cas9-induced Rho mutation in Xenopus laevis tadpoles inhibits Müller glial cell proliferation [70]. T17M rhodopsin expression induces the upregulation of IL-1β, IL-6 and NFκB and the IB1A microglia markers in C57BL6 mice [71]. Proline substitution with leucine (P347L) in rhodopsin gene in transgenic rat strain induces rapid destruction of the outer nuclear layer, by CHOP and BiP activation [72]. Subretinal injection of fused zinc-finger to the KRAB domain in combination to a RHO cDNA driven by the GNAT1 promotor in pigs restores Rho gene expression and retinal function [73]. CRISPR-cas9 gene therapy in S334ter-3 rats increases visual acuity and retinal preservation [74]. AAV-miR-2014 delivery in RHO-P247S transgenic mice enhances retinal function [75] |
Nrl | CRISPR-Cas9 engineered NRL-deficient ESC retinal organoids exhibit an abnormal number of photoreceptors expressing S-Opsin [76]. AAV-delivered CRISPR-cas9 Nrl gene knockdown in RHO-P347S Rd10 mice prevents retinal degeneration [77]. | |
Nr2e3 | AAV-delivered CRISPR-cas9 Nr2e3 gene knockdown in Rd10 mice prevents retinal degeneration [78]. | |
PRPF | AAV-associated CRISPR-cas9 Prpf31 gene augmentation in mice restores retinal function [79]. | |
RP1 | Dual Cas9/sgRNA successfully reduces RP1 expression in edited Hap1-EF1a-RP1 cells [80]. | |
Autosomal Recessive Retinitis Pigmentosa | RHO | HEK293 and HT1080 human cells lines expressing E249ter or W161ter mutants exhibit lower rhodopsin mRNA levels [81]. |
RPGR | AAV-delivered CRISPR-cas9 restores RPGRORF15 reading frame in rd9 mice [82]. AAV-delivered CRISPR-cas9 restores photoreceptor preservation in Rpgr−/yCas9+/WT mice [83]. | |
CNGB1 | CNGB1 expression augmentation in Cngb1−/− mice using an AAV vector restores vision and delays retinal degeneration [84] (pp. 733–739). | |
TULP1 | Single-knockout (tulp1+/−) and double-knockout zebrafish models for the expression of Tulp1 significantly alters ciliogenesis through the downregulation of tektin2 [85]. AAV-mediated Tulp1 gene expression editing restores Tulp1 mRNA and protein levels [86]. | |
FAM161A | Fam161a knockout mice display retinal degeneration phenotype as well as enhanced molecular generative markers [87]. Homozygous Fam161a p.Arg512∗ have altered visual acuity due to complete loss of the outer nuclear layer and photoreceptor cell death [88]. |
5.2.1. Physiological Signaling Pathways of the Retina
5.2.2. Phototransduction
5.2.3. Photoreceptor Cell Death
5.3. Autosomal Dominant-Linked Mutations
5.3.1. Rhodopsin-Induced Autosomal Dominant Retinitis Pigmentosa
5.3.2. Non-Rhodopsin-Related Autosomal Dominant Mutations
5.4. Autosomal Recessive-Linked Mutations
5.4.1. Rhodopsin-Induced Autosomal Recessive Retinitis Pigmentosa
5.4.2. Non-Rhodopsin-Related Autosomal Recessive Mutations
5.5. Identification of Gene Targets Involved in Retinitis Pigmentosa for Novel Gene Therapy Treatments
6. Stem Cell Therapy
6.1. Various Models and Sources
6.1.1. Embryonic and Pluripotent Stem Cells
6.1.2. Bone Marrow Stem Cells Therapies
6.1.3. Therapies Based on Stem Cell-Derived RPE
6.1.4. Therapies Based on Retinal Progenitor Cells
7. Novel Therapeutic Targets in Preclinical Phase: Optogenetics
7.1. Microbial-Derived Opsins
7.2. Animal-Derived Opsins
8. Novel Therapeutic Targets in Preclinical Phase: Neuroprotective Agents
8.1. Neuroprotective Pathways
8.2. Neurotropic Factors
8.3. Anti-Apoptotic Agents
8.4. Antioxidant Agents
9. Novel Therapeutic Targets in Preclinical Phase: Exosomes
10. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Exosome Source | Models | Observed Effect |
---|---|---|
MSC-Exos | Hyaluronic acid-induced retinal detachment in Sprague–Dawley rat | Diminished TNFα and IL-β expression Enhancement of LC3-II and LC3-I ratio Decrease of Atg5 cleavage Decrease in photoreceptor cell apoptosis [228] |
Rd10 mice | Diminished TNFα, IL-β and IL-6 expression Enhanced photoreceptor cell survival Microglial, Müller cell and macrophage activation inhibition miR-146a upregulation [159,229] | |
N-methyl-N-nitrosourea (MNU)-induced retinal detachment in C57BL6 mice | Decrease in photoreceptor cell apoptosis miR-21 upregulation [232]. | |
RPE-Exos | N-methyl-N-nitrosourea (MNU)-induced retinal detachment in C57BL6 mice | Enhanced photoreceptor cell survival Diminished TNFα, IL-β and IL-6 mRNA expression Diminished Bax and caspase-3 mRNA expression Enhanced Bcl-2 mRNA expression [231]. |
Inflammatory cytokine-induced extracellular vesicle release in ARPE-19 cell line | T cell proliferation inhibition by TNFα and IL-6 production [227]. | |
NPC-Exos | Royal College of Surgeons rats | Decrease in photoreceptor cell apoptosis Inhibition of retinal microglia activation Diminished TNFα, IL-β and COX-2 expression [234]. |
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Wu, K.Y.; Kulbay, M.; Toameh, D.; Xu, A.Q.; Kalevar, A.; Tran, S.D. Retinitis Pigmentosa: Novel Therapeutic Targets and Drug Development. Pharmaceutics 2023, 15, 685. https://doi.org/10.3390/pharmaceutics15020685
Wu KY, Kulbay M, Toameh D, Xu AQ, Kalevar A, Tran SD. Retinitis Pigmentosa: Novel Therapeutic Targets and Drug Development. Pharmaceutics. 2023; 15(2):685. https://doi.org/10.3390/pharmaceutics15020685
Chicago/Turabian StyleWu, Kevin Y., Merve Kulbay, Dana Toameh, An Qi Xu, Ananda Kalevar, and Simon D. Tran. 2023. "Retinitis Pigmentosa: Novel Therapeutic Targets and Drug Development" Pharmaceutics 15, no. 2: 685. https://doi.org/10.3390/pharmaceutics15020685