The discovery of vascular endothelial-derived growth factor (VEGF) has revolutionized our understanding of vasculogenesis and angiogenesis during development and physiological homeostasis. Over a ...short span of two decades, our understanding of the molecular mechanisms by which VEGF coordinates neurovascular homeostasis has become more sophisticated. The central role of VEGF in the pathogenesis of diverse cancers and blinding eye diseases has also become evident. Elucidation of the molecular regulation of VEGF and the transformative development of multiple therapeutic pathways targeting VEGF directly or indirectly is a powerful case study of how fundamental research can guide innovation and translation. It is also an elegant example of how agnostic discovery and can transform our understanding of human disease. This review will highlight critical nodal points in VEGF biology, including recent developments in immunotherapy for cancer and multitarget approaches in neovascular eye disease.
Since it discovery two decades ago, VEGF has emerged as an important modulator of vascular biology, with therapeutics targeting VEGF signaling being central to the treatment of cancer and eye disease.
NAD+ availability decreases with age and in certain disease conditions. Nicotinamide mononucleotide (NMN), a key NAD+ intermediate, has been shown to enhance NAD+ biosynthesis and ameliorate various ...pathologies in mouse disease models. In this study, we conducted a 12-month-long NMN administration to regular chow-fed wild-type C57BL/6N mice during their normal aging. Orally administered NMN was quickly utilized to synthesize NAD+ in tissues. Remarkably, NMN effectively mitigates age-associated physiological decline in mice. Without any obvious toxicity or deleterious effects, NMN suppressed age-associated body weight gain, enhanced energy metabolism, promoted physical activity, improved insulin sensitivity and plasma lipid profile, and ameliorated eye function and other pathophysiologies. Consistent with these phenotypes, NMN prevented age-associated gene expression changes in key metabolic organs and enhanced mitochondrial oxidative metabolism and mitonuclear protein imbalance in skeletal muscle. These effects of NMN highlight the preventive and therapeutic potential of NAD+ intermediates as effective anti-aging interventions in humans.
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•NMN suppresses age-associated body weight gain and enhances energy metabolism•NMN improves insulin sensitivity, eye function, and other features with no toxicity•NMN prevents age-associated gene expression changes in a tissue-specific manner•NMN is an effective anti-aging intervention that could be translated to humans
Mills et al. conducted a 12-month-long administration of nicotinamide mononucleotide (NMN), a key natural NAD+ intermediate, to normal wild-type mice, demonstrating that NMN effectively mitigates age-associated physiological decline in mice without any obvious toxicity. These results highlight the significant potential of NMN as an effective anti-aging intervention in humans.
VEGF-A antagonists have revolutionized wet AMD treatment. Several challenges remain including high treatment burden requiring repeated intraocular injections for persistent disease. Brolucizumab ...directly inhibits VEGF-A function, providing visual outcomes comparable to aflibercept (an FDA-approved VEGF-A antagonist). Anatomic retinal outcomes including retinal fluid, a marker of disease activity, favored brolucizumab. To view this Bench to Bedisde, open or download the PDF.
VEGF-A antagonists have revolutionized wet AMD treatment. Several challenges remain including high treatment burden requiring repeated intraocular injections for persistent disease. Brolucizumab directly inhibits VEGF-A function, providing visual outcomes comparable to aflibercept (an FDA-approved VEGF-A antagonist). Anatomic retinal outcomes including retinal fluid, a marker of disease activity, favored brolucizumab. To view this Bench to Bedisde, open or download the PDF.
Photoreceptor death is the endpoint of many blinding diseases. Identifying unifying pathogenic mechanisms in these diseases may offer global approaches for facilitating photoreceptor survival. We ...found that rod or cone photoreceptor-specific deletion of nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in the major NAD+ biosynthetic pathway beginning with nicotinamide, caused retinal degeneration. In both cases, we could rescue vision with nicotinamide mononucleotide (NMN). Significantly, retinal NAD+ deficiency was an early feature of multiple mouse models of retinal dysfunction, including light-induced degeneration, streptozotocin-induced diabetic retinopathy, and age-associated dysfunction. Mechanistically, NAD+ deficiency caused metabolic dysfunction and consequent photoreceptor death. We further demonstrate that the NAD+-dependent mitochondrial deacylases SIRT3 and SIRT5 play important roles in retinal homeostasis and that NAD+ deficiency causes SIRT3 dysfunction. These findings demonstrate that NAD+ biosynthesis is essential for vision, provide a foundation for future work to further clarify the mechanisms involved, and identify a unifying therapeutic target for diverse blinding diseases.
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•Rod or cone photoreceptor-specific deletion of Nampt causes retinal degeneration•Mouse models of retinal dysfunction exhibit early retinal NAD+ deficiency•SIRT3/SIRT5 is important for NAD+-dependent retinal homeostasis•NAD+ deficiency causes metabolic dysfunction and SIRT3 dysfunction
Despite genotypic and phenotypic diversity, blinding diseases often share a common endpoint of photoreceptor death. Lin et al. find that the dominant mammalian NAD+ biosynthesis pathway beginning with nicotinamide is essential for vision and that retinal NAD+ deficiency is an early feature of retinal dysfunction that precedes retinal degeneration.
IMPORTANCE: Biomarker testing for asymptomatic, preclinical Alzheimer disease (AD) is invasive and expensive. Optical coherence tomographic angiography (OCTA) is a noninvasive technique that allows ...analysis of retinal and microvascular anatomy, which is altered in early-stage AD. OBJECTIVE: To determine whether OCTA can detect early retinal alterations in cognitively normal study participants with preclinical AD diagnosed by criterion standard biomarker testing. DESIGN, SETTING, AND PARTICIPANTS: This case-control study included 32 participants recruited from the Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St Louis, St Louis, Missouri. Results of extensive neuropsychometric testing determined that all participants were cognitively normal. Participants underwent positron emission tomography and/or cerebral spinal fluid testing to determine biomarker status. Individuals with prior ophthalmic disease, media opacity, diabetes, or uncontrolled hypertension were excluded. Data were collected from July 1, 2016, through September 30, 2017, and analyzed from July 30, 2016, through December 31, 2017. MAIN OUTCOMES AND MEASURES: Automated measurements of retinal nerve fiber layer thickness, ganglion cell layer thickness, inner and outer foveal thickness, vascular density, macular volume, and foveal avascular zone were collected using an OCTA system from both eyes of all participants. Separate model III analyses of covariance were used to analyze individual data outcome. RESULTS: Fifty-eight eyes from 30 participants (53% female; mean SD age, 74.5 5.6 years; age range, 62-92 years) were included in the analysis. One participant was African American and 29 were white. Fourteen participants had biomarkers positive for AD and thus a diagnosis of preclinical AD (mean SD age, 73.5 4.7 years); 16 without biomarkers served as a control group (mean SD age, 75.4 6.6 years). The foveal avascular zone was increased in the biomarker-positive group compared with controls (mean SD, 0.364 0.095 vs 0.275 0.060 mm2; P = .002). Mean (SD) inner foveal thickness was decreased in the biomarker-positive group (66.0 9.9 vs 75.4 10.6 μm; P = .03). CONCLUSIONS AND RELEVANCE: This study suggests that cognitively healthy individuals with preclinical AD have retinal microvascular abnormalities in addition to architectural alterations and that these changes occur at earlier stages of AD than has previously been demonstrated. Longitudinal studies in larger cohorts are needed to determine whether this finding has value in identifying preclinical AD.
Loss of retinal photoreceptor cells is a critical event in loss of vision. A new, albeit tentative, strategy to rectify the loss of photoreceptor cells involves reprogramming fibroblasts into ...chemically induced photoreceptor-like cells.
Aging is a significant risk factor for impaired tissue functions and chronic diseases. Age-associated decline in systemic NAD+ availability plays a critical role in regulating the aging process ...across many species. Here, we show that the circulating levels of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) significantly decline with age in mice and humans. Increasing circulating eNAMPT levels in aged mice by adipose-tissue-specific overexpression of NAMPT increases NAD+ levels in multiple tissues, thereby enhancing their functions and extending healthspan in female mice. Interestingly, eNAMPT is carried in extracellular vesicles (EVs) through systemic circulation in mice and humans. EV-contained eNAMPT is internalized into cells and enhances NAD+ biosynthesis. Supplementing eNAMPT-containing EVs isolated from young mice significantly improves wheel-running activity and extends lifespan in aged mice. Our findings have revealed a novel EV-mediated delivery mechanism for eNAMPT, which promotes systemic NAD+ biosynthesis and counteracts aging, suggesting a potential avenue for anti-aging intervention in humans.
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•Circulating levels of eNAMPT decline with age in both mice and humans•Increasing eNAMPT promotes NAD+, counteracts aging, and extends healthspan in mice•eNAMPT is contained exclusively in extracellular vesicles (EVs) in mice and humans•Supplementing eNAMPT in EVs improves physical activity and extends lifespan in mice
Yoshida et al. demonstrate that the levels of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) decline with age in mice and humans. Increasing eNAMPT promotes NAD+, counteracting aging and extending healthspan. eNAMPT is contained in extracellular vesicles (EVs). Supplementing eNAMPT-containing EVs improves physical activity and extends mouse lifespan, suggesting a potential anti-aging intervention.
To evaluate the relative efficacy of as needed versus treat and extend regimen for the treatment of neovascular age-related macular degeneration (AMD).
We conducted a systematic review of studies ...that evaluated the efficacy of as needed or treat and extend regimen for neovascular AMD by searching multiple databases up to December 2013. Included studies were selected based on study duration of no less than 12 months, availability of outcome data, treatment protocol for as needed groups or pro re nata (PRN) receiving bevacizumab or ranibizumab, and all studies with treat extend protocols following the 'inject and extend' regimen. The outcome data were pooled and analysed.
1046 peer reviewed articles meeting our initial search criteria were returned. After further review by two independent reviewers, 8 studies meeting treat and extend protocol and 62 studies meeting PRN protocol were included. The mean improvement in visual acuity in the PRN group was 5.4 ETDRS letters compared with 10.4 ETDRS letters in the treat and extend group. The PRN group received an average of 5.60 injections at 1 year compared with 8.09 in the treat and extend group. Central retinal thickness improved on average by 100.32 µ in the PRN group compared with 87.7 µ in the treat and extend group.
Though our study suggests superiority of the treat and extend regimen to PRN treatment in a 12-month period, this review demonstrates the need for randomised clinical trials to confirm our findings and to evaluate long-term efficacy outcomes with these regimens compared with monthly therapy.
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