Last update 01 Nov 2024

SIRPβ1

Last update 01 Nov 2024

Basic Info

Synonyms

CD172 antigen-like family member B, CD172b, signal regulatory protein beta 1

+ [5]

Introduction-

Drugs associated with SIRPβ1

ELA-026

Target

SIRPα x SIRPβ1 x SIRPγ

Mechanism

SIRPα modulators [+2]

Active Org.

Electra Therapeutics, Inc.Startup

Originator Org.

Electra Therapeutics, Inc.Startup

Active Indication

Lymphohistiocytosis, Hemophagocytic [+1]

Inactive Indication-

Drug Highest PhasePhase 1

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with SIRPβ1

EUCTR2021-001387-20-IT / Unknown statusPhase 1

A Phase 1b, Open-label, Single-arm, Multicenter Study to Evaluate the Safety, Efficacy and Pharmacokinetics of Multiple Doses of ELA026 in Adults and Adolescents with Secondary Hemophagocytic Lymphohistiocytosis (sHLH). - N/A

Start Date-

Sponsor / Collaborator

Electra Therapeutics, Inc.Startup

NCT05416307 / RecruitingPhase 1

An Open-label, Single-arm, Multicenter Study to Evaluate the Safety, Efficacy and Pharmacokinetics of Multiple Doses of ELA026 in Participants With Secondary Hemophagocytic Lymphohistiocytosis (sHLH)

Hemophagocytic lymphohistiocytosis is a rare, aggressive and life-threatening syndrome of excessive immune activation. ELA026 is a fully human IgG1 SIRP-directed monoclonal antibody designed to reduce the myeloid and T cells driving the inflammation. The purpose of this study is to assess the safety, efficacy pharmacokinetics and pharmacodynamics of ELA026 in participants with secondary hemophagocytic lymphohistiocytosis.

Start Date19 May 2022

Sponsor / Collaborator

Electra Therapeutics, Inc.Startup

NCT05556863 / CompletedPhase 1

A Randomized, Double-blind, Placebo-controlled Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ELA026 Following Intravenous and/or Subcutaneous Administration of Single and Multiple Doses in Healthy Adults

ELA026 is a fully human IgG1 SIRP-directed monoclonal antibody designed to reduce the myeloid and T cells driving the inflammation. The purpose of this study is to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of ELA026 in Single and Multiple Doses in Healthy Adults.

Start Date18 Oct 2021

Sponsor / Collaborator

Electra Therapeutics, Inc.Startup

100 Clinical Results associated with SIRPβ1

100 Translational Medicine associated with SIRPβ1

0 Patents (Medical) associated with SIRPβ1

Literatures (Medical) associated with SIRPβ1

19 Mar 2024·Journal of Alzheimer's Disease

An Insertion Within SIRPβ1 Shows a Dual Effect Over Alzheimer’s Disease Cognitive Decline Altering the Microglial Response

Article

Author: Furniet, María Del Carmen ; Rodriguez-Rodriguez, Eloy ; García-Madrona, Sebastián ; Sánchez-Juan, Pascual ; Nieto, María Dolores ; González-Pérez, Antonio ; Alarcón-Martín, Emilio ; De la Guía, Paz ; Alegret, Montserrat ; Lage, Carmen ; López de la Rica, María ; Huerto Vilas, Raquel ; Roberto, Natalia ; Jiménez-Sánchez, Rocío ; Orellana, Adelina ; Hernández, Isabel ; Bernal Sánchez-Arjona, María ; Sanchez-Mejias, Elisabeth ; Sánchez-Fernández, Ana ; Sanabria, Ángela ; Gonzalez-Palma, Laura ; Fibla Palazon, Joan ; Torrecilla, Javier ; Garrido-Martín, Diego ; Menéndez-González, Manuel ; Piñol-Ripoll, Gerard ; Carracedo, Ángel ; Ruiz, Agustín ; Muñoz-Castro, Clara ; Rueda, Lourdes ; Macías, Juan ; Pérez-Cordón, Alba ; García-González, Pablo ; Calero, Miguel ; Espinosa, Ana ; García-Alberca, José María ; Rosende-Roca, Maitée ; Govantes, Fernando ; Mendoza, Silvia ; Martín Montes, Ángel ; Mejias-Ortega, Marina ; Vitorica, Javier ; Urbano, Concepción ; García-Peralta, María ; Buiza-Rueda, Dolores ; Peña, Isabel ; Pino-Angeles, Almudena ; Laplana, Marina ; Moreno-Grau, Sonia ; Tena, Juan Jesus ; Martínez Rodríguez, Carmen ; Royo, Jose Luis ; Lopez, Aroa ; Cruz-Gamero, Jose Manuel ; Del Ser, Teodoro ; Quintela, Inés ; Royo-Aguado, Jose Luis ; Rosas Allende, Irene ; Carrillejo, Rosario ; de Rojas, Itziar ; Navarro, Victoria ; Mancilla, Tomás ; Fernández-Fuertes, Marta ; Lopez-Gutierrez, Lidia ; Frank-García, Ana ; Marquié, Marta ; Tomas-Gallardo, Laura ; Gris, Esther ; Gutierrez, Antonia ; Diez-Fairen, Mónica ; Franco-Macías, Emilio ; Alvarez, Ignacio ; Tárraga, Lluís ; Medina, Miguel ; Gonzalez, Irene ; Pineda, Juan A ; Rábano, Alberto ; Pastor, Ana Belén ; Álvarez, Victoria ; Corma-Gómez, Anaïs ; Pareja, Nuria ; Zafra, Carmen ; Mir, Pablo ; Garcia-Ribas, Guillermo ; Ocejo, Olga ; Pastor, Pau ; Polvillo, Rocio ; Boada, Mercè ; Ortega, Gemma ; Sotolongo-Grau, Oscar ; Valero, Sergi ; Montrreal, Laura ; Reyes-Engel, Armando ; Sáez, María Eugenia ; Arias Pastor, Alfonso ; Bullido, María José ; Real, Luis Miguel ; Guigo, Roderic ; Jimenez, Sebastian ; García-Casares, Natalia ; Luque, Macarena ; Ruiz, Maximiliano ; Bravo, Maria Jose

Background: Microglial dysfunction plays a causative role in Alzheimer’s disease (AD) pathogenesis. Here we focus on a germline insertion/deletion variant mapping SIRPβ1, a surface receptor that triggers amyloid-β(Aβ) phagocytosis via TYROBP. Objective: To analyze the impact of this copy-number variant in SIRPβ1 expression and how it affects AD molecular etiology. Methods: Copy-number variant proxy rs2209313 was evaluated in GERALD and GR@ACE longitudinal series. Hippocampal specimens of genotyped AD patients were also examined. SIRPβ1 isoform-specific phagocytosis assays were performed in HEK393T cells. Results: The insertion alters the SIRPβ1 protein isoform landscape compromising its ability to bind oligomeric Aβ and its affinity for TYROBP. SIRPβ1 Dup/Dup patients with mild cognitive impairment show an increased cerebrospinal fluid t-Tau/Aβ ratio (p = 0.018) and a higher risk to develop AD (OR = 1.678, p = 0.018). MRIs showed that Dup/Dup patients exhibited a worse initial response to AD. At the moment of diagnosis, all patients showed equivalent Mini-Mental State Examination scores. However, AD patients with the duplication had less hippocampal degeneration (p < 0.001) and fewer white matter hyperintensities. In contrast, longitudinal studies indicate that patients bearing the duplication allele show a slower cognitive decline (p = 0.013). Transcriptional analysis also shows that the SIRPβ1 duplication allele correlates with higher TREM2 expression and an increased microglial activation. Conclusions: The SIRPβ1 internal duplication has opposite effects over MCI-to-Dementia conversion risk and AD progression, affecting microglial response to Aβ. Given the pharmacological approaches focused on the TREM2-TYROBP axis, we believe that SIRPβ1 structural variant might be considered as a potential modulator of this causative pathway.

12 Jul 2023·Alzheimer's research & therapy

Longitudinal APOE4- and amyloid-dependent changes in the blood transcriptome in cognitively intact older adults.

Article

Author: Van Laere, Koen ; Kordjani, Amine ; Vandenberghe, Rik ; Schaeverbeke, Jolien ; Dupont, Patrick ; Cleynen, Isabelle ; Zielonka, Magdalena ; Luckett, Emma S ; De Meyer, Steffi ; Adamczuk, Katarzyna

BACKGROUNDGene expression is dysregulated in Alzheimer's disease (AD) patients, both in peripheral blood and post mortem brain. We investigated peripheral whole-blood gene (co)expression to determine molecular changes prior to symptom onset.METHODSRNA was extracted and sequenced for 65 cognitively healthy F-PACK participants (65 (56-80) years, 34 APOE4 non-carriers, 31 APOE4 carriers), at baseline and follow-up (interval: 5.0 (3.4-8.6) years). Participants received amyloid PET at both time points and amyloid rate of change derived. Accumulators were defined with rate of change ≥ 2.19 Centiloids. We performed differential gene expression and weighted gene co-expression network analysis to identify differentially expressed genes and networks of co-expressed genes, respectively, with respect to traits of interest (APOE4 status, amyloid accumulation (binary/continuous)), and amyloid positivity status, followed by Gene Ontology annotation.RESULTSThere were 166 significant differentially expressed genes at follow-up compared to baseline in APOE4 carriers only, whereas 12 significant differentially expressed genes were found only in APOE4 non-carriers, over time. Among the significant genes in APOE4 carriers, several had strong evidence for a pathogenic role in AD based on direct association scores generated from the DISQOVER platform: NGRN, IGF2, GMPR, CLDN5, SMIM24. Top enrichment terms showed upregulated mitochondrial and metabolic pathways, and an exacerbated upregulation of ribosomal pathways in APOE4 carriers compared to non-carriers. Similarly, there were 33 unique significant differentially expressed genes at follow-up compared to baseline in individuals classified as amyloid negative at baseline and positive at follow-up or amyloid positive at both time points and 32 unique significant differentially expressed genes over time in individuals amyloid negative at both time points. Among the significant genes in the first group, the top five with the highest direct association scores were as follows: RPL17-C18orf32, HSP90AA1, MBP, SIRPB1, and GRINA. Top enrichment terms included upregulated metabolism and focal adhesion pathways. Baseline and follow-up gene co-expression networks were separately built. Seventeen baseline co-expression modules were derived, with one significantly negatively associated with amyloid accumulator status (r² = - 0.25, p = 0.046). This was enriched for proteasomal protein catabolic process and myeloid cell development. Thirty-two follow-up modules were derived, with two significantly associated with APOE4 status: one downregulated (r² = - 0.27, p = 0.035) and one upregulated (r² = 0.26, p = 0.039) module. Top enrichment processes for the downregulated module included proteasomal protein catabolic process and myeloid cell homeostasis. Top enrichment processes for the upregulated module included cytoplasmic translation and rRNA processing.CONCLUSIONSWe show that there are longitudinal gene expression changes that implicate a disrupted immune system, protein removal, and metabolism in cognitively intact individuals who carry APOE4 or who accumulate in cortical amyloid. This provides insight into the pathophysiology of AD, whilst providing novel targets for drug and therapeutic development.

01 Jan 2023·Frontiers in genetics

A frameshift variant in the SIRPB1 gene confers susceptibility to Crohn's disease in a Chinese population.

Article

Author: Tang, Jian ; Wan, Xingyang ; Zhang, JunXiao ; Zhang, Caibin ; Diao, Na ; Gao, Xiang ; Ren, Donglin

Background: Crohn's disease (CD), a chronic gastrointestinal inflammatory disease, is increasing in China. With a focus on Han Chinese families with CD, the aim of this study was to find genetic variations that increase CD susceptibility by genome sequencing, genetic association, expression, and functional research. Materials and methods: We performed family-based genome sequencing (WGS) analysis on 24 patients with CD from 12 families and then filtered shared potential causal variants by incorporating association results from meta-analyses of CD GWAS and immunology genes and in silico variant effect prediction algorithms. Replication analyses were performed in an independent cohort including 381 patients with CD and 381 control subjects. Results: There were 92 genetic variants significantly associated with CD in Chinese individuals. Among them, 61 candidate loci were validated in replication analyses. As a result, patients carrying a rare frameshift variant (c.1143_1144insG; p. Leu381_Leu382fs) in gene SIRPB1 had significantly higher risk to develop CD (p = 0.03, OR 4.59, 95% CI 0.98-21.36, 81.82% vs. 49.53%). The frameshift variation induced tyrosine phosphorylation of Syk, Akt, and Jak2, elevated the expression of SIRPB1 at the mRNA and protein levels, activated DAP12, and controlled the activation of NF-κB in macrophages. Additionally, it promoted the synthesis of the pro-inflammatory cytokines IL-1, TNF-, and IL-6. Conclusion: Our results suggest that the rare gain-of-function frameshift variant in SIRPB1 is associated in Han Chinese patients with CD. The functional mechanism of SIRPB1 and its downstream inflammatory pathways was preliminarily explored in CD.

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SIRPβ1

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