Ретинит пигментозный: генетика, мутации и механизмы развития.

Gradual retinal degeneration leading to progressive sight loss

Retinitis pigmentosa (RP) is one of the most common forms of inherited retinal degeneration. There are multiple genes that code for proteins needed in the visual pathway, when mutated, they can cause the retinitis pigmentosa phenotype. Inheritance patterns of RP have been identified as autosomal dominant, autosomal recessive, X linked, and maternally (mitochondrially) acquired, and are dependent on the specific RP gene mutations present in the parental generation. (Of note, Autosomal Dominant RP Type 11 (PRPF 31) can be inherited as a genotype only, because of incomplete penetrance, thus coded for in the DNA but, does not manifest the disease as a phenotype.) In 1989, a mutation of the gene for rhodopsin, a pigment that plays an essential part in the visual transduction cascade enabling vision in low light conditions, was identified. The rhodopsin gene encodes a principal protein of photoreceptor outer segments. Mutations in this gene most commonly presents as missense mutations or misfolding of the rhodopsin protein, and most frequently follow autosomal dominant inheritance patterns. Since the discovery of the rhodopsin gene, more than 100 RHO mutations have been identified, accounting for 15% of all types of retinal degeneration, and approximately 25% of autosomal dominant forms of RP. Over 100 mutations have been reported to date in the opsin gene associated with the RP since the Pro23His mutation in the intradiscal domain of the protein was first reported in 1990. These mutations are found throughout the opsin gene and are distributed along the three domains of the protein (the intradiscal, transmembrane, and cytoplasmic domains). One of the main biochemical causes of RP in the case of rhodopsin mutations is protein misfolding, and the disruption of molecular chaperones. It was found that the mutation of codon 23 in the rhodopsin gene, in which proline is changed to histidine, accounts for the largest fraction of rhodopsin mutations in the United States. Several other studies have reported various codon mutations associated with retinitis pigmentosa, including Thr58Arg, Pro347Leu, Pro347Ser, as well as deletion of Ile 255. In 2000, a rare mutation in codon 23 was reported causing autosomal dominant retinitis pigmentosa, in which proline changed to alanine. However, this study showed that the retinal dystrophy associated with this mutation was characteristically mild in presentation and course. Furthermore, there was greater preservation in electroretinography amplitudes than the more prevalent Pro23His mutation. Autosomal recessive inheritance patterns of RP have been identified in at least 45 genes. Mutations in four pre mRNA splicing factors are known to cause autosomal dominant retinitis pigmentosa. These are PRPF3 (human PRPF3 is HPRPF3; also PRP3), PRPF8, PRPF31 and PAP1. These factors are ubiquitously expressed and it is proposed that defects in a ubiquitous factor (a protein expressed everywhere) should only cause disease in the retina because the retinal photoreceptor cells have a far greater requirement for protein processing (rhodopsin) than any other cell type. The somatic, or X linked inheritance patterns of RP are currently identified with the mutations of six genes, the most common occurring at specific loci in the RPGR and RP2 genes. Additionally, animal models suggest that the retinal pigment epithelium fails to phagocytose the outer rod segment discs that have been shed, leading to an accumulation of outer rod segment debris. In mice that are homozygous recessive for retinal degeneration mutation, rod photoreceptors stop developing and undergo degeneration before cellular maturation completes. A defect in cGMP phosphodiesterase has also been documented; this leads to toxic levels of cGMP. Oxidative damage associated with lipid peroxidation is a potential cause of cone cell death in retinitis pigmentosa.

There is currently no cure for retinitis pigmentosa, but the efficacy and safety of various prospective treatments are currently being evaluated. The efficiency of various supplements, such as vitamin A, DHA, NAC, and lutein, in delaying disease progression remains an unresolved, yet prospective treatment option. Clinical trials investigating optic prosthetic devices, gene therapy mechanisms, and retinal sheet transplantations are active areas of study in the partial restoration of vision in retinitis pigmentosa patients.

Studies have demonstrated the delay of rod photoreceptor degeneration by the daily intake of 15000 IU (equivalent to 4.5 mg) of vitamin A palmitate; thus, stalling disease progression in some patients. Recent investigations have shown that proper vitamin A supplementation can postpone blindness by up to 10 years (by reducing the 10% loss pa to 8.3% pa) in some patients in certain stages of the disease.

MD Stem Cells, a clinical research company using autologous bone marrow derived stem cells (BMSC) in the treatment of retinal and optic nerve disease, published results from the Retinitis Pigmentosa cohort within their ongoing NIH registered Stem Cell Ophthalmology Study II (SCOTS2) clinical trial (NCT 03011541). Outcomes were encouraging with 45.5% of eyes showing an average of 7.9 lines of improvement (40.9% LogMAR improvement over baseline) and 45.5% of eyes showing stable acuity over the follow up. Results were statistically significant(p=0.016). Retinitis Pigmentosa continues to be treated and evaluated in the study.

The Argus retinal prosthesis became the first approved treatment for the disease in February 2011, and is currently available in Germany, France, Italy, and the UK. Interim results on 30 patients long term trials were published in 2012. The Argus II retinal implant has also received market approval in the US. The device may help adults with RP who have lost the ability to perceive shapes and movement to be more mobile and to perform day to day activities. In June 2013, twelve hospitals in the US announced they would soon accept consultation for patients with RP in preparation for the launch of Argus II later that year. The Alpha IMS is a subretinal implant involving the surgical implantation of a small image recording chip beneath the optic fovea. Measures of visual improvements from Alpha IMS studies require the demonstration of the device's safety before proceeding with clinical trials and granting market approval.

The goal of gene therapy studies is to virally supplement retinal cells expressing mutant genes associated with the retinitis pigmentosa phenotype with healthy forms of the gene; thus, allowing the repair and proper functioning of retinal photoreceptor cells in response to the instructions associated with the inserted healthy gene. Clinical trials investigating the insertion of the healthy RPE65 gene in retinas expressing the LCA2 retinitis pigmentosa phenotype measured modest improvements in vision; however, the degradation of retinal photoreceptors continued at the disease related rate. Likely, gene therapy may preserve remaining healthy retinal cells while failing to repair the earlier accumulation of damage in already diseased photoreceptor cells.

One study at UC Berkeley found that disulfiram, a drug used to treat alcoholism in humans, had potential to partially restore vision loss in rats with retinitis pigmentosa, even during late stages of the disease. Efforts to continue research in humans is ongoing.

The progressive nature of and lack of a definitive cure for retinitis pigmentosa contribute to the inevitably discouraging outlook for patients with this disease. While complete blindness is rare, the person's visual acuity and visual field will continue to decline as initial rod photoreceptor and later cone photoreceptor degradation proceeds. Studies indicate that children carrying the disease genotype benefit from presymptomatic counseling in order to prepare for the physical and social implications associated with progressive vision loss. While the psychological prognosis can be slightly alleviated with active counseling the physical implications and progression of the disease depend largely on the age of initial symptom manifestation and the rate of photoreceptor degradation, rather than access to prospective treatments. Corrective visual aids and personalized vision therapy provided by Low Vision Specialists may help patients correct slight disturbances in visual acuity and optimize their remaining visual field. Support groups, vision insurance, and lifestyle therapy are additional useful tools for those managing progressive visual decline. with approximately 1/4,000 individuals experiencing the non syndromic form of their disease within their lifetime. It is estimated that 1.5 million people worldwide are currently affected. Early onset RP occurs within the first few years of life and is typically associated with syndromic disease forms, while late onset RP emerges from early to mid adulthood. Autosomal dominant and recessive forms of retinitis pigmentosa affect both male and female populations equally; however, the less frequent X linked form of the disease affects male recipients of the X linked mutation, while females usually remain unaffected carriers of the RP trait. The X linked forms of the disease are considered severe, and typically lead to complete blindness during later stages. In rare occasions, a dominant form of the X linked gene mutation will affect both males and females equally. Due to the genetic inheritance patterns of RP, many isolate populations exhibit higher disease frequencies or increased prevalence of a specific RP mutation. Pre existing or emerging mutations that contribute to rod photoreceptor degeneration in retinitis pigmentosa are passed down through familial lines; thus, allowing certain RP cases to be concentrated to specific geographical regions with an ancestral history of the disease. Several hereditary studies have been performed to determine the varying prevalence rates in Maine (USA), Birmingham (England), Switzerland (affects 1/7000), Denmark (affects 1/2500), and Norway. Navajo Indians display an elevated rate of RP inheritance as well, which is estimated as affecting 1 in 1878 individuals. Despite the increased frequency of RP within specific familial lines, the disease is considered non discriminatory and tends to equally affect all world populations.

Future treatments may involve retinal transplants, artificial retinal implants, gene therapy, stem cells, nutritional supplements, and/or drug therapies. 2012: Scientists at the University of Miami Bascom Palmer Eye Institute presented data showing protection of photoreceptors in an animal model when eyes were injected with mesencephalic astrocyte derived neurotrophic factor (MANF). Researchers at the University of California, Berkeley were able to restore vision to blind mice by exploiting a "photoswitch" that activates retinal ganglion cells in animals with damaged rod and cone cells. 2015: A study by Bakondi et al. at Cedars Sinai Medical Center showed that CRISPR/Cas9 can be used to treat rats with the autosomal dominant form of retinitis pigmentosa. Researchers find that two molecules, rod derived cone viability factor (RdCVF) and Nrf2, can protect cone photoreceptors in mouse models of retinitis pigmentosa. 2016: RetroSense Therapeutics aimed to inject viruses with DNA from light sensitive algae into the eyes of several blind people (who have retinitis pigmentosa). If successful, they will be able to see in black and white. In 2017 the FDA approved the gene therapy voretigene neparvovec to treat people with biallelic RPE65 mutation associated retinal dystrophy. In 2020, a literature review estimated the experimental therapeutic technique called transcorneal electrical stimulation as "probably effective" (level B) in retinitis pigmentosa, based on the evidence available at that time. In 2021 an optogenetics application of the protein Channelrhodopsin in a human patient was reported with partial recovery of non functional vision in a series of one patient only. They did not use standard protocol to measure visual improvement, but created their own criteria. The serendipitous discovery of the novel algal channelrhodopsin used came out of the 1000 Plant Genomes Project.