Spatiotemporal control of genome engineering in cone photoreceptors.

BACKGROUND: Cones are essential for color recognition, high resolution, and central vision; therefore cone death causes blindness. Understanding the pathophysiology of each cell type in the retina is key to developing therapies for retinal diseases. However, studying the biology of cone cells in the rod-dominant mammalian retina is particularly challenging. In this study, we used a bacterial artificial chromosome (BAC) recombineering method to knock in the "CreERT2" sequence into the Gnat2 and Arr3 genes, respectively and generated three novel inducible CreERT2 mice with different cone cell specificities. RESULTS: These models (Gnat2CreERT2, Arr3T2ACreERT2, and Arr3P2ACreERT2) express temporally controllable Cre recombinase that achieves conditional alleles in cone photoreceptors. Cre-LoxP recombination can be induced as early as postnatal day (PD) two upon tamoxifen injection at varying efficiencies, ranging from 10 to 15% in Gnat2CreERT2, 40% in Arr3T2ACreERT2, and 100% in Arr3P2ACreERT2. Notably, knocking in the P2A-CreERT2 cassette does not affect cone cell morphology and functionality. Most cone-phototransduction enzymes, including Opsins, CNGA3, etc. are not altered except for a reduction in the Arr3 transcript. CONCLUSIONS: The Arr3P2ACreERT2 mouse, an inducible cone-specific Cre driver, is a valuable line in studying cone cell biology, function, as well as its relationship with rod and other retinal cells. Moreover, the Cre activity can be induced by delivering tamoxifen intragastrically as early as PD2, which will be useful for studying retinal development or in rapid degenerative mouse models.

Effect of the Brief Instructional Video Intervention on the Quality of Cardiopulmonary Resuscitation.

Background: Chest compressions are the basis of cardiopulmonary resuscitation (CPR), and high-quality chest compressions can improve survival rate in patients with out-of-hospital cardiac arrest. Although many efforts have been made to improve the quality of CPR in inexperienced adults, the results are still not high, especially during emergencies. The primary purpose of this study is to investigate whether a brief instructional chest compression-only CPR video could improve chest compression quality in inexperienced adults. Methods: One hundred adults with no CPR experience (age: 20.28 ± 2.28 years; women: 50, men: 50) participated in this study. Participants completed body composition and handgrip strength measurements, and performed two CPR quality tests on the Laerdal® Little Anne QCPR Manikin, namely without video-CPR (WV-CPR) and video-CPR (V-CPR). The WV-CPR quality test was performed first. After 2 minutes of continuous chest compression, the participants rested for 10 seconds and repeated 3 cycles (phase 1, phase 2, and phase 3). After resting for more than 72 hours, V-CPR quality test was conducted. During the V-CPR with video intervention, the participants also continued to compress the chest for 2 minutes, and then rested for 10 seconds, repeating 3 cycles. Results: In phase 1, compared with WV-CPR, the V-CPR has a significant increase (p < 0.001) in chest compression fraction (CCF) (56.31 ± 33.22% vs. 41.82 ± 32.30%) and percent of correct compression rate (PCCR) (96.17 ± 8.45% vs. 26.31 ± 37.55%). In addition, the V-CPR has significantly lower (p < 0.001) chest compression rate (CCR) (110.85 ± 2.40 cpm vs. 128.86 ± 24.52 cpm) and rating of perceived exertion (RPE) (11.89 ± 2.25 vs. 12.87 ± 2.25). For phases 2 through 3, V-CPR and WV-CPR achieved significant differences in CCF, CCD, CCR, PCCR, and RPE (p < 0.01). There were significant differences (p < 0.05) in CCF, CCD, chest compression rebound rate, and RPE among the different administration stages of both WV-CPR and V-CPR. Conclusions: The results of this study revealed that a brief instructional chest compression-only CPR video could improve chest compression quality for inexperienced adults by reducing fatigue and CCR, and increasing CCF and PCCR.

HIF2α activation and mitochondrial deficit due to iron chelation cause retinal atrophy.

Iron accumulation causes cell death and disrupts tissue functions, which necessitates chelation therapy to reduce iron overload. However, clinical utilization of deferoxamine (DFO), an iron chelator, has been documented to give rise to systemic adverse effects, including ocular toxicity. This study provided the pathogenic and molecular basis for DFO-related retinopathy and identified retinal pigment epithelium (RPE) as the target tissue in DFO-related retinopathy. Our modeling demonstrated the susceptibility of RPE to DFO compared with the neuroretina. Intriguingly, we established upregulation of hypoxia inducible factor (HIF) 2α and mitochondrial deficit as the most prominent pathogenesis underlying the RPE atrophy. Moreover, suppressing hyperactivity of HIF2α and preserving mitochondrial dysfunction by α-ketoglutarate (AKG) protects the RPE against lesions both in vitro and in vivo. This supported our observation that AKG supplementation alleviates visual impairment in a patient undergoing DFO-chelation therapy. Overall, our study established a significant role of iron deficiency in initiating DFO-related RPE atrophy. Inhibiting HIF2α and rescuing mitochondrial function by AKG protect RPE cells and can potentially ameliorate patients' visual function.

Moderating Effects of Religious Tourism Activities on Environmental Risk, Leisure Satisfaction, Physical and Mental Health and Well-Being among the Elderly in the Context of COVID-19.

The purpose of this study is to explore whether religious tourism activities can create a safe leisure environment and improve the well-being of the elderly during the COVID-19 pandemic, with the participants in the Baishatun Mazu pilgrimage in Taiwan as the subjects of this study. A mixed research method was used. First, statistical software and the Pearson product-moment correlation coefficient were used to analyze the data. Then the respondents' opinions were collected. Finally, a multivariate analysis method was used to discuss the results of analysis. The findings showed that the elderly respondents thought that the epidemic prevention information and leisure space planning for the pilgrimage made them feel secure. The elderly believed the scenery, religious atmosphere, and commodities en route could reduce the perception of environmental risks to tourists, relieve pressure on the brain, and increase social opportunities. Therefore, the friendlier the leisure environment around the pilgrimage, the greater the leisure satisfaction among the elderly respondents. The happier the elderly felt, the less they considered the concentration of airborne contaminants, including viruses. The better their physical and mental health was, the less likely they were to want to ask for religious goods.

CRISPR genome surgery in a novel humanized model for autosomal dominant retinitis pigmentosa.

Mutations in rhodopsin (RHO) are the most common causes of autosomal dominant retinitis pigmentosa (adRP), accounting for 20% to 30% of all cases worldwide. However, the high degree of genetic heterogeneity makes development of effective therapies cumbersome. To provide a universal solution to RHO-related adRP, we devised a CRISPR-based, mutation-independent gene ablation and replacement (AR) compound therapy carried by a dual AAV2/8 system. Moreover, we developed a novel hRHOC110R/hRHOWT humanized mouse model to assess the AR treatment in vivo. Results show that this humanized RHO mouse model exhibits progressive rod-cone degeneration that phenocopies hRHOC110R/hRHOWT patients. In vivo transduction of AR AAV8 dual vectors remarkably ablates endogenous RHO expression and overexpresses exogenous WT hRHO. Furthermore, the administration of AR during adulthood significantly hampers photoreceptor degeneration both histologically and functionally for at least 6 months compared with sole gene replacement or surgical trauma control. This study demonstrates the effectiveness of AR treatment of adRP in the human genomic context while revealing the feasibility of its application for other autosomal dominant disorders.

Long-term vitamin A supplementation in a preclinical mouse model for RhoD190N-associated retinitis pigmentosa.

Retinitis pigmentosa (RP) is caused by one of many possible gene mutations. The National Institutes of Health recommends high daily doses of vitamin A palmitate for RP patients. There is a critical knowledge gap surrounding the therapeutic applicability of vitamin A to patients with the different subtypes of the disease. Here, we present a case report of a patient with RP caused by a p.D190N mutation in Rhodopsin (RHO) associated with abnormally high quantitative autofluorescence values after long-term vitamin A supplementation. We investigated the effects of vitamin A treatment strategy on RP caused by the p.D190N mutation in RHO by exposing Rhodopsin p.D190N (RhoD190N/+) and wild-type (WT) mice to experimental vitamin A-supplemented and standard control diets. The patient's case suggests that the vitamin A treatment strategy should be further studied to determine its effect on RP caused by p.D190N mutation in RHO and other mutations. Our mouse experiments revealed that RhoD190N/+ mice on the vitamin A diet exhibited higher levels of autofluorescence and lipofuscin metabolites compared to WT mice on the same diet and isogenic controls on the standard control diet. Vitamin A supplementation diminished photoreceptor function in RhoD190N/+ mice while preserving cone response in WT mice. Our findings highlight the importance of more investigations into the efficacy of clinical treatments like vitamin A for patients with certain genetic subtypes of disease and of genotyping in the precision care of inherited retinal degenerations.

Mouse Models of Achromatopsia in Addressing Temporal "Point of No Return" in Gene-Therapy.

Achromatopsia is characterized by amblyopia, photophobia, nystagmus, and color blindness. Previous animal models of achromatopsia have shown promising results using gene augmentation to restore cone function. However, the optimal therapeutic window to elicit recovery remains unknown. Here, we attempted two rounds of gene augmentation to generate recoverable mouse models of achromatopsia including a Cnga3 model with a knock-in stop cassette in intron 5 using Easi-CRISPR (Efficient additions with ssDNA inserts-CRISPR) and targeted embryonic stem (ES) cells. This model demonstrated that only 20% of CNGA3 levels in homozygotes derived from target ES cells remained, as compared to normal CNGA3 levels. Despite the low percentage of remaining protein, the knock-in mouse model continued to generate normal cone phototransduction. Our results showed that a small amount of normal CNGA3 protein is sufficient to form "functional" CNG channels and achieve physiological demand for proper cone phototransduction. Thus, it can be concluded that mutating the Cnga3 locus to disrupt the functional tetrameric CNG channels may ultimately require more potent STOP cassettes to generate a reversible achromatopsia mouse model. Our data also possess implications for future CNGA3-associated achromatopsia clinical trials, whereby restoration of only 20% functional CNGA3 protein may be sufficient to form functional CNG channels and thus rescue cone response.

Direct Transformation of Crystalline MoO3 into Few-Layers MoS2.

We fabricated large-area atomically thin MoS2 layers through the direct transformation of crystalline molybdenum trioxide (MoO3) by sulfurization at relatively low temperatures. The obtained MoS2 sheets are polycrystalline (~10-20 nm single-crystal domain size) with areas of up to 300 × 300 µm2, 2-4 layers in thickness and show a marked p-type behavior. The synthesized films are characterized by a combination of complementary techniques: Raman spectroscopy, X-ray diffraction, transmission electron microscopy and electronic transport measurements.

PKM2 ablation enhanced retinal function and survival in a preclinical model of retinitis pigmentosa.

Retinitis pigmentosa (RP) is a neurodegenerative disorder that causes irreversible vision loss in over 1.5 million individuals world-wide. The genetic heterogeneity of RP necessitates a broad therapy that is able to provide treatment in a gene- and mutation- non-specific manner. In this study, we identify the therapeutic benefits of metabolic reprogramming by targeting pyruvate kinase M2 (PKM2) in a Pde6ß preclinical model of RP. The genetic contributions of PKM2 inhibition in retinal degeneration were evaluated through histology and electroretinogram (ERG) followed by a statistical analysis using a linear regression model. Notably, PKM2 ablation resulted in thicker retinal layers in Pde6ß-mutated mice as compared to the controls, suggesting greater photoreceptor survival. Consistent with these anatomical findings, ERG analyses revealed that the maximum b-wave is on average greater in Pkm2 knockout mice than in mice with intact Pkm2, indicating enhanced photoreceptor function. These rescue phenotypes from Pkm2 ablation in a preclinical model of RP indicate that a metabolome reprogramming may be useful in treating RP.

Reduced adiponectin:leptin ratio associated with inhalation exposure to vinyl chloride monomer.

The hepatic toxicity of vinyl chloride monomer (VCM) has often been reported, but few studies have assessed insulin resistance or adipose tissue dysfunction. We analyzed the chronic health effects of moderate exposure to VCM on factory workers in Taiwan. Data were collected from personal air samples, urine samples, and immunohistochemical (IHC) examinations of 122 recruited voluntary participants. Air samples were analyzed to assess personal levels of exposure to VCM and ethylene dichloride (EDC). Urine samples were collected from each worker before they started and after they finished their daily shift. Urinary thiodiglycolic acid (TDGA) levels were analyzed using high-performance liquid chromatography-tandem mass spectrometry (HPLC/MS/MS). IHC examinations included liver function and serum adipokine level tests for insulin resistance. Consequently, the participants included for the final analysis were 113. After confounders had been adjusted for, the airborne VCM concentration significantly (P = 0.043) correlated with pre-shift urinary TDGA levels (ß = 0.194). A multivariate analysis showed a significant (P = 0.013) inverse correlation between the adiponectin:leptin ratio and the airborne VCM concentration (ß = -0.283), which means that exposure to VCM might increase the risk of insulin resistance and adiponectin abnormalities. We hypothesized that pre-shift urinary TDGA levels can be used as exposure biomarkers for the exposure of workers to VCM.

Hypoxic drive caused type 3 neovascularization in a preclinical model of exudative age-related macular degeneration.

Hypoxia associated with the high metabolic demand of rods has been implicated in the pathology of age-related macular degeneration (AMD), the most common cause of adult blindness in the developed world. The majority of AMD-associated severe vision loss cases are due to exudative AMD, characterized by neovascularization. To further investigate the causes and histopathology of exudative AMD, we conditionally induced hypoxia in a novel preclinical AMD model (Pde6gcreERT2/+;Vhl-/-) by targeting Vhl and used multimodal imaging and immunohistochemistry to track the development of hypoxia-induced neovascularization. In addition to developing a preclinical model that phenocopies exudative AMD, our studies revealed that the photoreceptor hypoxic response initiates and drives type 3 neovascularization, mainly in the outer retina. Activation of the VHL-HIF1a-VEGF-EPO pathway in the adult retina led to long-term neovascularization, retinal hemorrhages and compromised retinal layers. Our novel preclinical model would accelerate the testing of therapies that use metabolomic approaches to ameliorate AMD.

CAPN5 genetic inactivation phenotype supports therapeutic inhibition trials.

Small molecule pharmacological inhibition of dominant human genetic disease is a feasible treatment that does not rely on the development of individual, patient-specific gene therapy vectors. However, the consequences of protein inhibition as a clinical therapeutic are not well-studied. In advance of human therapeutic trials for CAPN5 vitreoretinopathy, genetic inactivation can be used to infer the effect of protein inhibition in vivo. We created a photoreceptor-specific knockout (KO) mouse for Capn5 and compared the retinal phenotype to both wild-type and an existing Capn5 KO mouse model. In humans, CAPN5 loss-of-function (LOF) gene variants were ascertained in large exome databases from 60,706 unrelated subjects without severe disease phenotypes. Ocular examination of the retina of Capn5 KO mice by histology and electroretinography showed no significant abnormalities. In humans, there were 22 LOF CAPN5 variants located throughout the gene and in all major protein domains. Structural modeling of coding variants showed these LOF variants were nearby known disease-causing variants within the proteolytic core and in regions of high homology between human CAPN5 and 150 homologs, yet the LOF of CAPN5 was tolerated as opposed to gain-of-function disease-causing variants. These results indicate that localized inhibition of CAPN5 is a viable strategy for hyperactivating disease alleles.

Mechanisms of neurodegeneration in a preclinical autosomal dominant retinitis pigmentosa knock-in model with a RhoD190N mutation.

D190N, a missense mutation in rhodopsin, causes photoreceptor degeneration in patients with autosomal dominant retinitis pigmentosa (adRP). Two competing hypotheses have been developed to explain why D190N rod photoreceptors degenerate: (a) defective rhodopsin trafficking prevents proteins from correctly exiting the endoplasmic reticulum, leading to their accumulation, with deleterious effects or (b) elevated mutant rhodopsin expression and unabated signaling causes excitotoxicity. A knock-in D190N mouse model was engineered to delineate the mechanism of pathogenesis. Wild type (wt) and mutant rhodopsin appeared correctly localized in rod outer segments of D190N heterozygotes. Moreover, the rhodopsin glycosylation state in the mutants appeared similar to that in wt mice. Thus, it seems plausible that the injurious effect of the heterozygous mutation is not related to mistrafficking of the protein, but rather from constitutive rhodopsin activity and a greater propensity for chromophore isomerization even in the absence of light.

The effect of mental countermeasures on neuroimaging-based concealed information tests.

During the last decade and a half, functional magnetic resonance imaging (fMRI) has been used to determine whether it is possible to detect concealed knowledge by examining brain activation patterns, with mixed results. Concealed information tests rely on the logic that a familiar item (probe) elicits a stronger response than unfamiliar, but otherwise comparable items (irrelevants). Previous work has shown that physical countermeasures can artificially modulate neural responses in concealed information tests, decreasing the accuracy of these methods. However, the question remains as to whether purely mental countermeasures, which are much more difficult to detect than physical ones, can also be effective. An fMRI study was conducted to address this question by assessing the effect of attentional countermeasures on the accuracy of the classification between knowledge and no-knowledge cases using both univariate and multivariate analyses. Results replicate previous work and show reliable group activation differences between the probe and the irrelevants in fronto-parietal networks. Critically, classification accuracy was generally reduced by the mental countermeasures, but only significantly so with region of interest analyses (both univariate and multivariate). For whole-brain analyses, classification accuracy was relatively low, but it was not significantly reduced by the countermeasures. These results indicate that mental countermeasure need to be addressed before these paradigms can be used in applied settings and that methods to defeat countermeasures, or at least to detect their use, need to be developed. HIGHLIGHTS: FMRI-based concealed information tests are vulnerable to mental countermeasures Measures based on regions of interest are affected by mental countermeasures Whole-brain analyses may be more robust than region of interest ones Methods to detect mental countermeasure use are needed for forensic applications.

Genetic Rescue Reverses Microglial Activation in Preclinical Models of Retinitis Pigmentosa.

Microglia cells (MGCs) play a key role in scavenging pathogens and phagocytosing cellular debris in the central nervous system and retina. Their activation, however, contributes to the progression of multiple degenerative diseases. Given the potential damage created by MGCs, it is important to better understand their mechanism of activation. Here, we explored the role of MGCs in the context of retinitis pigmentosa (RP) by using four independent preclinical mouse models. For therapeutic modeling, tamoxifen-inducible CreER was introduced to explore changes in MGCs when RP progression halted. The phenotypes of the MGCs were observed using live optical coherence tomography, live autofluorescence, and immunohistochemistry. We found that, regardless of genetic background, MGCs were activated in neurodegenerative conditions and migrated beyond the layers where they are typically found to the inner and outer segments, where degeneration was ongoing. Genetic rescue not only halted degeneration but also deactivated MGCs, regardless of whether the intervention occurred at the early, middle, or late stage of the disease. These findings suggest that halting long-term disease progression may be more successful by downregulating MGC activity while co-administering the therapeutic intervention.

HTRA1, an age-related macular degeneration protease, processes extracellular matrix proteins EFEMP1 and TSP1.

High-temperature requirement protein A1 (HTRA1) is a serine protease secreted by a number of tissues including retinal pigment epithelium (RPE). A promoter variant of the gene encoding HTRA1 is part of a mutant allele that causes increased HTRA1 expression and contributed to age-related macular degeneration (AMD) in genomewide association studies. AMD is characterized by pathological development of drusen, extracellular deposits of proteins and lipids on the basal side of RPE. The molecular pathogenesis of AMD is not well understood, and understanding dysregulation of the extracellular matrix may be key. We assess the high-risk genotype at 10q26 by proteomic comparison of protein levels of RPE cells with and without the mutation. We show HTRA1 protein level is increased in high-risk RPE cells along with several extracellular matrix proteins, including known HTRA1 cleavage targets LTBP-1 and clusterin. In addition, two novel targets of HTRA1 have been identified: EFEMP1, an extracellular matrix protein mutated in Doyne honeycomb retinal dystrophy, a genetic eye disease similar to AMD, and thrombospondin 1 (TSP1), an inhibitor of angiogenesis. Our data support the role of RPE extracellular deposition with potential effects in compromised barrier to neovascularization in exudative AMD.

Gene Therapy Restores Mfrp and Corrects Axial Eye Length.

Hyperopia (farsightedness) is a common and significant cause of visual impairment, and extreme hyperopia (nanophthalmos) is a consequence of loss-of-function MFRP mutations. MFRP deficiency causes abnormal eye growth along the visual axis and significant visual comorbidities, such as angle closure glaucoma, cystic macular edema, and exudative retinal detachment. The Mfrp rd6 /Mfrp rd6 mouse is used as a pre-clinical animal model of retinal degeneration, and we found it was also hyperopic. To test the effect of restoring Mfrp expression, we delivered a wild-type Mfrp to the retinal pigmented epithelium (RPE) of Mfrp rd6 /Mfrp rd6 mice via adeno-associated viral (AAV) gene therapy. Phenotypic rescue was evaluated using non-invasive, human clinical testing, including fundus auto-fluorescence, optical coherence tomography, electroretinography, and ultrasound. These analyses showed gene therapy restored retinal function and normalized axial length. Proteomic analysis of RPE tissue revealed rescue of specific proteins associated with eye growth and normal retinal and RPE function. The favorable response to gene therapy in Mfrp rd6 /Mfrp rd6 mice suggests hyperopia and associated refractive errors may be amenable to AAV gene therapy.

Genetic rescue models refute nonautonomous rod cell death in retinitis pigmentosa.

Retinitis pigmentosa (RP) is an inherited neurodegenerative disease, in which the death of mutant rod photoreceptors leads secondarily to the non-cell autonomous death of cone photoreceptors. Gene therapy is a promising treatment strategy. Unfortunately, current methods of gene delivery treat only a fraction of diseased cells, yielding retinas that are a mosaic of treated and untreated rods, as well as cones. In this study, we created two RP mouse models to test whether dying, untreated rods negatively impact treated, rescued rods. In one model, treated and untreated rods were segregated. In the second model, treated and untreated rods were diffusely intermixed, and their ratio was controlled to achieve low-, medium-, or high-efficiency rescue. Analysis of these mosaic retinas demonstrated that rescued rods (and cones) survive, even when they are greatly outnumbered by dying photoreceptors. On the other hand, the rescued photoreceptors did exhibit long-term defects in their outer segments (OSs), which were less severe when more photoreceptors were treated. In summary, our study suggests that even low-efficiency gene therapy may achieve stable survival of rescued photoreceptors in RP patients, albeit with OS dysgenesis.

Oxidized multiwalled carbon nanotubes decorated with silver nanoparticles for fluorometric detection of dimethoate.

A novel method for the detection of dimethoate based on the peroxidase-like activity of silver-nanoparticles-modified oxidized multiwalled carbon nanotubes (AgNPs/oxMWCNTs) has been developed. The synthesized AgNPs/oxMWCNTs showed excellent peroxidease-like catalytic activity in hydrogen peroxide-Amplex red (AR) system (AR is oxidized to resorufinat, with the resorufin fluorescence at 584nm being used to monitor the catalytic activity). After dimethoate was added to AgNPs/oxMWCNTs, the interaction between dimethoate and the AgNPs inhibited the catalytic activity of AgNPs/oxMWCNTs. The decrease in fluorescence was used for the detection of dimethoate in the range of 0.01-0.35µgmL-1 (R2=0.998) with a detection limit of 0.003µgmL-1 (signal/noise=3). This method exhibited good selectivity for the detection of dimethoate even in the presence of high concentration of other pesticides. Consequently, the method was applied to measure the concentration of dimethoate residue in lake water and fruit, thus obtaining satisfactory results.

Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration.

Retinitis pigmentosa (RP) encompasses a diverse group of Mendelian disorders leading to progressive degeneration of rods and then cones. For reasons that remain unclear, diseased RP photoreceptors begin to deteriorate, eventually leading to cell death and, consequently, loss of vision. Here, we have hypothesized that RP associated with mutations in phosphodiesterase-6 (PDE6) provokes a metabolic aberration in rod cells that promotes the pathological consequences of elevated cGMP and Ca2+, which are induced by the Pde6 mutation. Inhibition of sirtuin 6 (SIRT6), a histone deacetylase repressor of glycolytic flux, reprogrammed rods into perpetual glycolysis, thereby driving the accumulation of biosynthetic intermediates, improving outer segment (OS) length, enhancing photoreceptor survival, and preserving vision. In mouse retinae lacking Sirt6, effectors of glycolytic flux were dramatically increased, leading to upregulation of key intermediates in glycolysis, TCA cycle, and glutaminolysis. Both transgenic and AAV2/8 gene therapy-mediated ablation of Sirt6 in rods provided electrophysiological and anatomic rescue of both rod and cone photoreceptors in a preclinical model of RP. Due to the extensive network of downstream effectors of Sirt6, this study motivates further research into the role that these pathways play in retinal degeneration. Because reprogramming metabolism by enhancing glycolysis is not gene specific, this strategy may be applicable to a wide range of neurodegenerative disorders.