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Liang Q, Cheng X, Wang J, Owen L, Shakoor A, Lillvis JL, Zhang C, Farkas M, Kim IK, Li Y, DeAngelis M, Chen R. A multi-omics atlas of the human retina at single-cell resolution. Cell Genom 2023;3(6):100298.Abstract
Cell classes in the human retina are highly heterogeneous with their abundance varying by several orders of magnitude. Here, we generated and integrated a multi-omics single-cell atlas of the adult human retina, including more than 250,000 nuclei for single-nuclei RNA-seq and 137,000 nuclei for single-nuclei ATAC-seq. Cross-species comparison of the retina atlas among human, monkey, mice, and chicken revealed relatively conserved and non-conserved types. Interestingly, the overall cell heterogeneity in primate retina decreases compared with that of rodent and chicken retina. Through integrative analysis, we identified 35,000 distal cis-element-gene pairs, constructed transcription factor (TF)-target regulons for more than 200 TFs, and partitioned the TFs into distinct co-active modules. We also revealed the heterogeneity of the cis-element-gene relationships in different cell types, even from the same class. Taken together, we present a comprehensive single-cell multi-omics atlas of the human retina as a resource that enables systematic molecular characterization at individual cell-type resolution.
Garg I, Miller JB. Semi-automated algorithm using directional filter for the precise quantification of non-perfusion area on widefield swept-source optical coherence tomography angiograms. Quant Imaging Med Surg 2023;13(6):3688-3702.Abstract
BACKGROUND: The clinical application of optical coherence tomography angiography (OCTA) has been well documented in literature with its promising potential in dye-less evaluation of various retinal vascular pathologies. Recent advances in OCTA help us gather wider field of view with 12 mm × 12 mm and montage compared to the standard dye-based scans, which has a higher accuracy and sensitivity in detection of peripheral pathologies. The aim of this study is to build a semi-automated algorithm to precisely quantify the non-perfusion areas (NPAs) on widefield swept-source optical coherence tomography angiography (WF SS-OCTA). METHODS: All subjects underwent imaging on 100 kHz SS-OCTA device acquiring 12 mm × 12 mm angiograms centered on fovea and optic disc. After a comprehensive literature review, a novel algorithm using FIJI (ImageJ) was designed to calculate the NPAs (mm2) after excluding the threshold and segmentation artifact areas from the total field of view. Segmentation and threshold artifacts were first removed from enface structure images using the spatial variance and mean filter respectively. Vessel enhancement was achieved by using 'Subtract Background' followed by directional filter. The cut off for Huang's fuzzy black and white thresholding was defined from the pixel values based of the foveal avascular zone. Then, the NPAs were calculated using the 'Analyze Particles' command with a minimum size of ~0.15 mm2. Finally, the artifact area was subtracted from to give the corrected NPAs. RESULTS: Our cohort had 44 eyes of 30 control patients and 107 eyes of 73 patients with diabetes mellitus (both median age 55 years, P=0.89). Of 107 eyes, 21 eyes had no evidence of diabetic retinopathy (DR), 50 eyes had non-proliferative DR and 36 eyes had proliferative DR. The median NPA was 0.20 (0.07-0.40) in controls, 0.28 (0.12-0.72) in no DR, 5.54 (3.12-9.10) in non-proliferative DR and 13.38 (8.73-26.32) in proliferative DR eyes. Using mixed effects-multiple linear regression analysis adjusting for age, there was significant progressive increase in NPA with increasing DR severity. CONCLUSIONS: This is one of the first study to use the directional filter for WFSS-OCTA image processing which is known to be superior to other Hessian based multiscale, linear, and non-linear filters especially for vascular analysis. Our method could greatly refine and streamline the calculation of signal void area proportion, while being much quicker and accurate than manual delineation of NPAs and subsequent estimation. This combined with the wide field of view can have a great prognostic and diagnostic clinical impact for future applications in DR and other ischemic retinal pathologies.
Halawa OA, Kang J, Parikh AA, Oh G, Glynn RJ, Friedman DS, Kim DH, Zebardast N. Relationship between Claims-Based Frailty Index and Eye Care Utilization among Medicare Beneficiaries with Glaucoma. Ophthalmology 2023;130(6):646-654.Abstract
PURPOSE: To determine differences in eye care utilization by frailty levels among Medicare beneficiaries with glaucoma. DESIGN: Retrospective cohort study. PARTICIPANTS: Medicare fee-for-service beneficiaries over 65 years of age with glaucoma, identified using International Classification of Diseases codes before July 1, 2014. METHODS: By using a validated claims-based frailty index (range, 0-1), beneficiaries were classified as nonfrail/prefrail (0-0.19), mildly frail (0.20-0.29), and moderate-to-severely frail (≥ 0.30). Negative binomial regression analyses were used to estimate incident rate ratios (IRRs) of eye care utilization by frailty levels between July 1, 2014, and December 31, 2016. MAIN OUTCOME MEASURES: Current Procedural Terminology codes for eye examinations and eye care-related office visits; eye care-related inpatient and emergency department (ED) encounters; eye care-related nursing facility and home-visit encounters; visual field (VF) and retinal nerve fiber layer (RNFL) OCT tests; and selective laser trabeculoplasties (SLTs) and glaucoma surgeries. RESULTS: Among 76 260 Medicare beneficiaries with glaucoma, the mean age was 78.9 years (standard deviation, 7.8), female beneficiaries constituted 60.5%, and 78.7% of beneficiaries self-identified as non-Hispanic White. According to a claims-based frailty index, 79.5% of beneficiaries were nonfrail/prefrail, 17.1% were mildly frail, and 3.4% were moderate-to-severely frail. Moderate-to-severely frail beneficiaries were less likely than nonfrail/prefrail beneficiaries to have outpatient encounters (IRR, 0.85, 95% confidence interval [CI], 0.83-0.88); VF tests (IRR, 0.64, 95% CI, 0.60-0.67); RNFL OCT tests (IRR, 0.77, 95% CI, 0.73-0.81); SLT (IRR, 0.74, 95% CI, 0.60-0.92); and glaucoma surgery (IRR, 0.74, 95% CI 0.55-0.99), after adjusting for age, gender, glaucoma severity, race, and socioeconomic status. Compared with nonfrail/prefrail beneficiaries, moderate-to-severely frail beneficiaries had higher rates of inpatient/ED encounters (IRR, 5.03, 95% CI, 2.36-10.71) and nursing facility/home-visit encounters (IRR, 34.89, 95% CI, 14.82-82.13). CONCLUSIONS: Compared with nonfrail/prefrail Medicare beneficiaries with glaucoma, beneficiaries with moderate-to-severe frailty had lower rates of eye care utilization in the outpatient setting and higher rates of utilization in acute care settings. This suggests that frail patients may receive less disease monitoring and fewer interventions for their glaucoma management. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.
Chua M, Kim D, Choi J, Lee NG, Deshpande V, Schwab J, Lev MH, Gonzalez RG, Gee MS, Do S. Tackling prediction uncertainty in machine learning for healthcare. Nat Biomed Eng 2023;7(6):711-718.Abstract
Predictive machine-learning systems often do not convey the degree of confidence in the correctness of their outputs. To prevent unsafe prediction failures from machine-learning models, the users of the systems should be aware of the general accuracy of the model and understand the degree of confidence in each individual prediction. In this Perspective, we convey the need of prediction-uncertainty metrics in healthcare applications, with a focus on radiology. We outline the sources of prediction uncertainty, discuss how to implement prediction-uncertainty metrics in applications that require zero tolerance to errors and in applications that are error-tolerant, and provide a concise framework for understanding prediction uncertainty in healthcare contexts. For machine-learning-enabled automation to substantially impact healthcare, machine-learning models with zero tolerance for false-positive or false-negative errors must be developed intentionally.
Parekh M, Ruzza A, Rovati M, Tzamalis A, Romano D, Gupta N, Vaddavalli P, Bhogal M, Jhanji V, Sawant O, Semeraro F, Ponzin D, Jacob S, Dragnea DC, Rodriguez-Calvo-De-Mora M, Ní Dhubhghaill S, Fogla R, Sharma N, Jurkunas UV, Ferrari S, Romano V. DMEK surgical training: An instructional guide on various wet-lab methods. Surv Ophthalmol 2023;68(6):1129-1152.Abstract
Descemet membrane endothelial keratoplasty (DMEK) is a partial-thickness corneal transplantation procedure that involves selective transplantation of the Descemet membrane and endothelium. DMEK offers significant advantages over other keratoplasty techniques, such as faster visual rehabilitation, better final visual acuity due to minimal optical interface effects, lower risk of allograft rejection, and less long-term dependence on topical steroids. Despite all its advantages, DMEK has been found to be more challenging than other corneal transplantation techniques, and its steep learning curve appears to be an obstacle to its widespread use and adoption by corneal surgeons worldwide. DMEK surgical training laboratories (wet labs) provide a window of opportunity for surgeons to learn, prepare, manipulate, and deliver these grafts in a risk-free environment. Wet labs are a significant learning tool, especially for those institutions that have limited tissue availability in their local centers. We provide a step-by-step guide for preparing DMEK grafts using different techniques on human and nonhuman models with instructional videos. This article should eventually help the trainees and the educators understand the requirements for performing DMEK and conducting a DMEK wet lab and develop their skills and interests from a wide variety of available techniques.
Song X, Zhang H, Zhang Y, Goh B, Bao B, Mello SS, Sun X, Zheng W, Gazzaniga FS, Wu M, Qu F, Yin Q, Gilmore MS, Oh SF, Kasper DL. Gut microbial fatty acid isomerization modulates intraepithelial T cells. Nature 2023;619(7971):837-843.Abstract
The human gut microbiome constantly converts natural products derived from the host and diet into numerous bioactive metabolites1-3. Dietary fats are essential micronutrients that undergo lipolysis to release free fatty acids (FAs) for absorption in the small intestine4. Gut commensal bacteria modify some unsaturated FAs-for example, linoleic acid (LA)-into various intestinal FA isomers that regulate host metabolism and have anticarcinogenic properties5. However, little is known about how this diet-microorganism FA isomerization network affects the mucosal immune system of the host. Here we report that both dietary factors and microbial factors influence the level of gut LA isomers (conjugated LAs (CLAs)) and that CLAs in turn modulate a distinct population of CD4+ intraepithelial lymphocytes (IELs) that express CD8αα in the small intestine. Genetic abolition of FA isomerization pathways in individual gut symbionts significantly decreases the number of CD4+CD8αα+ IELs in gnotobiotic mice. Restoration of CLAs increases CD4+CD8αα+ IEL levels in the presence of the transcription factor hepatocyte nuclear factor 4γ (HNF4γ). Mechanistically, HNF4γ facilitates CD4+CD8αα+ IEL development by modulating interleukin-18 signalling. In mice, specific deletion of HNF4γ in T cells leads to early mortality from infection by intestinal pathogens. Our data reveal a new role for bacterial FA metabolic pathways in the control of host intraepithelial immunological homeostasis by modulating the relative number of CD4+ T cells that were CD4+CD8αα+.
André C, Lebreton F, Van Tyne D, Cadorette J, Boody R, Gilmore MS, Bispo PJM. Microbiology of Eye Infections at the Massachusetts Eye and Ear: An 8-Year Retrospective Review Combined With Genomic Epidemiology. Am J Ophthalmol 2023;255:43-56.Abstract
PURPOSE: Ocular bacterial infections are important causes of morbidity and vision loss. Early antimicrobial therapy is necessary to save vision, but their efficacy is increasingly compromised by antimicrobial resistance (AMR). We assessed the etiology of ocular bacterial infections seen at Massachusetts Eye and Ear and investigated the molecular epidemiology and AMR profiles of contemporary isolates. DESIGN: Laboratory investigation. METHODS: We used a combination of phenotypic tests and genome sequencing to identify the predominant lineages of leading ocular pathogens and their AMR profiles. RESULTS: A total of 1601 isolates were collected from 2014 to 2021, with Staphylococcus aureus (n = 621), coagulase-negative staphylococci (CoNS) (n = 234), Pseudomonas aeruginosa (n = 213), Enterobacteriaceae (n = 167), and Streptococcus pneumoniae (n = 95) being the most common. Resistance was high among staphylococci, with methicillin resistance (MR) detected in 28% of S aureus and 39.8% of CoNS isolates. Multidrug resistance (MDR) was frequent among MR staphylococci (MRSA 60%, MRCoNS 76.1%). The population of S aureus isolates consisted mainly of 2 clonal complexes (CCs): CC8 (26.1%) and CC5 (24.1%). CC5 strains carried a variety of AMR markers, resulting in high levels of resistance to first-line therapies. Similarly, the population of ocular Staphylococcus epidermidis was homogenous with most belonging to CC2 (85%), which were commonly MDR (48%). Conversely, ocular S pneumoniae, P aeruginosa, and Enterobacteriaceae were often susceptible to first-line therapies and grouped into highly diverse genetic populations. CONCLUSION: Our data showed that ocular bacterial infections in our patient population are disproportionately caused by strains that are resistant to clinically relevant antibiotics and are associated with major epidemic genotypes with both community and hospital associations.
Han X, Lains I, Li J, Li J, Chen Y, Yu B, Qi Q, Boerwinkle E, Kaplan R, Thyagarajan B, Daviglus M, Joslin CE, Cai J, Guasch-Ferré M, Tobias DK, Rimm E, Ascherio A, Costenbader K, Karlson E, Mucci L, Eliassen HA, Zeleznik O, Miller J, Vavvas DG, Kim IK, Silva R, Miller J, Hu F, Willett W, Lasky-Su J, Kraft P, Richards BJ, Macgregor S, Husain D, Liang L. Integrating genetics and metabolomics from multi-ethnic and multi-fluid data reveals putative mechanisms for age-related macular degeneration. Cell Rep Med 2023;4(7):101085.Abstract
Age-related macular degeneration (AMD) is a leading cause of blindness in older adults. Investigating shared genetic components between metabolites and AMD can enhance our understanding of its pathogenesis. We conduct metabolite genome-wide association studies (mGWASs) using multi-ethnic genetic and metabolomic data from up to 28,000 participants. With bidirectional Mendelian randomization analysis involving 16,144 advanced AMD cases and 17,832 controls, we identify 108 putatively causal relationships between plasma metabolites and advanced AMD. These metabolites are enriched in glycerophospholipid metabolism, lysophospholipid, triradylcglycerol, and long chain polyunsaturated fatty acid pathways. Bayesian genetic colocalization analysis and a customized metabolome-wide association approach prioritize putative causal AMD-associated metabolites. We find limited evidence linking urine metabolites to AMD risk. Our study emphasizes the contribution of plasma metabolites, particularly lipid-related pathways and genes, to AMD risk and uncovers numerous putative causal associations between metabolites and AMD risk.
Teebagy S, Jastrzembski BG, Oke I. The Association of Vision Concerns With the Physical and Mental Well-being of Adolescents in the United States. Am J Ophthalmol 2023;256:35-38.Abstract
PURPOSE: To describe the prevalence of vision concerns among US adolescents and the association of time spent worrying about eyesight with physical and mental health. DESIGN: Cross-sectional study. METHODS: This study included adolescent children (age 12 to ≤18 years) particpating in the 2005-2008 National Health and Nutrition Examination Survey with completed visual function questionnaires and eye examinations. Vision concerns were identified by a survey question of time spent worrying about eyesight and response was treated as a dichotomous variable. Recent poor physical and mental health was defined as at least 1 day of poor health within the last month. Odds ratios (ORs) derived from survey-weighted multivariable logistic regression models were used to identify factors associated with vision concerns in the adolescent population, adjusting for participant demographics and refractive correction. RESULTS: The survey participants included 3100 adolescents (mean [SD] age, 15.5 [2.0] years; 49% [n = 1545] female). Vision concerns were expressed by 24% (n=865) of adolescents. Vision concerns were more prevalent among female (29% vs 19%, P < .001), low-income (30% vs 23%, P < .001), and uninsured (31% vs 22%, P = .006) adolescents. Participants worried about their eyesight were more likely to have undercorrected refractive error (OR 2.07, 95% CI 1.43-2.98). Poor recent mental health (OR 1.30, 95% CI 1.01-1.67), but not physical health (OR 1.00, 95% CI 0.69-1.45), was associated with adolescent vision concerns. CONCLUSIONS: Female, low-income, and uninsured adolescents living in the United States are more likely to report worrying about their vision and often have uncorrected or undercorrected refractive errors.
Miura M, Leon P, Nahum Y, Böhm MS, Mimouni M, Belin MW, Johns L, Ciolino JB. Recurrent Keratoconus: Corneal Transplants for Keratoconus Develop Tomographic Ectatic Changes. Cornea 2023;42(6):708-713.Abstract
PURPOSE: The purpose of this study was to evaluate postoperative Scheimpflug imaging changes during the first 5 years after penetrating keratoplasty (PK) in patients with keratoconus (KC). METHODS: This retrospective, interventional case series includes 31 eyes of 31 patients who underwent their first PK with a history of KC. Postoperative Scheimpflug imaging was performed 3 months after the removal of the last suture (baseline) and then repeated 3 and 5 years after the PK. Demographic data, donor and host trephination diameter, and Scheimpflug imaging (Pentacam HR, Oculus, Germany) parameters indicative of ectasia were analyzed to evaluate postoperative graft changes that occur after PK. RESULTS: The maximal keratometry (Kmax) progressed significantly between baseline (53.5 ± 6.1 D) and postoperative year 3 and year 5 [56.5 ± 6.1 diopter (D) and 58.8 ± 7.9 D, P < 0.001]. Significant changes were also observed for the anterior best fit sphere and posterior best fit sphere ( P < 0.001 for 3 and 5 years compared with baseline). Kmax increased by at least 2 Ds for 74.2% of patients and up to 7 Ds or more for 25.8% of the patients. A significant inverse correlation was observed for host trephine size and progression of Kmax (r = -0.52, P = 0.01), which indicated that larger host trephination size was associated with a smaller increase in postoperative Kmax. CONCLUSIONS: Tomographic graft changes indicative of ectasia were observed within 3 to 5 years after PK in patients with KC. These changes were observed more frequently and sooner after corneal transplants than previously reported.
Ludwig CA, Vail D, Al-Moujahed A, Callaway NF, Saroj N, Moshfeghi A, Moshfeghi DM. Epidemiology of rhegmatogenous retinal detachment in commercially insured myopes in the United States. Sci Rep 2023;13(1):9430.Abstract
Myopia is a known risk factor for rhegmatogenous retinal detachment (RRD). Given global trends of increasing myopia, we aimed to determine the absolute risk (incidence rate) of RRD in non-myopes, myopes and high myopes in the United States over ten years. We performed a retrospective cohort study of 85,476,781 commercially insured patients enrolled in the Merative™ Marketscan® Research Database. The incidence rate of RRD in phakic patients in the United States was 39-fold higher in high myopes than non-myopes (868.83 per 100,000 person-years versus 22.44 per 100,000 person-years) and three-fold higher in myopes than non-myopes (67.51 per 100,000 person-years versus 22.44 per 100,000 person-years). The incidence rate was significantly higher in males in each category (P < 0.01). Combined, the incidence rate of RRD in phakic patients in the United States from 2007 to 2016 was 25.27 RRDs per 100,000 person-years, a rate higher than those in prior published studies in North America, South America, Europe, Asia, and Australia. The absolute risk of myopia and high myopia increased from 2007 to 2016. The risk of RRD in phakic high myopes rose with increasing age. Notably, the magnitude of increased risk of RRD in myopes varied substantially according to the minimum follow-up period in our models and should be accounted for when interpreting data analyses.
Freedman SF, Del Monte MA, Diva U, Donahue SP, Drack AV, Dutta R, Fung SSM, Imperiale M, Jordan CO, Lenhart PD, Lim ME, McCourt EA, Nihalani BR, Sabahi T, Stahl ED, Miraldi Utz VA, Wilson EM, Yen KG, VanderVeen DK. Prevalence of cerebrotendinous xanthomatosis among patients diagnosed with early-onset idiopathic bilateral cataracts: final analysis. J AAPOS 2023;Abstract
Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive bile acid synthesis disorder caused by pathologic variants in CYP27A1, a gene involved in bile acid synthesis. Impaired function in this gene leads to accumulation of plasma cholestanol (PC) in various tissues, often in early childhood, resulting in such clinical signs as infantile diarrhea, early-onset bilateral cataracts, and neurological deterioration. The current study aimed to identify cases of CTX in a population of patients with a greater CTX prevalence than the general population, to facilitate early diagnosis. Patients diagnosed with early-onset, apparently idiopathic, bilateral cataracts between the ages of 2 and 21 years were enrolled. Genetic testing of patients with elevated PC and urinary bile alcohol (UBA) levels was used to confirm CTX diagnosis and determine CTX prevalence. Of 426 patients who completed the study, 26 met genetic testing criteria (PC ≥ 0.4 mg/dL and positive UBA test), and 4 were confirmed to have CTX. Prevalence was found to be 0.9% in enrolled patients, and 15.4% in patients who met the criteria for genetic testing.
Brant A, Kolomeyer N, Goldberg JL, Haller J, Lee CS, Lee AY, Lorch AC, Lum F, Miller JW, Parke DW, Hyman L, Pershing S. United States Population Disparities in Ophthalmic Care: Blindness and Visual Impairment in the IRIS® Registry (Intelligent Research in Sight). Ophthalmology 2023;130(11):1121-1137.Abstract
PURPOSE: To evaluate associations of patient characteristics with United States eye care use and likelihood of blindness. DESIGN: Retrospective observational study. PARTICIPANTS: Patients (19 546 016) with 2018 visual acuity (VA) records in the American Academy of Ophthalmology's IRIS® Registry (Intelligent Research in Sight). METHODS: Legal blindness (20/200 or worse) and visual impairment (VI; worse than 20/40) were identified from corrected distance acuity in the better-seeing eye and stratified by patient characteristics. Multivariable logistic regressions evaluated associations with blindness and VI. Blindness was mapped by state and compared with population characteristics. Eye care use was analyzed by comparing population demographics with United States Census estimates and proportional demographic representation among blind patients versus a nationally representative US population sample (National Health and Nutritional Examination Survey [NHANES]). MAIN OUTCOME MEASURES: Prevalence and odds ratios for VI and blindness; proportional representation in the IRIS® Registry, Census, and NHANES by patient demographics. RESULTS: Visual impairment was present in 6.98% (n = 1 364 935) and blindness in 0.98% (n = 190 817) of IRIS patients. Adjusted odds of blindness were highest among patients ≥ 85 years old (odds ratio [OR], 11.85; 95% confidence interval [CI], 10.33-13.59 vs. those 0-17 years old). Blindness also was associated positively with rural location and Medicaid, Medicare, or no insurance vs. commercial insurance. Hispanic (OR, 1.59; 95% CI, 1.46-1.74) and Black (OR, 1.73; 95% CI, 1.63-1.84) patients showed a higher odds of blindness versus White non-Hispanic patients. Proportional representation in IRIS Registry relative to the Census was higher for White than Hispanic (2- to 4-fold) or Black (11%-85%) patients (P < 0.001). Blindness overall was less prevalent in NHANES than IRIS Registry; however, prevalence in adults aged 60+ was lowest among Black participants in the NHANES (0.54%) and second highest among comparable Black adults in IRIS (1.57%). CONCLUSIONS: Legal blindness from low VA was present in 0.98% of IRIS patients and associated with rural location, public or no insurance, and older age. Compared with US Census estimates, minorities may be underrepresented among ophthalmology patients, and compared with NHANES population estimates, Black individuals may be overrepresented among blind IRIS Registry patients. These findings provide a snapshot of US ophthalmic care and highlight the need for initiatives to address disparities in use and blindness. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Brown EE, Scandura MJ, Pierce EA. Expression of NMNAT1 in the photoreceptors is sufficient to prevent NMNAT1-associated retinal degeneration. Mol Ther Methods Clin Dev 2023;29:319-328.Abstract
Nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) is a ubiquitously expressed enzyme involved in nuclear NAD+ production throughout the body. However, mutations in the NMNAT1 gene lead to retina-specific disease with few reports of systemic effects. We have previously demonstrated that AAV-mediated gene therapy using self-complementary AAV (scAAV) to ubiquitously express NMNAT1 throughout the retina prevents retinal degeneration in a mouse model of NMNAT1-associated disease. We aimed to develop a better understanding of the cell types in the retina that contribute to disease pathogenesis in NMNAT1-associated disease, and to identify the cell types that require NMNAT1 expression for therapeutic benefit. To achieve this goal, we treated Nmnat1V9M/V9M mice with scAAV using cell type-specific promoters to restrict NMNAT1 expression to distinct retinal cell types. We hypothesized that photoreceptors are uniquely vulnerable to NAD+ depletion due to mutations in NMNAT1. Consistent with this hypothesis, we identified that treatments that drove NMNAT1 expression in the photoreceptors led to preservation of retinal morphology. These findings suggest that gene therapies for NMNAT1-associated disease should aim to express NMNAT1 in the photoreceptor cells.

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