Differential effects of risuteganib and bevacizumab on AMD cybrid cells

Schneider, Kevin; Chwa, Marilyn; Atilano, Shari R.; Shao, Zixuan; Park, John; Karageozian, Hampar; Karageozian, Vicken; Kenney, M. Cristina

doi:10.1016/j.exer.2020.108287

Cited by 8 publications

(7 citation statements)

References 46 publications

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“…Previous studies also found RSG beneficially regulated disease-relevant genes in RPE cells, 24 , 25 but this is the first report of a similar behavior in a Müller cell line. To confirm the observed RNA-seq expression profiles, we used qRT-PCR to validate the expression of 12 genes each in ARPE-19 and MIO-M1 cells, selected for known function in ECM organization and cell adhesion, migration, death, and proliferation.…”

Section: Discussionsupporting

confidence: 44%

“…Our current findings suggest RSG's therapeutic effect may involve favorably regulation of cell death, neovascularization, inflammation, and metabolic dysfunction, which are involved in the pathophysiology of the clinically studied retinal diseases. 24 , 25 These results expand our understanding of RSG's mechanism of action and support further clinical trials in the currently targeted indications and other pathologically relevant retinal diseases such as retinitis pigmentosa and glaucoma. More broadly, these pathological mechanisms are present in many human diseases, where RSG may potentially serve as a novel therapeutic option.…”

Section: Discussionmentioning

confidence: 54%

“… 60 , 61 In the context of RSG biology, regulation of integrin signaling pathways is not surprising as the drug has been shown to modulate expression of integrin genes and integrin-associated processes such as cell adhesion and migration. 24 , 25 …”

Section: Discussionmentioning

confidence: 99%

“… 24 In RPE cells constructed to contain AMD donor mitochondria, RSG exposure reduced the expression of apoptosis and angiogenesis genes. 25 …”

Section: Introductionmentioning

confidence: 99%

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The Transcriptome Profile of Retinal Pigment Epithelium and Müller Cell Lines Protected by Risuteganib Against Hydrogen Peroxide Stress

Shao

Chwa

Atilano

et al. 2022

Journal of Ocular Pharmacology and Therapeutics

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Purpose: Oxidative stress contributes to the pathogenesis of vision-impairing diseases. In the retina, retinal pigment epithelium (RPE) and Müller cells support neuronal homeostasis, but also contribute to pathological development under stressed conditions. Recent studies found that the investigational drug risuteganib (RSG) has a good safety profile, provided protection in experimental models, and improved visual acuity in patients. The present in vitro study evaluated the effects of RSG in RPE and Müller cell lines stressed with the oxidant hydrogen peroxide (H 2 O 2 ). Methods: Human RPE (ARPE-19) and Müller (MIO-M1) cell lines were treated with various combinations of RSG and H 2 O 2 . Trypan blue assay was used to investigate the effect of compounds on cell viability. Gene expression was measured using RNA sequencing to identify regulated genes and the biological processes and pathways involved. Results: Trypan blue assay found RSG pre-treatment significantly protected against H 2 O 2 -induced cell death in ARPE-19 and MIO-M1 cells. Transcriptome analysis found H 2 O 2 regulated genes in several disease-relevant biological processes, including cell adhesion, migration, death, and proliferation; ECM organization; angiogenesis; metabolism; and immune system processes. RSG pre-treatment modulated these gene expression profiles in the opposite direction of H 2 O 2 . Pathway analysis found genes in integrin, AP-1, and syndecan signaling pathways were regulated. Expression of selected RSG-regulated genes was validated using qRT-PCR. Conclusions: RSG protected cultured human RPE and Müller cell lines against H 2 O 2 -induced cell death and mitigated the associated transcriptome changes in biological processes and pathways relevant to the pathogenesis of retinal diseases. These results demonstrate RSG reduced oxidative stress-induced toxicity in two retinal cell lines with potential relevance to the treatment of human diseases.

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Section: Discussionsupporting

confidence: 44%

Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 99%

“… 24 In RPE cells constructed to contain AMD donor mitochondria, RSG exposure reduced the expression of apoptosis and angiogenesis genes. 25 …”

Section: Introductionmentioning

confidence: 99%

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The Transcriptome Profile of Retinal Pigment Epithelium and Müller Cell Lines Protected by Risuteganib Against Hydrogen Peroxide Stress

Shao

Chwa

Atilano

et al. 2022

Journal of Ocular Pharmacology and Therapeutics

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“…15 In RPE cells containing mitochondria derived from AMD patients, risuteganib exposure was associated with reduced expression of genes associated with apoptosis (BAX), angiogenesis (VEGFA) and integrin function (ITGB1). 16 Pharmacokinetics studies found risuteganib has a long half-life in the retina after intravitreal injection, whereas ex vivo studies suggest the peptide may be specifically localized to the RPE cells, where it may play a role in preserving and reversing the diseased cellular state. 17 This is further supported by studies from multiple labs that demonstrated improved mitochondrial bioenergetics and metabolic activity after risuteganib treatment, indicating potential reactivation of patient RPE with diminished mitochondrial function.…”

Section: Introductionmentioning

confidence: 99%

Safety and Efficacy of Intravitreal Risuteganib for Non-Exudative AMD: A Multicenter, Phase 2a, Randomized, Clinical Trial

Boyer¹,

González²,

Kunimoto³

et al. 2021

Ophthalmic Surg Lasers Imaging Retina

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BACKGROUND AND OBJECTIVE:To evaluate the safety and efficacy of 1.0 mg risuteganib in subjects with nonexudative age-related macular degeneration (AMD). PATIENTS AND METHODS:This was a phase 2a, prospective, double-masked, sham-controlled study. Eyes with nonexudative (dry) AMD and Early Treatment Diabetic Retinopathy Study (ETDRS) bestcorrected visual acuity (BCVA) between 20/40 and 20/200 were included. Subjects were randomized to intravitreal 1.0 mg risuteganib or sham injection. At Week 16, subjects in the risuteganib group received a second 1.0-mg dose and the sham group crossed over to receive a dose of 1.0 mg risuteganib and were evaluated at Week 28. The primary endpoint was proportion of subjects with 8 letters ETDRS or more BCVA gain from baseline to Week 28 in the risuteganib group versus baseline to Week 12 for the sham group. BCVA was tested and subjects were observed for adverse events (AEs) every 4 weeks until completion of the study at 32 weeks. RESULTS:Forty-five subjects (risuteganib, n = 29; sham, n = 16) were enrolled in the study, of whom 39 (risuteganib, n = 25; sham, n = 14) completed the study and were included in the per protocol efficacy analysis. At baseline, mean age was 78.8 and 75.9 years and mean BCVA was 67.1 and 64.4 letters in the sham and risuteganib groups, respectively. The primary endpoint was met by 48% of the risuteganib group at Week 28 and 7% of the sham group at Week 12 (P = .013). Of the risuteganib subjects, 20% gained 15 letters or more at Week 28, whereas no patients in the sham group at Week 12 achieved this visual acuity gain. The only ocular treatmentrelated treatment-emergent AE was vitreous floaters, which spontaneously recovered without sequelae. No drug-related serious AE was reported. CONCLUSIONS:Risuteganib demonstrated significant BCVA improvement in patients with non-exudative AMD. No drug-related AEs were seen during a 32week observation period.

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Environmental exposures to cadmium and lead as potential causes of eye diseases

Ebrahimi,

Vergroesen

et al. 2024

Journal of Trace Elements in Medicine and Biology

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Differential effects of risuteganib and bevacizumab on AMD cybrid cells

Cited by 8 publications

References 46 publications

The Transcriptome Profile of Retinal Pigment Epithelium and Müller Cell Lines Protected by Risuteganib Against Hydrogen Peroxide Stress

The Transcriptome Profile of Retinal Pigment Epithelium and Müller Cell Lines Protected by Risuteganib Against Hydrogen Peroxide Stress

Safety and Efficacy of Intravitreal Risuteganib for Non-Exudative AMD: A Multicenter, Phase 2a, Randomized, Clinical Trial

Environmental exposures to cadmium and lead as potential causes of eye diseases

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