scholarly journals Rod photoreceptor clearance due to misfolded rhodopsin is linked to a DAMP-immune checkpoint switch

2020 ◽  
pp. jbc.RA120.016053
Author(s):  
Sang Joon Lee ◽  
Wei Wang ◽  
Lei Jin ◽  
Xiaoqin Lu ◽  
Lei Gao ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Glucose Transport ◽  
Immune Checkpoint ◽  
Visual Pigment ◽  
Peripheral Vision ◽  
Live Cells ◽  
Rod Photoreceptor ◽  
Rod Photoreceptors ◽  
Molecular Pattern ◽  
Cone Function

Chronic ER stress resulting from misfolding of the visual pigment rhodopsin (RHO) can lead to loss of rod photoreceptors, which initiates Retinitis Pigmentosa, characterized initially by diminished nighttime and peripheral vision.  Cone photoreceptors depend on rods for glucose transport, which the neurons use for assembly of visual pigment-rich structures; as such, loss of rods also leads to a secondary loss of cone function, diminishing high resolution color vision utilized for tasks including reading, driving and facial recognition.  If dysfunctional rods could be maintained to continue to serve this secondary cone preservation function, it might benefit to patients with Retinitis Pigmentosa, but the mechanisms by which rods are removed are not fully established. Using pigs expressing mutant RHO , we find that induction of a Danger-Associated Molecular Pattern (DAMP) “eat me” signal on the surface of mutant rods is correlated with targeting the live cells for programmed cell removal (PrCR) by retinal myeloid cells.  Glucocorticoid therapy leads to replacement of this DAMP with a “don’t eat me” immune checkpoint on the rod surface and inhibition of PrCR.  Surviving rods then continue to promote glucose transport to cones, maintaining their viability.

scholarly journals A Zebrafish Model of Retinitis Pigmentosa Shows Continuous Degeneration and Regeneration of Rod Photoreceptors

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2242
Author(s):  
Abirami Santhanam ◽  
Eyad Shihabeddin ◽  
Joshua A. Atkinson ◽  
Duc Nguyen ◽  
Ya-Ping Lin ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Transgenic Fish ◽  
Model Systems ◽  
Brdu Incorporation ◽  
Rod Photoreceptor ◽  
Adult Fish ◽  
Zebrafish Model ◽  
Rod Photoreceptors ◽  
Outer Segments ◽  
Regenerative Therapies

More than 1.5 million people suffer from Retinitis Pigmentosa, with many experiencing partial to complete vision loss. Regenerative therapies offer some hope, but their development is challenged by the limited regenerative capacity of mammalian model systems. As a step toward investigating regenerative therapies, we developed a zebrafish model of Retinitis Pigmentosa that displays ongoing regeneration. We used Tol2 transgenesis to express mouse rhodopsin carrying the P23H mutation and an epitope tag in zebrafish rod photoreceptors. Adult and juvenile fish were examined by immunofluorescence, TUNEL and BrdU incorporation assays. P23H transgenic fish expressed the transgene in rods from 3 days post fertilization onward. Rods expressing the mutant rhodopsin formed very small or no outer segments and the mutant protein was delocalized over the entire cell. Adult fish displayed thinning of the outer nuclear layer (ONL) and loss of rod outer segments, but retained a single, sparse row of rods. Adult fish displayed ongoing apoptotic cell death in the ONL and an abundance of proliferating cells, predominantly in the ONL. There was a modest remodeling of bipolar and Müller glial cells. This transgenic fish will provide a useful model system to study rod photoreceptor regeneration and integration.

Ayurvedic management of Retinitis Pigmentosa (Doshandha) - A Case Study

2017 ◽  
Vol 2 (05) ◽  
Author(s):  
Anju D. ◽  
Pushpa Raj Poudel ◽  
Ajoy Viswam ◽  
Ashwini M. J.
Keyword(s):  
Retinitis Pigmentosa ◽  
Low Vision ◽  
Symptomatic Relief ◽  
Retinal Dystrophy ◽  
Treatment Protocol ◽  
Signs And Symptoms ◽  
Photoreceptor Cells ◽  
Rod Photoreceptor ◽  
Night Time ◽  
Initial Symptoms

Retinitis pigmentosa (RP) is an inherited, degenerative eye disease that causes severe vision impairment due to the progressive degeneration of rod photoreceptor cells in retina. This form of retinal dystrophy manifests initial symptoms independentof age; thus, RP diagnosis occurs anywhere from early infancy to late adulthood. This primary pigmentary retinal dystrophy is a hereditary disorder predominantly affecting the rods more than the cones. The main classical triads of retinitis pigmentosa are arteriolar attenuation, Retinal bone spicule pigmentation and Waxy disc pallor. The main treatment of retinitis pigmentosa is by using Low vision aids (LVA) and Genetic counseling. As such a complete cure for retinitis pigmentosa is not present. So a treatment protocol has to be adopted that helps in at least the symptomatic relief. In Ayurveda, the signs and symptoms of this can be compared with the Lakshanas of Doshandha which is one among the Dristigata Roga. It is considered as a diseased condition in which sunset will obliterate the Dristi Mandala and makes the person blind at night time. During morning hours the rising sunrays will disperse the accumulated Dosas from Dristi to clear vision. This disease resembles Kaphajatimira in its pathogenesis, but the night blindness is the special feature. Since the disease is purely Kaphaja, a treatment attempt is planned in Kaphara and Brimhana line. The present paper discusses a case of retinitis pigmentosa and it’s Ayurvedic Treatment.

IMMU-06. COMBINATORIAL IMMUNE CHECKPOINT INHIBITORS FOR TARGETED INTRATUMORAL DELIVERY IN GBM

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi93-vi93
Author(s):  
Stephanie Sanders ◽  
Denise Herpai ◽  
Waldemar Debinski
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cell Activity ◽  
Live Cells ◽  
Normal Brain ◽  
Cytotoxic Therapies ◽  
Checkpoint Receptors

Abstract Glioblastoma (GBM) is an immunologically cold tumor. Using single cell sequencing of CD45+ cells we confirmed that T cells are present within GBM samples. These T cells are positive for exhaustion markers such as LAG3 and TIGIT, as well as CTLA4 and PD1 checkpoint receptors. Modulating T cell activity through use of immune checkpoint inhibitors (ICIs) has shown efficacy in the treatment of a variety of solid tumors, and the combination of anti-CTLA4 and anti-PD1 ICIs has shown increased efficacy over use of a single therapeutic. Additionally, targeting ICIs to the tumor cells may increase efficacy of this treatment. We therefore constructed a combinatorial ICI redirected to GBM via interleukin 13 receptor alpha 2 (IL13RA2), a receptor over-expressed on the majority of GBM cells but not normal brain. The first component of the construct, labeled with a histidine tag, targets CTLA4 while the second component, tagged with a StrepII tag, targets PD1. The tags added to the constructs will allow for purification of a combinatorial heterodimer simultaneously targeting PD1, CTLA4 and IL13RA2. We purified individual components via fast protein liquid chromatography (FPLC) using a proteinG column followed by a HisTrap or StrepTrap column. We obtained a recombinant, targeted multivalent ICI at > 95% purity. We found that these constructs are able to bind their target receptors via ELISA in which the Kd values ranged from picomolar to low nanomolar range. Additionally, our constructs bind their target on live cells by flow cytometry. We next designed a heterodimeric construct which can combinatorially target CTLA4 and PD1 while also directing the ICI therapy to GBM. These constructs in conjunction with other immune stimulants like cytotoxic therapies are intended to facilitate the interaction between T cells and GBM tumor cells directly in a tumor microenvironment.

scholarly journals Beyond Sector Retinitis Pigmentosa: Expanding the Phenotype and Natural History of the Rhodopsin Gene Codon 106 Mutation (Gly-to-Arg) in Autosomal Dominant Retinitis Pigmentosa

Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 1853
Author(s):  
Brian G. Ballios ◽  
Emily M. Place ◽  
Luis Martinez-Velazquez ◽  
Eric A. Pierce ◽  
Jason I. Comander ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Autosomal Dominant ◽  
Peripheral Vision ◽  
Visual Fields ◽  
Macular Disease ◽  
History Of ◽  
Intrafamilial Variability ◽  
Long Term Prognosis

Sector and pericentral are two rare, regional forms of retinitis pigmentosa (RP). While usually defined as stable or only very slowly progressing, the available literature to support this claim is limited. Additionally, few studies have analyzed the spectrum of disease within a particular genotype. We identified all cases (9 patients) with an autosomal dominant Rhodopsin variant previously associated with sector RP (RHO c.316G > A, p.Gly106Arg) at our institution. Clinical histories were reviewed, and testing included visual fields, multimodal imaging, and electroretinography. Patients demonstrated a broad phenotypic spectrum that spanned regional phenotypes from sector-like to pericentral RP, as well as generalized disease. We also present evidence of significant intrafamilial variability in regional phenotypes. Finally, we present the longest-reported follow-up for a patient with RHO-associated sector-like RP, showing progression from sectoral to pericentral disease over three decades. In the absence of comorbid macular disease, the long-term prognosis for central visual acuity is good. However, we found that significant progression of RHO p.Gly106Arg disease can occur over protracted periods, with impact on peripheral vision. Longitudinal widefield imaging and periodic ERG reassessment are likely to aid in monitoring disease progression.

scholarly journals Loss of PRCD alters number and packaging density of rhodopsin in rod photoreceptor disc membranes

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Emily R. Sechrest ◽  
Joseph Murphy ◽  
Subhadip Senapati ◽  
Andrew F. X. Goldberg ◽  
Paul S.-H. Park ◽  
...  
Keyword(s):  
High Fidelity ◽  
Rod Photoreceptor ◽  
Photoreceptor Degeneration ◽  
Wild Type ◽  
Photoreceptor Outer Segment ◽  
Rod Photoreceptors ◽  
Force Microscopy ◽  
Atomic Force ◽  
Photoreceptor Neurons ◽  
Precise Role

Abstract Progressive rod-cone degeneration (PRCD) is a small protein localized to photoreceptor outer segment (OS) disc membranes. Several mutations in PRCD are linked to retinitis pigmentosa (RP) in canines and humans, and while recent studies have established that PRCD is required for high fidelity disc morphogenesis, its precise role in this process remains a mystery. To better understand the part which PRCD plays in disease progression as well as its contribution to photoreceptor OS disc morphogenesis, we generated a Prcd-KO animal model using CRISPR/Cas9. Loss of PRCD from the retina results in reduced visual function accompanied by slow rod photoreceptor degeneration. We observed a significant decrease in rhodopsin levels in Prcd-KO retina prior to photoreceptor degeneration. Furthermore, ultrastructural analysis demonstrates that rod photoreceptors lacking PRCD display disoriented and dysmorphic OS disc membranes. Strikingly, atomic force microscopy reveals that many disc membranes in Prcd-KO rod photoreceptor neurons are irregular, containing fewer rhodopsin molecules and decreased rhodopsin packing density compared to wild-type discs. This study strongly suggests an important role for PRCD in regulation of rhodopsin incorporation and packaging density into disc membranes, a process which, when dysregulated, likely gives rise to the visual defects observed in patients with PRCD-associated RP.

scholarly journals Targeting of the NRL Pathway as a Therapeutic Strategy to Treat Retinitis Pigmentosa

2020 ◽  
Vol 9 (7) ◽  
pp. 2224 ◽  
Author(s):  
Spencer M. Moore ◽  
Dorota Skowronska-Krawczyk ◽  
Daniel L. Chao
Keyword(s):  
Retinitis Pigmentosa ◽  
Autosomal Recessive ◽  
Therapeutic Strategy ◽  
Leucine Zipper ◽  
Retinal Dystrophy ◽  
Rod Photoreceptor ◽  
Cone Photoreceptor ◽  
Future Directions ◽  
Inherited Retinal Dystrophy ◽  
Visual Acuity Loss

Retinitis pigmentosa (RP) is an inherited retinal dystrophy (IRD) with a prevalence of 1:4000, characterized by initial rod photoreceptor loss and subsequent cone photoreceptor loss with accompanying nyctalopia, visual field deficits, and visual acuity loss. A diversity of causative mutations have been described with autosomal dominant, autosomal recessive, and X-linked inheritance and sporadic mutations. The diversity of mutations makes gene therapy challenging, highlighting the need for mutation-agnostic treatments. Neural leucine zipper (NRL) and NR2E3 are factors important for rod photoreceptor cell differentiation and homeostasis. Germline mutations in NRL or NR2E3 leads to a loss of rods and an increased number of cones with short wavelength opsin in both rodents and humans. Multiple groups have demonstrated that inhibition of NRL or NR2E3 activity in the mature retina could endow rods with certain properties of cones, which prevents cell death in multiple rodent RP models with diverse mutations. In this review, we summarize the literature on NRL and NR2E3, therapeutic strategies of NRL/NR2E3 modulation in preclinical RP models, as well as future directions of research. In summary, inhibition of the NRL/NR2E3 pathway represents an intriguing mutation agnostic and disease-modifying target for the treatment of RP.

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