ORCID Profile
0000-0001-6635-6681
Current Organisations
University of Virginia
,
University of New South Wales
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Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 04-08-2020
DOI: 10.1167/IOVS.61.10.4
Publisher: Cold Spring Harbor Laboratory
Date: 08-11-2021
DOI: 10.1101/2021.11.05.467533
Abstract: Subretinal injection (SRI) in mice is widely used in retinal research, yet the learning curve (LC) of this surgically challenging technique is unknown. To evaluate the LC for SRI in a murine model, we analyzed training data from 3 clinically trained ophthalmic surgeons from 2018 to 2020. Successful SRI was defined as either the absence of retinal pigment epithelium (RPE) degeneration after phosphate buffer saline injection and the presence of RPE degeneration after Alu RNA injection. Multivariable survival-time regression models were used to evaluate the association between surgeon experience and success rate, with adjustment for injection agents, and to calculate an approximate case number to achieve a 95% success rate. A Cumulative Sum (CUSUM) analysis was performed and plotted in idually to monitor each surgeon’s simultaneous performance. Despite prior microsurgery experience, the combined average success rate of the first 50 cases in mice was only 27%. The predicted SRI success rate did not reach a plateau above 95% until approximately 364 prior cases. Using the 364-training case as a “cutoff” point, the predicted probability of success before and after the 364 th case was 65.38% and 99.32%, respectively ( P 0.0001). CUSUM analysis showed an initial upward slope and then remained within the decision intervals with an acceptable success rate set at 95% in the late stage. This study demonstrates the complexity and substantial LC for successful SRI in mice with high confidence. A systematic training system could improve the reliability and reproducibility of SRI-related experiments and improve the interpretation of experimental results using this technique. Our prediction model and monitor system allow objective quantification of technical proficiency in the field of subretinal drug delivery and gene therapy for the first time.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 10-2021
Abstract: Endogenous Alu cDNA triggers inflammasome-mediated cell death in age-related macular degeneration.
Publisher: Proceedings of the National Academy of Sciences
Date: 02-2021
Abstract: Alu elements, comprising more than 10% of the human genome, propagate via retrotransposition. This genomic expansion requires enzymatic activity of L1 that reverse transcribes Alu RNA into Alu cDNA in the nucleus. We report Alu also undergoes L1-mediated reverse transcription via self-priming in the cytoplasm independent of retrotransposition, providing evidence of human DNA synthesis in this cellular compartment. This newly discovered shunt molecule in the Alu replication cycle also induces death of the retinal pigmented epithelium, a hallmark of atrophic age-related macular degeneration. A Big Data Archeology analysis of multiple health insurance databases reveals that use of FDA-approved nucleoside reverse transcriptase inhibitors is associated with protection against macular degeneration, identifying a repurposing candidate for this blinding disease.
Publisher: Springer Science and Business Media LLC
Date: 14-04-2021
DOI: 10.1038/S41392-021-00537-Z
Abstract: Nonfibrillar amyloid-β oligomers (AβOs) are a major component of drusen, the sub-retinal pigmented epithelium (RPE) extracellular deposits characteristic of age-related macular degeneration (AMD), a common cause of global blindness. We report that AβOs induce RPE degeneration, a clinical hallmark of geographic atrophy (GA), a vision-threatening late stage of AMD that is currently untreatable. We demonstrate that AβOs induce activation of the NLRP3 inflammasome in the mouse RPE in vivo and that RPE expression of the purinergic ATP receptor P2RX7, an upstream mediator of NLRP3 inflammasome activation, is required for AβO-induced RPE degeneration. Two classes of small molecule inflammasome inhibitors—nucleoside reverse transcriptase inhibitors (NRTIs) and their antiretrovirally inert modified analog Kamuvudines—both inhibit AβOs-induced RPE degeneration. These findings crystallize the importance of P2RX7 and NLRP3 in a disease-relevant model of AMD and identify inflammasome inhibitors as potential treatments for GA.
Publisher: Springer Science and Business Media LLC
Date: 24-11-2018
DOI: 10.1038/EYE.2017.241
Publisher: MDPI AG
Date: 30-07-2018
Abstract: Neovascular age-related macular degeneration (nAMD) is one of the leading causes of blindness among the aging population. The current treatment options for nAMD include intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF). However, standardized frequent administration of anti-VEGF injections only improves vision in approximately 30–40% of nAMD patients. Current therapies targeting nAMD pose a significant risk of retinal fibrosis and geographic atrophy (GA) development in nAMD patients. A need exists to develop new therapies to treat nAMD with effective and long-term anti-angiogenic effects. Recent research on nAMD has identified novel therapeutic targets and angiogenic signaling mechanisms involved in its pathogenesis. For ex le, tissue factor, human intravenous immune globulin, interferon-β signaling, cyclooxygenase-2 (COX-2) and cytochrome P450 monooxygenase lipid metabolites have been identified as key players in the development of angiogenesis in AMD disease models. Furthermore, novel therapies such as NACHT, LRR and PYD domains containing protein 3 (NLRP3) inflammasome inhibition, inhibitors of integrins and tissue factor are currently being tested at the level of clinical trials to treat nAMD. The aim of this review is to discuss the scope for alternative therapies proposed as anti-VEGFs for the treatment of nAMD.
No related grants have been discovered for Praveen Yerramothu.