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1.
Clin Infect Dis ; 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38728385

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and RNA debris persist in viral reservoirs for weeks to months following infection, potentially triggering interferon production and chronic inflammation. RSLV-132 is a biologic drug composed of catalytically active human RNase1 fused to human IgG1 Fc and is designed to remain in circulation and digest extracellular RNA. We hypothesized that removal of SARS-CoV-2 viral RNA from latent reservoirs may improve inflammation, neuroinflammation, and fatigue associated with post-acute sequelae of SARS-CoV-2 infection (PASC). METHODS: This was a phase 2, double-blind, placebo-controlled randomized clinical trial in participants with a 24-week history of PASC and severe fatigue. The primary endpoint of the trial assessed the impact of 6 intravenous doses of RSLV-132 on the mean change from baseline at day 71 in the Patient-Reported Outcomes Measurement Information System Fatigue Short Form 7a (PROMIS Fatigue SF 7a). RESULTS: A statistically significant difference on day 71 was not observed with respect to the primary or secondary endpoints. This was likely due to a placebo response that increased during the trial. Statistically significant improvement in fatigue as measured by the PROMIS Fatigue SF 7a, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), and Physicians Global Assessment (PGA) instruments were observed earlier in the trial, with women demonstrating greater responses to RSLV-132 than men. CONCLUSION: While fatigue was not statistically significantly improved at Day 71, earlier timepoints revealed statistically significant improvement in fatigue and physician global assessment. The data suggest eliminating latent viral RNA by increasing serum RNase activity may improve fatigue in PASC patients. Women may respond better to this approach than men. Future studies will aim to confirm these findings.

2.
Lupus Sci Med ; 11(1)2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38325898

RESUMO

BACKGROUND: Circulating, extracellular RNA is the primary trigger of type I interferon in systemic lupus erythematosus (SLE), and interferon is known to play a central pathogenic role in the disease. RSLV-132 is a catalytically active human RNase molecule fused to human IgG1 Fc designed to digest RNA and thereby decrease the chronic inflammation associated with SLE. The drug was evaluated in a cohort of patients with SLE with moderate-severe cutaneous disease activity and the presence of RNA immune complexes. The primary objective of the study was the assessment of the impact of 13 doses of 10 mg/kg RSLV-132 over 6 months on the mean Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) score. METHODS: Sixty-five patients meeting the entry criteria of a baseline CLASI score of 10 or greater and positivity of at least one of five autoantibodies to RNA-binding proteins (SM/RNP, SSA/Ro, SSB/La, Sm, RNP) were randomly assigned (2:1) to receive 13 doses of RSLV-132 10 mg/kg or placebo, respectively. Participants received study drug for 24 weeks on days 1, 8, 15, 29, 43, 57, 71, 85, 99, 113, 127, 141 and 155 with an end-of-treatment visit on day 169 and a follow-up visit at the end of the study on day 215. The primary objective was assessed on days 85 and 169. Secondary objectives included assessment of systemic disease activity using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), the British Isles Lupus Assessment Group 2004 Index and the Physician's Global Assessment. Data from these instruments were used to calculate the SLE Responder Index 4 (SRI-4) and the British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) scores. RESULTS: The mean CLASI score change from baseline at day 169 was -5.7 (±7.0) in the placebo group and -6.2 (±8.5) in the RSLV-132 group. A subgroup of participants with moderate-severe systemic disease activity and high baseline SLEDAI scores (≥9) were analysed with respect to BICLA and SRI-4 responses. The RSLV-132 treated participants in the high SLEDAI subgroup had a greater percentage of BICLA responses (62% vs 44%) and SRI-4 responses (23% vs 11%) as compared with placebo. A second subgroup of participants with high baseline CLASI scores (≥21) were analysed with respect to BICLA and SRI-4 responses. The RSLV-132 treated participants in the high CLASI subgroup had a greater percentage of BICLA responses (28% vs 8%) and SRI-4 responses (39% vs 8%) as compared with placebo. CONCLUSIONS: Six months of RSLV-132 therapy consisting of a weekly loading dose of RSLV-132 for 1 month, followed by 5 months of biweekly administrations did not significantly improve the mean CLASI score relative to placebo in this cohort of patients with SLE. The study entry criteria selected patients with moderate-severe cutaneous disease activity and no minimum SLEDAI score, which resulted in a wide range of systemic disease activity from inactive to severe as measured by SLEDAI. When the participants with higher SLEDAI and CLASI scores were analysed, a trend towards clinical improvement favouring RSLV-132 was observed. The results warrant further evaluation of RSLV-132 in SLE and suggest that patients with more active systemic disease are most likely to benefit from RNase therapy.


Assuntos
Lúpus Eritematoso Discoide , Lúpus Eritematoso Sistêmico , Proteínas Recombinantes de Fusão , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Resultado do Tratamento , Ribonucleases/uso terapêutico , Imunoglobulina G/uso terapêutico , Lúpus Eritematoso Discoide/induzido quimicamente , Lúpus Eritematoso Discoide/tratamento farmacológico , RNA/uso terapêutico
3.
Arthritis Rheumatol ; 73(1): 143-150, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32798283

RESUMO

OBJECTIVE: To assess the safety and efficacy of RSLV-132, an RNase Fc fusion protein, in a phase II randomized, double-blind, placebo-controlled clinical trial in patients with primary Sjögren's syndrome (SS). METHODS: Thirty patients with primary SS were randomized to receive treatment with RSLV-132 or placebo intravenously once per week for 2 weeks, and then every 2 weeks for 12 weeks. Eight patients received placebo and 20 patients received RSLV-132 at a dose of 10 mg/kg. Clinical efficacy measures included the European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index, EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Profile of Fatigue (ProF), and the Digit Symbol Substitution Test (DSST). RESULTS: Patients randomized to receive RSLV-132 experienced clinically meaningful improvements in the ESSPRI score (P = 0.27), FACIT-F score (P = 0.05), ProF score (P = 0.07), and DSST (P = 0.02) from baseline to day 99, whereas patients who received placebo showed no changes in any of these clinical efficacy measures. This improvement was significantly correlated with increased expression of selected interferon-inducible genes (Pearson's correlations, each P < 0.05). CONCLUSION: Administration of RSLV-132 improved severe fatigue, as determined by 4 independent patient-reported measures of fatigue, in patients with primary SS.


Assuntos
Fadiga/fisiopatologia , Imunoglobulina G/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Ribonucleases/uso terapêutico , Síndrome de Sjogren/tratamento farmacológico , Adulto , Idoso , Método Duplo-Cego , Feminino , Expressão Gênica , Humanos , Interferons/genética , Interferons/imunologia , Fadiga Mental/fisiopatologia , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Síndrome de Sjogren/genética , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/fisiopatologia , Resultado do Tratamento
4.
Arthritis Rheumatol ; 73(4): 718-719, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33164338
5.
J Immunol ; 197(7): 2854-63, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27534558

RESUMO

The loss of tolerance and the presence of circulating autoantibodies directed against nuclear Ags is the hallmark of systemic lupus erythematosus (SLE). Many of these Ags are complexed with short, noncoding RNAs, such as U1 and Y1. The amount of U1 and Y1 RNA complexed with SLE patient Abs and immune complexes was measured in a cross-section of 228 SLE patients to evaluate the role of these RNA molecules within the known biochemical framework of SLE. The study revealed that SLE patients had significantly elevated levels of circulating U1 and/or Y1 RNA compared with healthy volunteers. In addition, the blood-borne RNA molecules were correlated with SLE disease activity and increased expression of IFN-inducible genes. To our knowledge, this study provides the first systematic examination of the role of circulating RNA in a large group of SLE patients and provides an important link with IFN dysregulation.


Assuntos
Regulação da Expressão Gênica , Interferons/imunologia , Lúpus Eritematoso Sistêmico/genética , RNA/sangue , Adulto , Reações Antígeno-Anticorpo , Autoanticorpos/imunologia , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , RNA/imunologia , RNA Citoplasmático Pequeno/sangue , RNA Nuclear Pequeno/sangue
6.
Mater Sci Eng C Mater Biol Appl ; 37: 20-7, 2014 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24582218

RESUMO

Thermosensitive interpenetrating gels were prepared by physically blending poly(N-isopropylacrylamide) (PNIPA) as the matrix and the following polysaccharides as interpenetrating phases: chitosan oligosaccharides (identified as QNAD and QNED) and soluble starch (STARCH). The molecular weight of the dispersed phase, the free water/bound water ratio and the thermosensitivity (transition temperature: LCST) of the gels were determined. It was found that these gels are pseudoplastic and that their viscosity depends on the molecular weight of the dispersed phase. LCST transition occurred around 35-37°C. The morphology of the porosity of the freeze-dried samples was studied by Scanning Electron Microscopy (SEM). An in vitro test of cell hemolysis on blood agar showed that these gels are noncytotoxic. According to the results obtained, these interpenetrating gels show characteristics of an injectable material, and have a transition LCST at body temperature, which reinforces their potential to be used in the surgical field and as scaffolds for tissue engineering.


Assuntos
Resinas Acrílicas/química , Quitosana/química , Géis/química , Oligossacarídeos/química , Amido/química , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/toxicidade , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Hemólise/efeitos dos fármacos , Temperatura , Engenharia Tecidual , Água/química
7.
J Biol Chem ; 277(7): 5524-8, 2002 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-11733513

RESUMO

A cDNA encoding a novel, human, dual-specific protein phosphatase was identified in the Incyte data base. The open reading frame predicted a protein of 184 amino acids related to the Vaccinia virus VH1 and human VH1-related (VHR) phosphatases. Expression VHR-related MKPX (VHX) was highest in thymus, but also detectable in monocytes and lymphocytes. A VHX-specific antiserum detected a protein with an apparent molecular mass of 19 kDa in many cells, including T lymphocytes and monocytes. VHX expression was not induced by T cell activation, but decreased somewhat at later time points. In vitro, VHX dephosphorylated the Erk2 mitogen-activated protein kinase with faster kinetics than did VHR, which is thought to be specific for Erk1 and 2. When expressed in Jurkat T cells, VHX had the capacity to suppress T cell antigen receptor-induced activation of Erk2 and of an NFAT/AP-1 luciferase reporter, but not an NF-kappaB reporter. Thus, VHX is a new member of the VH1/VHR group of small dual-specific phosphatases that act in mitogen-activated protein kinase signaling pathways.


Assuntos
Proteínas Tirosina Fosfatases/química , Proteínas Tirosina Fosfatases/metabolismo , Proteínas Repressoras , Sequência de Aminoácidos , Animais , Linhagem Celular , DNA Complementar/metabolismo , Fosfatase 3 de Especificidade Dupla , Fosfatases de Especificidade Dupla , Glutationa Transferase/metabolismo , Humanos , Immunoblotting , Células Jurkat , Ligantes , Luciferases/metabolismo , Linfócitos/enzimologia , Sistema de Sinalização das MAP Quinases , Camundongos , Fosfatases da Proteína Quinase Ativada por Mitógeno , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Monoéster Fosfórico Hidrolases/metabolismo , Fosforilação , Plasmídeos/metabolismo , Ligação Proteica , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Homologia de Sequência de Aminoácidos , Especificidade por Substrato , Linfócitos T/metabolismo , Timo/enzimologia , Fatores de Tempo , Distribuição Tecidual , Transfecção , Vacínia/enzimologia
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