The Survival of Cone Photoreceptors in Retinitis Pigmentosa

Wong, Fulton; Kwok, Shiu Y.

doi:10.1001/jamaophthalmol.2015.5490

Cited by 21 publications

(17 citation statements)

References 7 publications

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“…Interestingly, Nampt −rod/−rod mice also exhibited deficits in cone function, as manifested by a decline in the amplitudes of the photopic b-waves (Fig 1H). Although Nampt deletion was specifically in rods, this cone dysfunction was not surprising; cone photoreceptor degeneration is often observed as a secondary effect of rod photoreceptor degeneration since rods are required for cone survival (Ait-Ali et al, 2015; Wong and Kwok, 2016). Consistently, by 6 weeks, Nampt −rod/−rod mice had significantly worse photopic visual acuity compared to age-matched Nampt F/F controls (Fig 1I).…”

Section: Resultsmentioning

confidence: 99%

NAMPT-Mediated NAD+ Biosynthesis Is Essential for Vision In Mice

et al. 2016

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SUMMARY 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/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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Section: Resultsmentioning

confidence: 99%

NAMPT-Mediated NAD+ Biosynthesis Is Essential for Vision In Mice

et al. 2016

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“…WJ-MSCs secrete trophic factors that stimulate RPE or secrete trophic factors that are similar to those produced by RPE [19][20][21]. In studies using animal models, WJ-MSCs have been found to be effective in stopping the progression of retinal degeneration and for rescuing photoreceptors in the dormant phase [22][23][24][25][26]. WJ-MSCs are hypoimmunogenic and have significant immunomodulatory properties.…”

Section: Introductionmentioning

confidence: 99%

Management of retinitis pigmentosa by Wharton’s jelly derived mesenchymal stem cells: preliminary clinical results

Özmert

Arslan

2020

Stem Cell Res Ther

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Purpose: The aim of this study is to determine if umbilical cord Wharton's jelly derived mesenchymal stem cells implanted in sub-tenon space have beneficial effects on visual functions in retinitis pigmentosa patients by reactivating the degenerated photoreceptors in dormant phase. Material and methods:This prospective, open-label, phase-3 clinical trial was conducted between April of 2019 and October of 2019 at Ankara University Faculty of Medicine, Department of Ophthalmology. 32 RP patients (34 eyes) were included in the study. The patients were followed for 6 months after the Wharton's jelly derived mesenchymal stem cell administration, and evaluated with consecutive examinations. All patients underwent a complete routine ophthalmic examination, and best corrected visual acuity, optical coherens tomography angiography, visual field, multifocal and full-field electroretinography were performed. The quantitative results were obtained from a comparison of the pre-injection and final examination (6th month) values.Results: The mean best corrected visual acuity was 70.5 letters prior to Wharton's jelly derived mesenchymal stem cell application and 80.6 letters at the 6th month (p = 0.01). The mean visual field median deviation value was 27.3 dB before the treatment and 24.7 dB at the 6th month (p = 0.01). The mean outer retinal thickness was 100.3 μm before the treatment and 119.1 μm at 6th month (p = 0.01). In the multifocal electroretinography results, P1 amplitudes improved in ring1 from 24.8 to 39.8 nv/deg2 (p = 0.01), in ring2 from 6.8 to 13.6 nv/deg2 (p = 0.01), and in ring3 from 3.1 to 5.7 nv/deg2 (p = 0.02). P1 implicit times improved in ring1 from 44.2 to 32.4 ms (p = 0.01), in ring2 from 45.2 to 33.2 ms (p = 0.02), and in ring3 from 41.9 to 32.4 ms (p = 0.01). The mean amplitude improved in 16 Tds from 2.4 to 5.0 nv/deg2 (p = 0.01) and in 32 Tds from 2.4 to 4.8 nv/deg2 (p = 0.01) in the full-field flicker electroretinography results. Full field flicker electroretinography mean implicit time also improved in 16 Tds from 43.3 to 37.9 ms (p = 0.01). No ocular or systemic adverse events related to the two types of surgical methods and/or Wharton's jelly derived mesenchymal stem cells itself were observed during the follow-up period.Conclusion: RP is a genetic disorder that can result in blindness with outer retinal degeneration. Regardless of the type of genetic mutation, sub-tenon Wharton's jelly derived mesenchymal stem cell administration appears to be an effective and safe option. There are no serious adverse events or ophthalmic / systemic side effects for 6 months follow-up. Although the long-term adverse effects are still unknown, as an extraocular approach, subtenon implantation of the stem cells seems to be a reasonable way to avoid the devastating side effects of intravitreal/submacular injection. Further studies that include long-term follow-up are needed to determine the duration of efficacy and the frequency of application.

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“…Cones concentrated in the macula are responsible for high-resolution daylight vision utilized for reading, facial recognition and other daily tasks, and their loss of function is the most debilitating aspect of RP. This diminished cone function is highlighted by loss of functional structures including visual pigment-rich outer segments (OS), and mitochondrial-rich inner segments (IS) (Cai et al 2014; Litts et al 2015; Wong and Kwok 2016). Despite the loss of functional structures, there is long-term persistence of macular cone cell bodies consisting of little more than a nucleus in RP patients, which has been referred to as dormancy (Lin et al 2009; Busskamp et al 2010; Busskamp et al 2012; Sahel et al 2013; Wong and Kwok 2016).…”

Section: Introductionmentioning

confidence: 99%

“…This diminished cone function is highlighted by loss of functional structures including visual pigment-rich outer segments (OS), and mitochondrial-rich inner segments (IS) (Cai et al 2014; Litts et al 2015; Wong and Kwok 2016). Despite the loss of functional structures, there is long-term persistence of macular cone cell bodies consisting of little more than a nucleus in RP patients, which has been referred to as dormancy (Lin et al 2009; Busskamp et al 2010; Busskamp et al 2012; Sahel et al 2013; Wong and Kwok 2016). Although neuroprotective agents show promise in delaying onset of cone dormancy in RP animal models, they do not cause reassembly of cone IS or reactivation of OS synthesis, and thus, restoration of electrophysiologic function in dormant cones (Sahel et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Two-Step Reactivation of Dormant Cones in Retinitis Pigmentosa

et al. 2016

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Most Retinitis Pigmentosa (RP) mutations arise in rod photoreceptor genes, leading to diminished peripheral and nightime vision. Using a pig model of autosomal-dominant RP, we show glucose becomes sequestered in the retinal pigment epithelium (RPE), and thus is not transported to photoreceptors. The resulting starvation for glucose metabolites impairs synthesis of cone visual pigment -rich outer segments (OS), and then their mitochondrial-rich inner segments dissociate. Loss of these functional structures diminishes cone-dependent high-resolution central vision, which is utilized for most daily tasks. By transplanting wild-type rods, to restore glucose transport, or directly replacing glucose in the subretinal space, to bypass its retention in the RPE, we can regenerate cone functional structures, reactivating the dormant cells. Beyond providing metabolic building blocks for cone functional structures, we show glucose induces thioredoxin-interacting protein (Txnip) to regulate Akt signaling, thereby shunting metabolites toward aerobic glucose metabolism and regenerating cone OS synthesis.

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The Survival of Cone Photoreceptors in Retinitis Pigmentosa

Cited by 21 publications

References 7 publications

NAMPT-Mediated NAD+ Biosynthesis Is Essential for Vision In Mice

NAMPT-Mediated NAD+ Biosynthesis Is Essential for Vision In Mice

Management of retinitis pigmentosa by Wharton’s jelly derived mesenchymal stem cells: preliminary clinical results

Two-Step Reactivation of Dormant Cones in Retinitis Pigmentosa

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